genetic disease research project

The International Center for Genetic Disease (iCGD) is a platform that focuses on the analysis of patients and healthy subjects from different parts of the world for research into the causes and consequences, prevention, and treatment of disease. The iCGD brings together world-class clinicians and scientists and an unmatched dedication to multidisciplinary research, cutting-edge technology, and innovative methods. We also implement research, education, and clinical programs to build sustainable capacity in genomic medicine and in genetic research, with the aim of contributing to improved public health.

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Scaling Understanding, Advancing Care, and Developing Treatments for Rare Genetic Conditions

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'all of us' research project diversifies the storehouse of genetic knowledge.

Results from a DNA sequencer used in the Human Genome Project. National Human Genome Research Institute hide caption

Results from a DNA sequencer used in the Human Genome Project.

A big federal research project aimed at reducing racial disparities in genetic research has unveiled the program's first major trove of results.

"This is a huge deal," says Dr. Joshua Denny , who runs the All of Us program at the National Institutes of Health. "The sheer quantify of genetic data in a really diverse population for the first time creates a powerful foundation for researchers to make discoveries that will be relevant to everyone."

The goal of the $3.1 billion program is to solve a long-standing problem in genetic research: Most of the people who donate their DNA to help find better genetic tests and precision drugs are white.

"Most research has not been representative of our country or the world," Denny says. "Most research has focused on people of European genetic ancestry or would be self-identified as white. And that means there's a real inequity in past research."

For example, researchers "don't understand how drugs work well in certain populations. We don't understand the causes of disease for many people," Denny says. "Our project is to really correct some of those past inequities so we can really understand how we can improve health for everyone."

But the project has also stirred up debate about whether the program is perpetuating misconceptions about the importance of genetics in health and the validity of race as a biological category.

New genetic variations discovered

Ultimately, the project aims to collect detailed health information from more than 1 million people in the U.S., including samples of their DNA.

In a series of papers published in February in the journals Nature , Nature Medicine , and Communications Biology , the program released the genetic sequences from 245,000 volunteers and some analysis of those data.

"What's really exciting about this is that nearly half of those participants are of diverse race or ethnicity," Denny says, adding that researchers found a wealth of genetic diversity.

"We found more than a billion genetic points of variation in those genomes; 275 million variants that we found have never been seen before," Denny says.

"Most of that variation won't have an impact on health. But some of it will. And we will have the power to start uncovering those differences about health that will be relevant really maybe for the first time to all populations," he says, including new genetic variations that play a role in the risk for diabetes .

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Researchers gather health data for 'all of us'.

But one concern is that this kind of research may contribute to a misleading idea that genetics is a major factor — maybe even the most important factor — in health, critics say.

"Any effort to combat inequality and health disparities in society, I think, is a good one," says James Tabery , a bioethicist at the University of Utah. "But when we're talking about health disparities — whether it's black babies at two or more times the risk of infant mortality than white babies, or sky-high rates of diabetes in indigenous communities, higher rates of asthma in Hispanic communities — we know where the causes of those problem are. And those are in our environment, not in our genomes."

Race is a social construct, not a genetic one

Some also worry that instead of helping alleviate racial and ethnic disparities, the project could backfire — by inadvertently reinforcing the false idea that racial differences are based on genetics. In fact, race is a social category, not a biological one.

"If you put forward the idea that different racial groups need their own genetics projects in order to understand their biology you've basically accepted one of the tenants of scientific racism — that races are sufficiently genetically distinct from each other as to be distinct biological entities," says Michael Eisen , a professor of molecular and cell biology at the University of California, Berkeley. "The project itself is, I think, unintentionally but nonetheless really bolstering one of the false tenants of scientific racism."

While Nathaniel Comfort, a medical historian at Johns Hopkins, supports the All of Us program, he also worries it could give misconceptions about genetic differences between races "the cultural authority of science."

Denny disputes those criticisms. He notes the program is collecting detailed non-genetic data too.

"It really is about lifestyle, the environment, and behaviors, as well as genetics," Denny says. "It's about ZIP code and genetic code — and all the factors that go in between."

And while genes don't explain all health problems, genetic variations associated with a person's race can play an important role worth exploring equally, he says.

"Having diverse population is really important because genetic variations do differ by population," Denny says. "If we don't look at everyone, we won't understand how to treat well any individual in front of us."

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• human genome
• diversity in medicine

GREGoR Consortium

Genomics research to elucidate the genetics of rare diseases.

The GREGoR Consortium (Genomics Research to Elucidate the Genetics of Rare diseases) seeks to develop and apply approaches to discover the cause of currently unexplained rare genetic disorders.

Linking diseases to their genetic cause allows for improved genetic testing and a shortened diagnostic odyssey for families affected by rare disease, and can:

• improve care and expand treatment options
• facilitate connections with others affected by the same condition
• aid in medical care and family planning for related individuals
• help researchers understand the function of these genes in everyone

Whole-exome sequencing has helped researchers identify about 300 Mendelian disease genes each year, but this technique has not been successful in identifying the genes responsible for many Mendelian diseases. New approaches are needed and thus Consortium investigators will:

• engage in enhanced data sharing and collaboration
• apply new technologies, genome sequencing strategies, and analytical approaches

The Consortium will bring together communities affected by rare disease.  We will:

• help researchers leverage new technologies to advance gene discovery
• assist clinicians in connecting patients and families to Consortium Research Centers
• partner with advocacy groups both to spread awareness of our work and to improve understanding of barriers to research participation - especially amongst those who have been under-represented

News  &  Publications

The GREGoR Consortium is pleased to announce the 2024 GREGoR Research Grant awards and the Deborah Nickerson memorial awards to support workforce diversity in genomics research. 

The GREGoR Consortium will offer another round of awards to support workforce diversity in genomics research - this announcement will be posted in Fall 2024. The Consortium will not offer another round of Research Grant awards in the Fall of 2024.

Research Topics

The Center for Genetic Medicine’s faculty members represent 33 departments or programs across three Northwestern University schools and three Feinberg-affiliated healthcare institutions. Faculty use genetics and molecular genetic approaches to understand biological processes for a diverse range of practical and clinical applications.

Select a topic below to learn more and see a list of faculty associated with that type of research. For a full list of Center for Genetic Medicine members, visit our Members section .

  Animal Models of Human Disease

Using genetic approaches with model organisms to investigate cellular and physiological processes can lead to improved approaches for detection, prevention and treatment of human diseases.

VIEW MEMBERS

  Bioinformatics & Statistics

Bioinformatics, a discipline that unites biology, computer science, statistical methods, and information technology, helps researchers understand how genes or parts of genes relate to other genes, and how genes interact to form networks. These studies provide insight to normal cellular functions and how these functions are disturbed by disease. Statistics is central to genetic approaches, providing quantitative support for biological observations, and statistical genetics is heavily used by laboratories performing gene and trait mapping, sequencing and genotyping, epidemiology, population genetics and risk analysis.

  Cancer Genetics and Genomics

Cancer begins with genetic changes, or mutations, that disrupt normal regulation of cell proliferation, survival and death. Inherited genetic changes contribute to the most common cancers, like breast and colon cancer, and genetic testing can help identify risks for disease. Tumors also develop additional genetic changes, or somatic mutations, that promote cancer growth and tumor metastases. These genetic changes can be readily defined through DNA and RNA sequencing. Genetic changes within a tumor can be used to develop and guide treatment options.

  Cardiovascular Genetics

Cardiovascular disease is one of the leading causes of death in the US, and the risk of  cardiovascular disease is highly dependent inherited genetic changes. The most common forms of heart disease including heart failure, arrhythmias, and vascular disease are under heritable genetic changes. We work to identify and understand the functions of genes that affect the risk of developing cardiovascular disease, as well as to understand the function of genes involved in the normal and pathological development of the heart.

  Clinical and Therapeutics

Using genetic data identifies pathways for developing new therapies and applying existing therapies. DNA sequencing and epigenetic profiling of tumors helps define the precise defects responsible for cancer progression. We use genetic signals to validate pathways for therapy development.  We are using gene editing methods to correct genetic defects. These novel strategies are used to treat patients at Northwestern Memorial Hospital and the Ann & Robert H. Lurie Children's Hospital of Chicago.

  Development

The genomic blueprint of a single fertilized egg directs the formation of the entire organism. To understand the cellular processes that allow cells to create organs and whole animals from this blueprint, we use genetic approaches to investigate the development of model organisms and humans. Induced pluripotent stem cells can be readily generated from skin, blood or urine cells and used to mirror human developmental processes. These studies help us define how genes coordinate normal human development and the changes that occur in diseases, with the goal of improving detection, prevention and treatment of human disease.

  Epigenetics/Chromatin Structure/Gene Expression

Abnormal gene expression underlies many diseases, including cancer and cardiovascular diseases. We investigate how gene expression is regulated by chromatin structure and other regulators to understand abnormal gene expression in disease, and to learn how to manipulate gene expression for therapeutic purposes.

  Gene Editing/Gene Therapy

Gene editing tools like CRISPR/Cas can be used to directly alter the DNA code. This tool is being used to generate cell and animal models of human diseases and disease processes. Gene therapy is being used to treat human disease conditions.

  Genetic Counseling

As part of training in genetic counseling, each student completes a thesis project. These projects examine all aspects of genetic counseling ranging from family-based studies to mechanisms of genetic action. With the expansion of genetic testing, genetic counselors are now conducting research on outcomes, cost effectiveness, and quality improvement.

  Genetic Determinants of Cellular Biology

Genetic mutations ultimately change the functionality of the cells in which they are found. Mutations in genes encoding nuclear, cytoplasmic and extracellular matrix protein lead to many different human diseases, ranging from neurological and developmental disorders to cancer and heart disease. Using induced pluripotent stem cell and gene-editing technologies, it is now possible to generate and study nearly every human genetic disorder. Having cellular models of disease is necessary to develop new treatments.

  Immunology

Many immunological diseases, such as Rheumatoid arthritis, Lupus, scleroderma, and others have a genetic basis. We work to understand how genetic changes and misregulation contribute to immunological diseases, and use genetic approaches to investigate how the immune system functions.

  Infectious Disease/Microbiome

The susceptibility and/or pathological consequences of many infectious diseases have a genetic basis. We investigate how human genes interact with infectious diseases, and use genetic approaches to determine the interactions between pathogens and the host. Genetic tools, including deep sequencing, are most commonly used to define the microbiome as it undergoes adaptation and maladaptation to its host environment.

  Neuroscience

We work to understand how genes contribute to neurological diseases, and use genetic approaches to investigate how the nervous system functions. Epilepsy, movement disorders, and dementia are heritable and under genetic influence. Neuromuscular diseases including muscular dystrophies and myopathies arise from primary mutations and research in genetic correction is moving into human trials and drug approvals.

  Population Genetics/Epidemiology

Genetic data is increasingly available from large human populations and is advancing the population-level understanding of genetic risk. Northwestern participates in All-Of-US, which aims to build a cohort of one million citizens to expand genetic knowledge of human diseases. Race and ancestry have genetic determinants and genetic polymorphisms can help mark disease risks better than other markers of race/ancestry. We use epidemiology and population genetics to investigate the genetic basis of disease, and to assess how genetic diseases affect subgroups within broader populations.

  Reproduction

Research is examining how germ cells are specified. We study the broad range of biology required to transmit genetic information from one generation to another, and how to facilitate the process of reproduction when difficulties arise or to avoid passing on mutant genes.

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Groundbreaking study connects genetic risk for autism to changes observed in the brain

A groundbreaking study led by UCLA Health has unveiled the most detailed view of the complex biological mechanisms underlying autism, showing the first link between genetic risk of the disorder to observed cellular and genetic activity across different layers of the brain.

The study is part of the second package of studies from the National Institutes of Health consortium, PsychENCODE. Launched in 2015, the initiative, chaired by UCLA neurogeneticist Dr. Daniel Geschwind, is working to create maps of gene regulation across different regions of the brain and different stages of brain development. The consortium aims to bridge the gap between studies on the genetic risk for various psychiatric disorders and the potential causal mechanisms at the molecular level.

"This collection of manuscripts from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain," Geschwind said.

Geschwind's study on autism, one of nine published in the May 24 issue of Science , builds on decades of his group's research profiling the genes that increase the susceptibility to autism spectrum disorder and defining the convergent molecular changes observed in the brains of individuals with autism. However, what drives these molecular changes and how they relate to genetic susceptibility in this complex condition at the cellular and circuit level are not well understood.

Gene profiling for autism spectrum disorder, with a few exceptions in smaller studies, has long been limited to using bulk tissue from brains from autistic individuals after death. These tissue studies are unable to provide detailed information such as the differences in brain layer, circuit level and cell type-specific pathways associated with autism as well as mechanisms for gene regulation.

To address this, Geschwind used advances in single-cell assays, a technique that makes it possible to extract and identify the genetic information in the nuclei of individual cells. This technique provides researchers the ability to navigate the brain's complex network of different cell types.

More than 800,000 nuclei were isolated from post-mortem brain tissue of 66 individuals from ages 2 to 60, including 33 individuals with autism spectrum disorder and 30 neurotypical individuals who acted as controls. The individuals with autism included five with a defined genetic form called 15q duplication syndrome. Each sample was matched by age, sex, and cause of death balanced across cases and controls.

Through this, Geschwind and his team were able to identify the major cortical cell types affected in autism spectrum disorder, which included both neurons and their support cells, known as glial cells. In particular, the study found the most profound changes in the neurons that connect the two hemispheres and provide long range connectivity between different brain regions and a group of interneurons, called somatostatin interneurons that are important for maturation and refinement of brain circuits.

A critical aspect of this study was the identification of specific transcription factor networks -- the web of interactions whereby proteins control when a gene is expressed or inhibited -- that drive these changes that were observed. Remarkably, these drivers were enriched in known high-confidence autism spectrum disorder risk genes and influenced large changes in differential expression across specific cell subtypes. This is the first time that a potential mechanism connects changes occurring in brain in ASD directly to the underlying genetic causes.

Identifying these complex molecular mechanisms underlying autism and other psychiatric disorders studied could work to develop new therapeutics to treat these disorders.

"These findings provide a robust and refined framework for understanding the molecular changes that occur in brains in people with ASD -- which cell types they occur in and how they relate to brain circuits," Geschwind said. "They suggest that the changes observed are downstream of known genetic causes of autism, providing insight into potential causal mechanisms of the disease."

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Researchers find a single, surprising gene behind a disorder that causes intellectual disability

FILE - This microscope image shows the 46 human chromosomes, blue, with telomeres appearing as white pinpoints. Scientists have found the genetic cause of a neurodevelopmental disorder that they estimate affects as many as one in 20,000 young people. And they hope their discovery leads to a new diagnosis that can provide answers to families. They published their findings in the journal Nature Medicine on Friday (Hesed Padilla-Nash, Thomas Ried/National Cancer Institute/National Institutes of Health via AP, File)

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Scientists have found the genetic root of a disorder that causes intellectual disability, which they estimate affects as many as one in 20,000 young people. And they hope their discovery leads to a new diagnosis that can provide answers to families.

Those with the condition have a constellation of issues, which also include short stature, small heads, seizures and low muscle mass, said the researchers, who published their findings in the journal Nature Medicine on Friday.

“We were struck by how common this disorder is” when compared with other rare diseases linked to a single gene, said Ernest Turro of the Icahn School of Medicine at Mount Sinai, senior author of the study.

Syndromes like these can go unnoticed because the traits are sometimes so subtle doctors can’t recognize them by just looking at patients, said Dr. Charles Billington, a pediatric geneticist at the University of Minnesota who was not involved in the study.

“So certainly this wasn’t something that we necessarily had a name for,” he said. “We’re learning more about these syndromes that we recognize only once we are seeing the cause.”

Researchers said the mutations occurred in a small “non-coding” gene, meaning it doesn’t provide instructions for making proteins. Until now, all but nine of the nearly 1,500 genes known to be linked to intellectual disability in general are protein-coding genes. Most large genetic studies so far have used a sequencing technology that typically leaves out genes that don’t code for proteins.

This study used more comprehensive “whole-genome” sequencing data from 77,539 people enrolled in the British 100,000 Genomes Project, including 5,529 with an intellectual disability. The rare mutations researchers found in the gene, called RNU4-2, were strongly associated with the potential to develop intellectual disability.

The finding “opens the door to diagnoses” for thousands of families, said study author Andrew Mumford, research director of the South West England NHS Genomic Medicine Service.

More research is needed, Mumford said. How the mutation causes the disorder remains unclear and there is no treatment. But Billington said labs should be able to offer testing for this condition relatively quickly. And researchers said families should be able to find and support each other – and know they’re not alone.

“That can be incredibly comforting,” Mumford said.

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• Published: 29 April 2024

The Egypt Genome Project

• Mohamed A. Elmonem   ORCID: orcid.org/0000-0002-3154-1948 1 , 2 ,
• Neveen A. Soliman   ORCID: orcid.org/0000-0002-8942-1973 1 , 3 ,
• Ahmed Moustafa 1 , 4 ,
• Yehia Z. Gad   ORCID: orcid.org/0000-0002-8432-4541 5 , 6 ,
• Wael A. Hassan 1 ,
• Tarek Taha 1 ,
• Gina El-Feky 7 ,
• Mahmoud Sakr 7 &
• Khaled Amer   ORCID: orcid.org/0000-0001-6896-9449 1  

Nature Genetics ( 2024 ) Cite this article

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• Epidemiology
• Genetics research

The recently launched Egyptian Genome Project aims to sequence genomic variants of 100,000 apparently healthy Egyptian adults, with around 8,000 individuals suspected to have a genetic disease, as well as 200 ancient Egyptian mummies. The project will provide the first comprehensive genomic dataset from Egypt and North Africa.

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Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt

Mohamed A. Elmonem, Neveen A. Soliman, Ahmed Moustafa, Wael A. Hassan, Tarek Taha & Khaled Amer

Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

Mohamed A. Elmonem

Department of Pediatrics, Center for Pediatric Nephrology and Transplantation (CPNT), Faculty of Medicine, Cairo University, Cairo, Egypt

Neveen A. Soliman

Departments of Biology and Bioinformatics and Integrative Genomics Laboratory, American University in Cairo, Cairo, Egypt

Ahmed Moustafa

Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Center, Cairo, Egypt

Yehia Z. Gad

Ancient DNA laboratory, National Museum of Egyptian Civilization, Cairo, Egypt

Academy of Scientific Research and Technology, Cairo, Egypt

Gina El-Feky & Mahmoud Sakr

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Elmonem, M.A., Soliman, N.A., Moustafa, A. et al. The Egypt Genome Project. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01739-1

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Genetic Disease and Therapy

Theodore l. roth.

1 Medical Scientist Training Program, University of California, San Francisco, California 94143, USA

2 Department of Microbiology and Immunology and Diabetes Center, University of California, San Francisco, California 94143, USA

3 Innovative Genomics Institute, University of California, Berkeley, California 94720, USA

4 Gladstone Institutes, San Francisco, California 94158, USA

Alexander Marson

5 Department of Medicine, University of California, San Francisco, California 94143, USA

6 Parker Institute for Cancer Immunotherapy, San Francisco, California 94129, USA

7 Chan Zuckerberg Biohub, San Francisco, California 94158, USA

8 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human’s complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.

INTRODUCTION

Early history of genetic disease and therapy.

Subtle changes to the genetic code can result in profoundly debilitating and diverse pathologies. The hereditary nature of human traits has been described since classical times. In the history of modern medicine, the first known genetic disorder, alkaptonuria, was described at the turn of the twentieth century, giving rise to the recognition of inborn errors of metabolism ( 1 ). Diseases with their basis in mutations and alterations of the human genetic code represent a massive burden, and recognized genetic disorders affect more than 5% of live births and more than two-thirds of miscarriages ( 2 , 3 ). Beyond highly penetrant monogenic disorders and large-scale chromosomal alterations, the heritability of many common diseases has long suggested a genetic basis for more prevalent disorders such as cardiovascular disease ( 4 ). The prospect of passing genetic afflictions on to the next generation adds to the fear of these disorders.

The first heritable alteration in a protein linked to disease was identified in sickle cell anemia in the late 1940s, with the discovery of altered shifts during electrophoresis, a change that corresponded with disease status among tested patients ( 5 , 6 ). Subsequently, once the DNA code for amino acids was deciphered, scientists recognized the potential for alterations in DNA to cause alterations in enzymes and thus disease. Prior to the advent of DNA sequencing, the cause of Down syndrome, identified in 1959 as the chromosomal abnormality trisomy 21, was the first human genetic alteration found to be associated with disease ( 7 ). Beginning in the 1960s, hereditary metabolic disorders such as phenylketonuria could be screened for biochemically without the need to know the causative gene’s location or sequence ( 8 ). The advent of Sanger sequencing and recombinant molecular biology in the 1970s and 1980s made the determination of DNA sequences widely accessible for the first time. The following decades, prior to the completion of the Human Genome Project in 2003, saw gene mapping consortia undergo herculean efforts to discover the causative genes in some of the most debilitating diseases, including the first mapped human genetic disorder, Huntington’s disease, in 1983 ( 9 ). With the diminishing costs of exome and whole-genome sequencing over the past 2 decades, genetic diagnosis has become increasingly feasible, even for conditions that were not previously recognized as genetic diseases.

Human Genomic Compartments

The genetic material in an adult human can be divided into compartments that differ in size, heritability, and diversity. The mitochondrial genome, the smallest (only 16.5 kb) but by far the most abundant, is inherited maternally and varies little among the human population. The traditional human genome contained in the nucleus is significantly larger and harbors mutations that cause the majority of traditional genetic diseases. The nuclear and mitochondrial genomes are determined at conception, although somatic mutations can drive mosaic disorders, cancer, and even aging.

More broadly, the adaptive immune receptor repertoire, which is a distinctive subset of the nuclear genome, and the microbial metagenome are determined only after conception, and their genetic complexity, at least as measured by the diversity of unique protein coding sequences, dwarfs that of the rest of the nuclear genome. The T and B cells of the adaptive immune system undergo somatic recombination, generating orders of magnitude more unique protein products than are possessed by the other genes of the nuclear genome, and together constitute the adaptive immune receptor repertoire. Finally, the nonhuman cells of the microbiome make up potentially the most dynamic and diverse genomic compartment of all, with a litany of different species, predominantly bacterial and viral, occupying structured niches across human skin, sexual organs, and gastrointestinal and respiratory tracts. Both the adaptive immune receptor repertoire and the microbial metagenome vary significantly more among individuals, and increasing research aims to understand how genetic alterations in immune receptor repertoires and the microbiome contribute to disease pathology.

Modes of Genetic Therapy

Disruptions in any of these compartments, interacting in many cases with environmental factors, can contribute to different classes of genetic disease. The simplicity of the DNA code has enticed researchers and clinicians since the 1960s with the curative promise of correction of genetic alterations, or gene therapy ( 10 ). Since the first successful ectopic expression of a foreign gene in human cells in the early 1970s ( 11 ), successive generations of gene therapy technology have increased the efficiency, specificity, and safety of gene transfers. These advances led to the first human gene therapy trials at the National Cancer Institute, National Institutes of Health, in the late 1980s ( 12 ), following a handful of unregulated and ultimately unpublished gene therapy attempts earlier that decade ( 13 ).

The rapid proliferation of gene therapies in the 1990s, with more than 500 trials initiated, came to a halt in the early 2000s following patient deaths in clinical trials for severe combined immunodeficiency (SCID) and a metabolic liver disorder. Further improvements in the safety and efficacy of gene transfer in the 2000s and 2010s ultimately led to the resurgence of new generations of gene therapy approaches and approval by the US Food and Drug Administration (FDA) of the first ex vivo chimeric antigen receptor T cell (CAR T)–based gene therapies in B cell malignancies in 2017 ( 14 , 15 ), as well as the first in vivo gene therapy for vision loss caused by Leber’s congenital amaurosis in 2017 ( 16 ).

In a broad context, genetic mutations can be altered in three general modes: bulk replacement or selection of the entire genomic compartment containing the mutation, nontargeted insertion into the genome of additional genetic material restoring enough functionality to compensate for the genetic defect (nontargeted addition), or specific correction of only the causative mutation or genetic alteration (gene editing). Bulk replacement represents the most basic form of gene therapy ( Figure 1 ). Selective reproduction and, more recently, preimplantation diagnostics offer the chance to preemptively avoid germline mutations in the nuclear genome. Mitochondrial replacement therapy followed by in vitro fertilization can effectively correct mitochondrial mutations by replacing a child’s entire mitochondrial genome with a “third parent.” Similarly, somatic mutations resulting in tumors can be removed in bulk from the body by surgery. Portions of the microbial metagenome are increasingly being therapeutically altered via fecal or microbial community transplants ( 17 ).

Gene therapies based on bulk replacement or selection of genetic compartments. ( a ) The mitochondrial genome of an affected mother’s oocyte can be replaced through transfer of its nucleus into a donor mother’s oocyte, which contains mitochondria unaffected by the mutation. ( b ) The nuclear genome can be selected through preimplantation diagnosis of in vitro–fertilized zygotes.

In many patients, however, a more practicable gene therapy is the nontargeted introduction of new genetic material to make up for the lost or deleterious function of mutated sequences ( Figure 2 ). This nontargeted addition of genetic material is common in the germline transgenesis of model organisms, but important ethical concerns have, appropriately, prevented additive gene therapies in the human germline. In the more therapeutically relevant somatic cells, successive generations of viral vectors, ranging from SV40 to retroviruses, adenoviruses, and now, prominently, adeno-associated virus (AAV) pseudotypes, have enabled ever greater control over the in vivo cell types receiving new, corrective genetic material, culminating in the recent FDA approval of an AAV2 vector specific for rod and cone photoreceptors ( 16 ). A separate line of technical development based on γ-retroviruses and lentiviruses has led to efficient ex vivo manipulation of the nuclear genome of hematopoietic stem cells (HSCs), as well as the adaptive repertoire of T cells, resulting in the similarly recently approved CAR T–based therapies ( 14 , 15 ).

Gene therapies based on nontargeted genetic addition or targeted gene editing. ( a ) Mutated genes in the mitochondrial genome can be integrated into the nuclear genome, with their protein products targeted for import into the mitochondria. Direct delivery of genetic material to the mitochondrial genome poses a greater challenge. ( b ) Adding or editing genetic material in the nuclear genome of the human germline poses significant ethical concerns. ( c ) Nontargeted addition or targeted editing in somatic cells, such as cells cultured ex vivo (e.g., hematopoietic stem cells and T cells). ( d ) Nontargeted addition or targeted editing in somatic cells in vivo, as in retinal cells, hepatocytes, or myocytes, critically depends on delivery platforms to carry DNA, RNA, and/or protein cargos to the cell type of interest.

However, the history of gene therapies for hemoglobinopathies, the first genetic diseases to be molecularly characterized, reveals the limitations of nontargeted genetic addition. The careful regulatory control of α- and β-hemoglobin during erythropoiesis prevented erythrocyte formation during early trials in patients with sickle cell anemia and other hemoglobinopathies when correct copies of hemoglobin were pseudorandomly added to the genome of their HSCs. The rapid recent development of targetable RNA-guided nucleases such as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/caspase-9), building upon earlier zinc-finger nuclease (ZFN) and transcription activator–like effector nuclease (TALEN) targetable nucleases, offers a simplified approach to treating such genetic diseases ( 18 ). By creating a double-stranded DNA break near the site of a mutation, these nucleases can prompt the cell to fix the damage via templated repair based on a separately provided DNA template containing the desired sequence. Diverse delivery technologies can ferry DNA encoding the ribonucleoprotein (RNA/protein) nuclease complexes (RNPs), or recombinant RNPs themselves, as well as DNA templates to correct specific mutations into target cell populations both ex vivo and increasingly in vivo. These gene editing technologies promise a generalizable ability to correct almost any mutation in the genome ( Figure 2 ).

Genetic disease has haunted families and their clinicians for generations. The unique properties of each human genomic compartment present distinct diagnostic and therapeutic challenges. Significant progress has been made in technologies to sequence DNA, deliver protein and DNA payloads to specific human cell populations ex vivo and in vivo, insert large stretches of new genetic material, and now even directly edit endogenous genetic loci. A growing suite of diagnostic and therapeutic options can target all of the human genomic compartments, and their further development offers the hope of generalized curative genetic therapies ( Figure 3 ).

Modular systems for genetic diagnosis and therapy. Gene therapies in all four human genetic compartments depend on the modular process of diagnosis, therapeutic design, and compartment-specific delivery of therapeutic reagents. Diagnosis of genetic disease is now centered around next-generation DNA sequencing to detect errors in the mitochondrial and nuclear genomes. Therapy can be based on bulk replacement or selection of the genetic compartment or the therapeutic nontargeted addition of new genetic material or targeted correction of causative mutations through gene editing. Delivery platforms targeting each genomic compartment in somatic cells, whether in vivo or ex vivo, can carry gene addition and editing reagents with distinct therapeutic sequences or specificities depending on the genetic diagnosis. Abbreviations: AAV, adeno-associated virus; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/caspase-9; TALEN, transcription activator–like effector nuclease; ZFN, zinc-finger nuclease.

MITOCHONDRIAL GENOME

The mitochondrial genome represents both the smallest and the most abundant set of genetic information in the human body. With a conservative estimate of more than a quadrillion copies present within an adult human, different human tissues possess between zero and thousands of mitochondria per cell, and each mitochondrion averages one to two copies of the 16.5-kb mitochondrial genome ( 19 , 20 ). All mitochondria in the body are generated by repetitive cycles of fission, derived from fewer than 10 mitochondria found in primordial egg cells at the greatest bottleneck during oogenesis ( 21 , 22 ), and are ultimately the progeny of an unbroken cycle of asexual reproduction going back to the first eukaryotic mitochondrial symbiote. This previously free-living ancestral symbiotic bacterium likely possessed thousands of genes ( 23 ). Over hundreds of millions of years, however, mitochondrial genes successively migrated to the relative safety of the nuclear genome through endosymbiotic gene transfer. The 37 mitochondrial genes remaining encode 22 transfer RNAs, 2 mitochondrial ribosomal RNAs, and 13 protein coding genes, which encode primarily quantumly linked members of the electron transport chain. These genes make up more than 90% of the genome, with the noncoding elements of the mitochondrial control region making up the remainder ( 24 ).

With its central importance for cellular energy conversion, the mitochondrial genome is highly conserved among humans, although it diverges widely in size and gene content across eukaryotes in general ( 25 ). Purifying selection drives the conservation of mitochondrial genomic sequences, as the error rate for mitochondrial DNA replication is approximately 100 times higher than for nuclear replication ( 26 ). Larger genetic alterations such as insertions/deletions (indels) and rearrangements are almost invariably nonviable, given the mitochondrial genome’s compactness. Mitochondria undergo strong purifying selection during oogenesis, and approximately one in five children possess de novo mitochondrial mutations, predominantly synonymous mutations ( 22 ). In somatic cells, continuous cycles of fission and fusion among mitochondria may enable continuous purifying selection for nonmutated copies of the mitochondrial genome. Extensive division of mitochondria throughout life ultimately leads to genetic changes, and somatic mosaicism within adults’ mitochondria is readily detectable. The mitochondria in an aged adult possess hundreds more genetic changes relative to the adult’s inherited genome ( 27 , 28 ).

Mitochondrial Genetic Disease

The critical and ubiquitous nature of mitochondrial function ensures that mutations within the mitochondrial genome can have large and deleterious effects on health. While the majority of mitochondrial mutations likely result in nonviable oocytes and are selected against prior to ovulation, mitochondrial disorders such as myopathies and neuropathies are diagnosed in approximately 1 in 5,000 live births ( 29 ). Germline mutations in every protein coding gene in the mitochondrial genome are linked to clinical disorders. More speculatively, accumulation of somatic mitochondrial mutations have been implicated in various diseases of aging ( 30 ).

The mitochondrial genome was the first human genetic compartment to be completely sequenced, with the entire genome determined by Sanger sequencing announced in 1981 ( 24 ). Today, whole–mitochondrial genome sequencing can be rapidly performed by next-generation sequencing, although mitochondrial sequencing is not a common component of newborn screening programs. Recently, the genetic mosaicism shown by mitochondria in adults has even enabled lineage tracing of human clonal cell populations, which may be useful in the diagnosis of age-related disorders ( 31 ).

Mitochondrial Gene Therapies

The unique inheritance of mitochondria, the onset of phenotypes quickly after fertilization, their copious numbers per cell, and the physical and chemical barriers surrounding them make gene therapies targeting the mitochondrial genome particularly challenging ( 32 ). Similarly, the compactness of mitochondrial genes makes strategies based on nontargeted insertion of new genetic material (e.g., using viral vectors) into the mitochondrial genome impractical. The centrality of mitochondrial gene function means that any genetic therapy likely must correct the majority of the cells in the body, favoring germline correction.

The small size and extremely conserved sequence of the human mitochondrial genome allow for bulk replacement of an oocyte’s mitochondria containing a known genetic disorder with a donor’s wild-type mitochondria, leading to what is popularly known as a three-parent baby ( Figure 1a ). This bulk mitochondrial genomic replacement actually occurs in reverse: The nuclear genome is removed from a donor’s oocyte and replaced with the nucleus from one of the intended mother’s oocytes, followed by in vitro fertilization ( 33 ). This germline genetic therapy was approved in the United Kingdom in 2016 for inherited mitochondrial disorders and results in heritable germline correction in the resulting children.

For patients born with de novo mitochondrial mutations, however, germline bulk mitochondrial replacement is only an option for their own potential children. The correction of mitochondrial mutations in somatic cells, especially in sufficient cells and tissues to be clinically effective, presents a significant challenge ( Figure 2a ). In some cases, mitochondrial genes can be integrated into the nuclear genome by use of nontargeted viral vectors, a process mirroring the evolutionary nuclear movement of mitochondrial genes. For example, in Leber’s hereditary optic neuropathy (LHON), a mitochondrial disorder resulting in acute vision loss in young adulthood caused by mutations in NADH ubiquinone oxidoreductase subunits (including ND4), nuclear insertion of corrected copies of the ND4 gene resulted in vision improvements in some human patients ( 34 ). Nontargeted addition of genetic material directly into mitochondria, although not the mitochondrial genome directly, has also been demonstrated in LHON through the use of a modified AAV capsid engineered to contain an endogenous mitochondrial targeting sequence ( 35 ). Viral injection of mitochondrial targeting sequence–modified AAVs containing corrected copies of ND4 , the causative gene resulting in acute vision loss in LHON, into the eyes of affected mice similarly resulted in vision improvements.

Targetable nucleases such as CRISPR/Cas9 could enable direct gene editing of the mitochondrial genome, although it is unclear whether microhomology-mediated or homology-directed repair (HDR) is common in mitochondria ( 36 , 37 ). More directly, when a mutation affects only a portion of mitochondria in a cell, targeted cutting and linearization of affected mitochondrial genome can result in relative loss of mutated compared with healthy mitochondria, as has been demonstrated in vitro using TALENs ( 38 ). Overall, however, mitochondrial gene therapies face great challenges in efficient in vivo delivery of genetic editing reagents into the mitochondrial matrix in enough somatic cells to achieve clinical benefit.

The mitochondrial genome contains the living relics of the fundamental symbiotic event at the dawn of eukaryotic life, ubiquitous in multiple copies in all cells of the body, with the exception of mature red blood cells. Its remaining genes play central roles in cellular energy transfers, and the rare mutations within them, affecting only about 0.02% of live births, lead to debilitating disorders. Germline genetic therapy involving the bulk replacement of an affected oocyte’s mitochondria could be an effective cure for mitochondrial genetic diseases, albeit only in subsequent generations. Somatic gene therapies targeting the mitochondrial genome are in early development, but they face great physical and biologic hurdles. In contrast, germline editing of nuclear genes is biologically and ethically much more complex, while somatic gene therapies of the nuclear genome have rapidly proliferated.

NUCLEAR GENOME

The classical human, or nuclear, genome has significantly greater size and complexity than the smaller mitochondrial genome and presents unique challenges for diagnosis and genetic therapies. The human nuclear genome contains approximately three billion base pairs, divided into two copies each of 22 autosomal chromosomes and either XX or XY sex chromosomes, one set inherited from each parent. Only ~2% of the genome encodes directly for 1 of the approximately 20,000 protein coding genes, although noncoding elements, structural elements such as centromeres and telomeres, regulatory elements such as promoters and enhancers, and functional RNA elements such as microRNAs and long noncoding RNAs make up significant portions of non–protein coding genomic space ( 39 ). Furthermore, repetitive and selfish genetic elements such as triplet repeats, short interspersed nuclear elements (SINEs), and long interspersed nuclear elements (LINEs) make up more than half of human genomic content ( 40 ). Each of the approximately 30 trillion cells in the adult body possesses a single diploid copy of the nuclear genome, with the exception of anuclear red blood cells, certain multinucleated myocytes and osteoclasts, and haploid gametes. On average, two unrelated humans’ genomes differ by approximately 0.1%, with four-fifths of this difference due to individual variability and the remaining fifth due to differences between human population groupings ( 41 ).

Germline Genetic Disease

The human genome has evolved at a rate of between 5 and 10 genetic changes per year ( 42 , 43 ). Human DNA polymerases combined with proofreading enzymes have an overall error rate of approximately 1 bp per 10 billion bp replicated, which can accumulate over the approximately 22 rounds of division an oocyte undergoes before fertilization as well as the hundreds of rounds of division, varying with paternal age, that a sperm cell undergoes ( 44 – 46 ). Small mutations and indels are not the only category of germline genetic changes, and errors in DNA replication and cell division can lead to repeat expansions, large deletions, chromosomal translocations, and autosomal and sex chromosome aneuploidy. However, extensive selective pressures are applied during gametogenesis and following fertilization, an estimated 10–40% of fertilized embryos do not implant, and overall 40–60% of fertilized pregnancies do not result in live birth ( 47 ). For example, out of 22 autosomal chromosomes, only aneuploidy of chromosome 21, resulting in Down syndrome, is compatible with prolonged life, whereas aneuploidy of any other autosome is fatal during embryogenesis or soon following birth. Overall, each human newborn contains an average of 10–20 maternally derived and 25–75 paternally derived de novo mutations in a newly fertilized embryo, which have the potential to occur in functional protein coding or noncoding sequences ( 48 , 49 ). Beyond de novo mutations, though, each newborn possesses inherited germline loss-of-function monoallelic mutations in approximately 100 genes, and even loss-of-function biallelic mutations in an estimated 20 genes ( 50 ).

Genetic diseases that manifest after birth often affect the nervous, immune, and metabolic systems, which are largely not under selective pressure in the supportive in utero environment. Out of 20,000 protein coding genes, mutations in more than 4,000 have been identified as causative of specific human genetic diseases ( 51 ). Approximately 3,000 protein coding genes are essential in human cell lines, and loss-of-function mutations in these genes are likely incompatible with gametogenesis or early embryonic development ( 52 ). Estimates of human population size and genetic diversity predict that all possible single-base-pair changes in the protein coding nuclear genome compatible with life are already present in the global human population ( 53 ). The complete classification of genotype-phenotype relations in single-protein genetic diseases is a possible, if long-term, goal.

However, the nuclear genome brims with complexity beyond its protein products, and increasingly mutations in noncoding regulatory and functional RNA elements have also been identified as causative for genetic disorders ( 54 ). Furthermore, genome-wide association studies (GWASs) conducted in the late 2000s and 2010s have associated numerous inherited genetic alterations with common diseases, although a hallmark finding of GWASs has been the relatively small contribution of each common inherited genetic alteration to the risk of common diseases ( 55 ).

Before next-generation sequencing along with the reference human genome became available in the 2000s, careful gene mapping of restriction fragment length polymorphisms (RFLPs) and other traceable areas of genetic variability led to the identification of causative genetic changes in diseases such as Huntington’s disease and muscular dystrophy ( 9 , 56 ), and even to RFLP-based diagnostic tests for disorders such as sickle cell anemia and thalassemia ( 57 ). Today, germline genetic diagnostics are clinically performed through a variety of assays. Common genetic disorders resulting in biochemical deficits can often be diagnosed chemically without sequencing, such as in newborn screening for phenylketonuria and galactosemia. Traditional karyotypes can diagnose large-scale chromosomal abnormalities, and single-nucleotide polymorphism microarrays can detect smaller-scale (but still many-kilobase) deletions ( 58 ). Targeted sequencing panels, performed either through exome sequencing with confirmatory Sanger sequencing or by Sanger sequencing directly, are the mainstay diagnostic for genetic diseases with consistent clinical phenotypes ( 54 ).

In patients without a clear previously described genetic syndrome, diagnostic whole-exome and, increasingly, whole-genome sequencing of the affected individual and both parents can reveal a causative genetic change in as many as 40% of patients ( 59 ). Large-scale chromosomal abnormalities can be diagnosed prior to birth from placental tissue or amniotic fluid, and these samples can also be used for DNA sequencing. Circulating fetal DNA in the mother’s blood offers a less invasive genetic diagnostic modality in individuals with clinical or hereditary suspicion of genetic disease ( 60 ). Advances in assisted reproductive technologies even enable genetic sequencing and diagnostics by removing a minimal number of cells during the earliest phases of cell division after in vitro fertilization ( 61 ). These preimplantation diagnostics, along with more traditional carrier testing of parents, can accurately diagnose the presence or risk of specific nuclear genetic diseases.

Genetic disease of the germline in many cases is diagnosable, even at the earliest stages of life. Therapeutic correction of these errors in information content can be performed within the germline or later in life in affected somatic tissues. In each case, gene therapy strategies can be divided into three categories: bulk replacement of the entire affected nuclear genome, even though only one base pair out of three billion may be disease causing; nontargeted addition of exogenous genetic material to compensate for the genetic error; and direct correction of the causative mutation by gene editing.

Germline Genetic Therapies

In the broadest sense, the affected nuclear genome of a patient, or future patient, with a germline genetic disease can be addressed preemptively through reproductive decision-making. In communities with known high carrier rates for a specific genetic disease, such as Ashkenazi Jewish communities carrying mutations in HEXA, the cause of Tay–Sachs disease, effective community-based screening and reproductive counseling have reduced the rate of children affected by Tay–Sachs to essentially zero in screened populations ( 62 ). Similarly, reproductive decision-making based on genetic diagnostics has enabled individual couples to prevent passing on genetic disorders through in vitro fertilization with sperm or egg donors, as well as through traditional adoption. All of these are, in a sense, bulk nuclear genome strategies to address germline genetic mutations ( Figure 1b ).

Direct addition of new genetic material to the human germline, or gene editing of endogenous germline sequences, is an ethically momentous step, and as of 2020 the scientific, medical, ethical, religious, and government communities broadly agree that it is inappropriate ( Figure 2b ) ( 63 , 64 ). Appropriate scientific outrage at the first publicly announced human germline gene editing attempts in 2018 ( 65 ) highlights the need for significant government and scientific oversight and regulation.

Somatic Genetic Disease

Mutations present at fertilization are inherited by every cell in the body, but genetic copying errors continue in each cycle of somatic cell division and continuously accumulate as a result of environmental factors such as ultraviolet light, radiation, and mutagen exposures. The varying accumulation of genetic errors in the final somatic cells of different tissues is emphasized by the linear correlation between the number of cell divisions a mature somatic cell type has undergone and that cell type’s propensity to develop into tumors ( 66 ). Cell types such as intestinal epithelial cells, whose stem cells can undergo hundreds of rounds of division ( 67 ), are much more likely to cause tumors than are low-division-number osteoblasts or neurons ( 66 ). Because mutations in one cell are inherited by all future somatic cells derived from it, changes during early phases of embryogenesis can result in large sections of tissue, and even entire organs, possessing sometimes deleterious mutations. Ultimately, two different somatic cells in an adult human can differ by thousands of base pairs due to this somatic mosaicism ( 68 – 70 ).

Somatic mutations during early development can cause many of the same genetic disorders as germline mutations, with severity depending on the degree of mosaicism and the end organs affected. For example, in ornithine transcarbamylase deficiency caused by X-linked recessive mutations in the OTC gene, patients with germline mutations rarely survive childhood without a liver transplant, but patients with somatic mutations, even those affecting substantial numbers of the affected cell type, hepatocytes, can live relatively normal lives with dietary modifications ( 71 ). Somatic mutations undergo many of the same selective pressures as the germline, with strong evidence of selection against missense mutations ( 70 ). However, somatic mutations that increase the rate of cellular division, especially in less differentiated stem populations, can proceed along well-defined mutational paths toward oncogenic transformations. In the case of colon cancers, the acquisition of early driver mutations in APC is followed by increased proliferation, mutations in KRAS, and finally mutations in p53, which in turn further decrease DNA copying fidelity and unleash a cascade of DNA changes that ultimately lead to cancer ( 72 ). More broadly, accumulation of somatic mutations in normal tissues throughout life may drive age-related declines in function in addition to increasing cancer risk ( 73 , 74 ).

Advances in DNA sequencing throughput, especially for high-coverage whole exomes and genomes, have similarly enhanced the ability to diagnose oncogenic and other deleterious genetic changes in somatic cells. Since the 1980s, when somatic mutations in tumor suppressor genes such as p53 and oncogenes such as KRAS were identified, ever greater numbers of oncogenic mutations have been cataloged ( 75 , 76 ). With the conclusion of The Cancer Genome Atlas sequencing project in 2018, thousands of mutations in an estimated 300 cancer driver genes were identified ( 77 ), leaving a long tail of only extremely rare mutations to identify by even larger-scale cancer cohort sequencing ( 78 ). Clinical somatic genome sequencing of tumor, precancerous, and healthy tissue is becoming increasingly routine, with single-mutation panels being replaced by multigene, exome, or whole-genome sequencing ( 79 ). With further development, less invasive methods such as cell-free DNA sequencing to detect DNA sequences and epigenetic alterations derived from early-stage tumors may even extend somatic genome sequencing to large-scale population screening applications ( 80 ).

Somatic Genetic Therapies

Gene therapies targeting the somatic genome can correct a genetic deficiency by specific endogenous gene editing and correction back to the normal sequence, nontargeted addition to the genome of exogenous genetic material to compensate for the mutation, or bulk replacement of the somatic genome. Gene therapies in the somatic genome are further differentiated by the need to replace, add, or correct genetic information only in the target tissue of interest, such as tissues of the liver, muscle, or eye. Furthermore, in certain cell types such as HSCs and T cells, which can be cultured outside the body, these gene therapies can be performed ex vivo and the altered cells returned to the patient. However, for the majority of target tissues, somatic gene therapies must overcome the challenge of delivering genetic material and editing reagents in vivo while avoiding rejection by the patient’s own immune system.

The bulk replacement of genetic alterations in the somatic genome is similarly difficult given the large numbers of cells that need to be genetically altered, in comparison to a single manipulated cell in germline therapies. In certain disorders such as polycystic kidney disease, which is caused by mutations in PKD1, PKD2, PKD3, and PKHD1 , replacement of the affected kidneys through transplantation effectively removes the disease-causing genetic material, although other organs such as the liver remain affected ( 81 ). Similarly, when tumors are operable, surgery in a sense allows for the bulk removal of mutated somatic genomes. Somatic mutational load can be reduced by avoidance of known environmental mutagen sources ( 73 ).

Nontargeted Addition to the Somatic Genome

The earliest gene therapies to bear that name were based on nontargeted additions to the nuclear genomes of ex vivo-cultured immune cells, particularly T cells and HSCs ( Figure 2b ). Following the successful engineering of the first replication-deficient retroviruses from Moloney murine leukemia virus (MMLV) in the early 1980s, which presaged later lentiviral vectors adapted from human immunodeficiency virus ( 82 , 83 ), large multiple-kilobase segments of new DNA could be pseudorandomly introduced into these cell types. The first gene transfer trial used an MMLV-derived retrovirus to add a heterologous tumor necrosis factor (TNF)-α expression cassette to T cells isolated from a metastatic melanoma patient’s tumors and expanded ex vivo ( 12 ).

While this first trial did not provide clinical benefit relative to earlier unmodified tumor-infiltrating lymphocyte trials, it precipitated a flood of additive ex vivo gene therapies in T cells and HSCs over the next 3 decades. Immediately following the first T cell trials, the nontargeted addition of a correct copy of the adenosine deaminase enzyme in the ex vivo–cultured HSCs of children with SCID resulted, in some cases, in a durable and so far lifelong cure in these early gene therapy patients ( 84 ). These additive ex vivo retroviral technologies have been extended to nontargeted integration of synthetic DNA sequences in current generations of CAR T–based therapies ( 85 ).

In parallel to the development of ex vivo gene addition therapies, viral vectors performing the dual function of targeting a specific human tissue type and delivering exogenous DNA have enabled in vivo gene addition to diverse somatic cell types ( Figure 2b ). Liver hepatocytes have been an active target tissue as protein-generating factories for the addition of missing or dysfunctional blood factors. In the cases of hemophilia A and B, caused by deficiency in circulating clotting factors VIII and IX, respectively, in vivo addition of new factor VIII and IX genes to hepatocytes has resulted in curative gene therapies ( 86 , 87 ). Multiple generations of viral delivery systems, ranging from adenoviruses to modern engineered AAV serotypes and pseudotypes, have drastically improved the efficacy, specificity, and immunologic safety profiles of in vivo somatic cell gene therapies ( 88 , 89 ). The retina has also seen a large number of gene therapy trials because of its uniquely accessible location and immunoprivileged tissue status. The first FDA-approved in vivo gene therapy indeed adds a heterologous copy of the RPE65 gene to the retinal cells of patients suffering from Leber’s congenital amaurosis, resulting in durable vision improvements ( 16 ).

However, nontargeted additive gene therapies suffer from a variety of constraints. Functionally, the genetic carrying capacity of current generations of commonly used AAV vectors is limited to approximately 4.5 kb, too small to encode cassettes expressing correct copies of large endogenous proteins such as, in an extreme case, the more than 10 kb of complementary DNA required to encode dystrophin, which is mutated in patients with muscular dystrophy ( 90 ). Similarly, early trials attempting to insert correct versions of α- or β-hemoglobin into the HSCs of patients with sickle cell anemia and thalassemia resulted in failure of erythropoiesis due to improper regulatory control over hemoglobin expression during erythrocyte development ( 91 ).

More importantly, patient deaths in gene therapy clinical trials around the turn of the millennium highlighted numerous safety issues in pseudorandomly integrating viral vectors. First, the 1999 death of a patient with ornithine transcarbamylase deficiency, who possessed a mild form of the disease due to somatic mosaicism, was traced to a massive immunologic response to the viral vector used to deliver the gene cargo in vivo to the patient’s hepatocytes ( 92 , 93 ). Furthermore, immune responses to newly corrected, and thus recognized as nonself, endogenous gene products may limit therapeutic efficacy in disorders such as Duchenne muscular dystrophy ( 94 ). The unintended consequences of the introduction of nontargeted genetic elements, including strong viral promoters to drive the heterologous therapeutic gene, were revealed by a rash of leukemias in early X-linked SCID clinical trials editing HSCs ex vivo ( 95 ). Viral vector copies that integrated adjacent to oncogenes such as LMO2 precipitated oncogenic transformation many years after initially successful therapies ( 96 , 97 ). Finally, the potential dangers of inappropriate regulatory control of pseudorandomly added gene products were underscored by the death of a patient with rheumatoid arthritis from a histoplasmosis fungal infection after successful gene therapy with an anti-TNF decoy receptor ( 98 ); on-target toxicity of the gene therapy potentially suppressed the patient’s ability to mount an effective immune response.

Gene Editing in the Somatic Genome

Gene therapies based on correcting the individual causative mutations in somatic cell types of interest could overcome many of these challenges with nontargeted genetic addition. All cells undergoing cell division attempt to repair DNA copying errors though a variety of DNA repair pathways, including HDR, wherein a mutation on one chromosome can be corrected by binding its homologous region on the other chromosome and undergoing templated repair ( 99 ). HDR is capable of scarlessly integrating exogenous DNA sequences at specific, user-defined sites in human cell lines in the 1980s, although initially at exceptionally low efficiencies ( 100 ). While critical for the generation of genetically modified model organisms ( 101 ), therapeutic application in human cells ex vivo or in vivo awaited the development of targetable DNA nucleases that could generate a double-stranded DNA break adjacent to the intended site of genetic correction.

These targeted double-stranded breaks increased the efficiency of HDR in human cells by many orders of magnitude and, in the 2000s, enabled the first targeted gene editing trials using ZFNs to correct SCID-causing mutations in IL2RG ( 102 ). The discovery and rapid development of RNA-guided nucleases, most prominently CRISPR/Cas9, in the mid-2010s made these gene editing reagents drastically simpler and cheaper to develop ( 103 , 104 ). Paired with a corrective exogenous DNA template containing homology arms, reagents to perform endogenous gene editing at almost any site in the human nuclear genome can be rapidly designed and synthesized. Even the DNA and protein components are combinable into a single-component system using a Cas9–reverse transcriptase fusion protein along with a guide RNA with an extended RNA sequence containing the intended mutation correction instead of homologous DNA ( 105 ). This process allows templated repair to follow nuclease recognition directly without the need for an additional DNA sequence, potentially simplifying reagent delivery.

Indeed, the challenge of delivering gene editing reagents into target cells represents a great hurdle for wider adoption of corrective gene therapies in somatic cells. For HSC and T cell populations that can be cultured ex vivo, physical delivery methods such as electroporation enable robust delivery of both ribonucleoproteins (e.g., Cas9–guide RNA complexes) and DNA HDR templates into target cells ( 106 ). In HSCs, electroporation of Cas9 RNPs targeting the sickle cell mutation in β-hemoglobin, coupled with the delivery of HDR templates containing a correct sequence using AAV6 vectors, has finally resulted in robust correction of the causative mutation in sickle cell anemia, the first molecularly described genetic disease ( 107 ). These corrected HSCs were able to fully differentiate and, crucially, undergo erythropoiesis. The ease of generating new editing reagents to target additional mutations may enable this strategy to be broadly applied across the genetic diseases of hematopoiesis ( 108 ). Beyond HSCs, we have shown how similar RNP electroporation strategies instead using nonviral DNA can be applied to directly correct causative mutations in differentiated T cell populations such as regulatory T cells ( 109 ).

Gene editing to repair endogenous genetic sequences also offers new avenues for in vivo somatic gene therapies. Notably, in conditions such as muscular dystrophy, where the protein product is too large for commonly used viral vectors, gene editing reagents have been designed and successfully delivered in mouse models, among many other rapidly developing preclinical in vivo therapeutics ( 110 , 111 ). In vivo gene editing further highlights the challenges of editing reagent delivery, as both large protein nucleases, or the DNA sequences encoding them, and corrective DNA HDR templates must be delivered to the somatic tissue of interest ( 112 ). Creative solutions involving curative treatments resulting from gene cutting only, without templated repair, may be possible in a handful of conditions. The development of smaller targetable nucleases, single-component templated repair systems ( 105 ), and most of all generalized improvements in delivery technology offers great hope for accelerating in vivo corrective gene therapies in somatic tissues.

MANIPULATING OTHER GENOMES

Adaptive immune receptor repertoire.

A subset of somatic cells contain a unique addition to the nuclear genome, the T and B cells of the adaptive immune system, which generate new antigen receptor gene products after conception through somatic recombination. The immune receptor repertoire of a young adult contains, conservatively, on the order of 10 11 unique antigenic receptors, generating almost six orders of magnitude more individual protein products than the nuclear genome ( 113 – 115 ), although repertoire diversity declines with age ( 116 ). The presence or lack of T cell receptor (TCR) genes within the T cell repertoire can contribute to the development of diseases such as type 1 diabetes mellitus and multiple sclerosis, while autoreactive B cell receptors (BCRs) underlie systemic lupus erythematosus, myasthenia gravis, and numerous other conditions ( 117 , 118 ). In the opposite context, the adaptive immune receptor repertoire sometimes lacks potentially useful TCRs and BCRs, such as those that would respond to liquid and solid tumors, due to regulatory mechanisms to guard against autoimmunity or so-called immune editing in the cancer microenvironment ( 119 ).

The adaptive immune receptor repertoire subset of the nuclear genome can be manipulated genetically through bulk replacement of the entire repertoire or through selective introduction of desired TCR and BCR sequences. The radiation sensitivity of the majority of these cells enables bulk replacement of this genomic compartment by autologous or allogenic bone marrow transplants, which have successfully been used in the treatment of severe autoimmune diseases such as systemic sclerosis ( 120 ). Specific introduction of desired antigen receptors can target antigens that are difficult to vaccinate against, such as endogenous peptides or masked pathogenic epitopes. Viral vectors have been clinically used to add new TCR genes at pseudorandom genome sites in primary human T cells since the 2000s ( 121 ). More broadly, CARs combining the binding properties of antibodies with the signaling properties of TCRs and costimulatory molecules have been engineered to redirect T cells to self-antigens also expressed on cancers, such as the B cell marker CD19 ( 85 ).

Theoretically, one can envision future personalized therapies based on the introduction of antigen receptors specific for various microbes or tumor antigens into the T and B cells of patients with cancer and infectious disease or with the goal of eliminating existing T and B cells specific for self-antigens from patients with autoimmune disease. Practical application of these ideas is challenging because of the enormous diversity of immune receptor repertoires. Identification of TCR, BCR, or synthetic antigen receptor genes that would work against particular microbes or tumors or react against particular self-antigens remains a key challenge. Given the enormous current interest and progress in sequencing T and B cell antigen receptors ( 114 ), it is possible that these challenges will be overcome as large-enough databases of receptor sequences are assembled.

Microbial Metagenome

In comparison to the mitochondrial and nuclear genomes, the most complex genetic compartment in terms of protein family diversity within the human body lies not within human cells but rather in the metagenome of the ubiquitous microbiota. Across human tissues, the adult human microbiome contains more than 30 trillion bacterial cells from on the order of 1,000 unique species ( 122 , 123 ). Different anatomic locations have distinct microbiomes, with varying degrees of diversity according to site, individual, time, and disease state ( 124 ). With an average bacterium containing approximately 3,000 protein coding genes, a single human’s overall microbial metagenome likely contains on the order of a million unique gene products ( 125 , 126 ). The microbial metagenome is not acquired until after birth and is initially inherited primarily from the mother through the vaginal passage, skin-to-skin contact, and breastfeeding. The genetic content of the human metagenome is also much more diverse both across an individual’s life and among individuals than the mitochondrial or nuclear genome. Between two random individuals the microbiome can differ in well over half of its content (although significantly less in cohabiting humans sharing a local environment and diet), in comparison to the average ~0.1% difference in nuclear genetic content between two unrelated individuals ( 127 ).

The presence or absence of specific pathogenic microbial components of the microbiome has traditionally been measured by direct culture ex vivo of the organism or detection of a specific disease after introduction to an animal host. Nucleic acid–specific methods such as polymerase chain reaction offer greater speed and flexibility and can detect pathogenic toxin genes differentially from the bacterial species that variably can possess them ( 128 ). At greater scale, 16S ribosomal sequencing takes advantage of the evolutionary conservation of ribosomal RNA to directly measure microbial species diversity. First pioneered in the 1970s ( 129 ) and since expanded through pairing with next-generation sequencing, 16S metagenomic sequencing can rapidly determine the genus-level diversity of the human microbiome ( 130 ). With further decreases in sequencing cost, bulk fragmentation of metagenomic DNA samples and computational assembly into species-specific genomes and transcriptomes increasingly allow definitive sampling of the metagenomic compartment ( 131 ).

As molecular techniques have helped identify nonculturable microbes, researchers have hypothesized that alterations in the human microbiome are associated with the development of various diseases, raising the possibility that manipulating the microbiome and its genetic products may be a therapeutic strategy for these diseases. So far, the only clinically widespread microbiome-targeted therapy has been bulk replacement of depleted microbiota (via fecal transplants) in Clostridium difficile –induced pseudomembranous colitis ( 17 ). Microbiome abnormalities in inflammatory bowel disease and other inflammatory and metabolic disorders have also been suggested. The broad concept of dysbiosis proposes alterations in the nature and diversity of microbiota as predisposing factors for these disorders. In order to use genetic approaches for restoring the diversity, it will be necessary to identify specific organisms that are perturbed and, furthermore, the genes of the organisms that may contribute to the disease.

Bacteria can readily be made to express exogenous genes on extragenomic plasmids, but direct editing of the bacterial genome may be required to maintain expression with the absence in vivo of traditional laboratory selection pressures. Nontargeted gene addition through bacteriophage vectors or integrative plasmids ( 132 ) as well as gene editing with CRISPR/Cas9 and other targetable tools have enabled large heritable changes to be made ex vivo in bacterial species of the human microbiome. In the common nuclear genetic disorder phenylketonuria, a strain of Escherichia coli Nissle engineered to heritably express phenylalanine-metabolizing enzymes showed persistent engraftment into mouse and primate microbiomes after oral introduction and ameliorated blood phenylalanine levels ( 133 ). Microbial populations edited ex vivo can be introduced into the normal flora similarly to nonedited therapeutic bacterial species. Engraftment can be further enhanced through targeted nutritional support for engineered strains ( 134 ).

With improved delivery methods targeting gene editing reagents to specific microbial species within the body, these therapeutic microbial genetic changes may ultimately be made in vivo, similar to the goals of in vivo gene therapies targeting somatic genomes and the adaptive immune receptor repertoire. The remarkable species specificity of bacteriophages has enabled delivery of gene editing reagents targeting pathogenic strains or even specific antibiotic resistance plasmids for destruction, and may allow for additive gene therapies as well ( 135 ). Whether through bulk replacement of the microbiome, gene editing ex vivo or in vivo of specific bacterial species, or recapitulation of physiologic exposures to normal flora, altering the genetic content of the diverse human metagenome could offer promising avenues for future research on genetic therapies.

CONCLUSIONS

The major genetic compartments in humans differ in genomic size, complexity, heritability, and diversity. Germline mutations in the mitochondrial and nuclear genomes often cause developmental disorders, although the great size of the nuclear genome ensures that the thousands of identified monogenic diseases present in diverse contexts. Accumulation of somatic mutations in the nuclear genome underlies the development of cancer, and somatic mutations in mitochondria may contribute to aging. More broadly, the microbial metagenome develops largely after birth and is characterized by much greater diversity among humans and variation over the course of life. Advances in next-generation DNA sequencing have made mitochondrial sequencing, clinical exome and whole-genome sequencing, and 16S and unbiased microbial sequencing widely available.

The genetic alterations revealed by these sequencing approaches are the correctable targets of gene therapies. Entire genomic compartments, such as the mitochondrial and nuclear genomes, can be addressed in bulk by use of modern assisted reproduction technologies, including mitochondrial replacement therapy and preimplantation diagnostics. Additive somatic cell gene therapies began with the development of viral vectors to infect human somatic cells that can be cultured ex vivo, such as T cells, and rapidly developed to include in vivo applications with viral pseudotypes with specific tissue tropisms. Most recently, dramatic advances in CRISPR/Cas9 and related targetable gene editing applications, where the specific causative mutation or gene is corrected at its endogenous locus, have expanded the horizons for more refined ex vivo and in vivo gene therapies.

Overall, the plummeting costs of DNA sequencing over the past 2 decades have accelerated the diagnosis of genetic diseases. Echoing these diagnostic advances, the unexpectedly rapid development of targetable gene editing in the 2010s has now made the design and testing of specific therapeutic reagents to correct genetic changes direct and accessible. One of the great continuing challenges to the widespread application of gene therapies lies in generalized platforms for the delivery of customizable gene editing reagents into the cell type and genomic compartment of interest in a patient’s specific genetic disease ( Figure 3 ). Beyond direct corrections of genetic diseases, new methodologies to rapidly discover synthetic genetic circuits capable of enhancing cellular function in diseases such as cancer and autoimmunity hold the promise of further gene therapy applications in engineered somatic cells ( 136 ). Increasingly, genetic diseases across human genetic compartments can be readily diagnosed, and the next generations of gene therapy platforms targeting each compartment are poised to offer flexible and personalized curative treatments.

SUMMARY POINTS

• Humans contain distinct genetic compartments: the mitochondrial genome; the nuclear genome including the adaptive immune receptor repertoire in specialized cells; and the microbial metagenome.
• Gene therapies for each of these compartments are based on three broad categories: bulk replacement or selection of affected genomes, nontargeted addition of new genetic information to compensate for genetic errors, and direct gene editing to correct causative genetic alterations.
• The mitochondrial and nuclear genomes are determined at conception and are consistent throughout life, with the exception of accumulation of somatic mutations and the adaptive immune receptor repertoire. Genetic disease is driven largely by mutations.
• Diagnosis of genetic disease through next-generation sequencing and design of corrective gene therapy reagents are now being widely adopted. Pairing gene addition or gene editing reagents with generalized delivery platforms to target specific genetic compartments in specific somatic cell types in vivo remains a daunting challenge.

ACKNOWLEDGMENTS

We thank members of the Marson lab for helpful discussions and Sarah Pyle for assistance creating figures. T.L.R. was supported by the UCSF Medical Scientist Training Program (T32GM007618), a UCSF Endocrinology Training Grant (T32 DK007418), and a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (F30DK120213). A.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund; is an investigator at the Chan Zuckerberg Biohub; and has received funding from the Innovative Genomics Institute, the American Endowment Foundation, and the Cancer Research Institute, as well as a Lloyd J. Old STAR award, a gift from the Jordan Family, and a gift from Barbara Bakar. A.M. is a member of the Parker Institute for Cancer Immunotherapy.

DISCLOSURE STATEMENT

T.L.R. and A.M. are cofounders of Arsenal Biosciences. T.L.R. served as the Chief Scientific Officer of Arsenal Biosciences. A.M. is a cofounder of Spotlight Therapeutics, served on the scientific advisory board of PACT Pharma, was an advisor to Trizell, and was an advisor to Juno Therapeutics. T.L.R. and A.M. own equity in Arsenal Biosciences, and A.M. owns equity in Spotlight Therapeutics and PACT Pharma. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem.

The Annual Review of Pathology: Mechanisms of Disease is online at pathol.annualreviews.org

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Existing drug shows promise as treatment for rare genetic disorder

NIH researchers find new pathways towards treatment for autoimmune polyendocrine syndrome type 1.

A drug approved to treat certain autoimmune diseases and cancers successfully alleviated symptoms of a rare genetic syndrome called autoimmune polyendocrine syndrome type 1 (APS-1). Researchers identified the treatment based on their discovery that the syndrome is linked to elevated levels of interferon-gamma (IFN-gamma), a protein involved in immune system responses, providing new insights into the role of IFN-gamma in autoimmunity. The study, led by researchers at the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, was published today in the New England Journal of Medicine .

In a three-stage study, conducted in mice and people, the researchers examined how APS-1 causes autoimmune disease. The syndrome is marked by dysfunction of multiple organs, usually beginning in childhood, and is fatal in more than 30% of cases. This inherited syndrome is caused by a deficiency in a gene that keeps the immune system’s T cells from attacking cells of the body, leading to autoimmunity; chronic yeast infections in the skin, nails, and mucous membranes; and insufficient production of hormones from endocrine organs, such as the adrenal glands. Symptoms include stomach irritation, liver inflammation, lung irritation, hair loss, loss of skin coloring, tissue damage, and organ failure.

In the first stage of this study, researchers led by scientists in NIAID’s Laboratory of Clinical Immunology and Microbiology examined the natural history of APS-1 in 110 adults and children. Blood and tissues were analyzed to compare gene and protein expression in people with and without APS-1. They found elevated IFN-gamma responses in the blood and tissues of people with APS-1, indicating that IFN-gamma may play an important role in the disease and providing a pathway to target for treatment.

In the second stage of the study, the scientists examined mice with the same gene deficiency that causes APS-1 in people, finding that the animals also experienced autoimmune tissue damage and elevated IFN-gamma levels. Mice also deficient in the gene for IFN-gamma did not have autoimmune tissue damage, which showed a direct link between IFN-gamma and APS-1 symptoms. With this understanding, the researchers looked for a drug that could be used to lower IFN-gamma activity in people. They selected ruxolitinib, a Janus kinase inhibitor, because it acts by shutting down the pathway driven by IFN-gamma. When ruxolitinib was administered to the mice with the gene deficiency that causes APS-1, IFN-gamma responses were normalized and T cells were prevented from infiltrating tissues and damaging organs. These results showed that ruxolitinib could alleviate effects of the gene deficiency, suggesting that it could be effective for treatment of APS-1 in people.

The researchers administered ruxolitinib, which was supplied by the NIH Clinical Center, to five people—two adults and three children—with APS-1 in the third stage of the study. The dosing and regimens were tailored to the individuals, and the treatments were continued for over a year. The drug was safe and tolerated well, and improvement in symptoms was seen in all study participants. Blood and tissue analyses revealed decreased production of IFN-gamma from T cells, as well as normalized levels of IFN-gamma in the blood. Many APS-1-related symptoms were reduced, including hair loss, oral yeast infections, stomach and bowel irritation, hives, and thyroid inflammation.

The results revealed that normalizing IFN-gamma levels using ruxolitinib could reduce the damaging effects of APS-1 in people. The scientists note that a study with a larger and more diverse group of patients is needed to determine whether ruxolitinib and similar drugs are suitable treatments for individuals with APS-1. They write that understanding the role of IFN-gamma in autoimmunity may lead to the development of treatments for related diseases. This research highlights the importance of finding the causes of and treatments for rare diseases.

Editorial note : APS-1 is also known as polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the literature.

V Oikonomou et al. The role of interferon-gamma in Autoimmune Polyendocrine Syndrome Type 1. New England Journal of Medicine DOI: 10.1056/NEJMoa2312665 (2024).

Michail S. Lionakis, M.D., Sc.D., chief of NIAID’s Fungal Pathogenesis Section and deputy chief of NIAID’s Laboratory of Clinical Immunology and Microbiology, is available to discuss this research.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Scientists Spot Gene Behind Form of Intellectual Disability Affecting Thousands Worldwide

By Dennis Thompson HealthDay Reporter

MONDAY, June 3, 2024 -- Mutations in a single newly identified gene are responsible for developmental disorders affecting tens of thousands of people worldwide, a new study claims.

The gene – RNU4-2 – can cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder, researchers report.

The discovery is significant because it represents one of the most common single-gene genetic causes of such disorders, ranking second only to a movement disorder called Rett syndrome, researchers said.

“Nowadays, finding a single gene that harbors genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual,” said lead researcher Daniel Greene , an assistant professor of genetics and genomics sciences at the Icahn School of Medicine at Mount Sinai in New York City. “Our discovery eluded researchers for years due to various sequencing and analytical challenges.”

More than 99% of genes known to harbor mutations that cause developmental disorders produce proteins through a process called encoding.

These disorders cause developmental delays that affect a person’s social, academic or occupational function, researchers said. They also cause intellectual delays that limit a person’s learning, reasoning and problem-solving skills.

Researchers figured that they might be overlooking some genetic causes of developmental disorder because non-coding genes that don’t produce proteins were being overlooked.

RNU4-2 is a non-coding gene, and researchers discovered it after using a U.K. genetics library to analyze over 41,000 non-coding genes in more than 5,500 people with intellectual disability and about 46,400 healthy people.

The new study appears in the journal Nature Medicine .

"What I found remarkable is how such a common cause of a neurodevelopmental disorder has been missed in the field because we've been focusing on coding genes,” Dr. Heather Mefford , a researcher with the Center for Pediatric Neurological Disease Research at St. Jude Children’s Research Hospital, said in a news release. Mefford was not involved with the research.

“This study's discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause,” Mefford continued. “It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening new diagnostic possibilities and research opportunities."

RNU4-2 is a very short gene, “but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi," said senior researcher Ernest Turro , an associate professor of genetics and genomic sciences at Icahn Mount Sinai.

“Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing,” Turro said in a Mount Sinai news release. “Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members, bringing many diagnostic odysseys to a close.”

More information

The U.S. Centers for Disease Control and Prevention has more about developmental disability .

SOURCE: Icahn School of Medicine at Mount Sinai, news release, May 31, 2024

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• Open access
• Published: 01 June 2024

Biomarkers for personalised prevention of chronic diseases: a common protocol for three rapid scoping reviews

• E Plans-Beriso   ORCID: orcid.org/0000-0002-9388-8744 1 , 2   na1 ,
• C Babb-de-Villiers 3   na1 ,
• D Petrova 2 , 4 , 5 ,
• C Barahona-López 1 , 2 ,
• P Diez-Echave 1 , 2 ,
• O R Hernández 1 , 2 ,
• N F Fernández-Martínez 2 , 4 , 5 ,
• H Turner 3 ,
• E García-Ovejero 1 ,
• O Craciun 1 ,
• P Fernández-Navarro 1 , 2 ,
• N Fernández-Larrea 1 , 2 ,
• E García-Esquinas 1 , 2 ,
• V Jiménez-Planet 7 ,
• V Moreno 2 , 8 , 9 ,
• F Rodríguez-Artalejo 2 , 10 , 11 ,
• M J Sánchez 2 , 4 , 5 ,
• M Pollan-Santamaria 1 , 2 ,
• L Blackburn 3 ,
• M Kroese 3   na2 &
• B Pérez-Gómez 1 , 2   na2  

Systematic Reviews volume  13 , Article number:  147 ( 2024 ) Cite this article

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Introduction

Personalised prevention aims to delay or avoid disease occurrence, progression, and recurrence of disease through the adoption of targeted interventions that consider the individual biological, including genetic data, environmental and behavioural characteristics, as well as the socio-cultural context. This protocol summarises the main features of a rapid scoping review to show the research landscape on biomarkers or a combination of biomarkers that may help to better identify subgroups of individuals with different risks of developing specific diseases in which specific preventive strategies could have an impact on clinical outcomes.

This review is part of the “Personalised Prevention Roadmap for the future HEalThcare” (PROPHET) project, which seeks to highlight the gaps in current personalised preventive approaches, in order to develop a Strategic Research and Innovation Agenda for the European Union.

To systematically map and review the evidence of biomarkers that are available or under development in cancer, cardiovascular and neurodegenerative diseases that are or can be used for personalised prevention in the general population, in clinical or public health settings.

Three rapid scoping reviews are being conducted in parallel (February–June 2023), based on a common framework with some adjustments to suit each specific condition (cancer, cardiovascular or neurodegenerative diseases). Medline and Embase will be searched to identify publications between 2020 and 2023. To shorten the time frames, 10% of the papers will undergo screening by two reviewers and only English-language papers will be considered. The following information will be extracted by two reviewers from all the publications selected for inclusion: source type, citation details, country, inclusion/exclusion criteria (population, concept, context, type of evidence source), study methods, and key findings relevant to the review question/s. The selection criteria and the extraction sheet will be pre-tested. Relevant biomarkers for risk prediction and stratification will be recorded. Results will be presented graphically using an evidence map.

Inclusion criteria

Population: general adult populations or adults from specific pre-defined high-risk subgroups; concept: all studies focusing on molecular, cellular, physiological, or imaging biomarkers used for individualised primary or secondary prevention of the diseases of interest; context: clinical or public health settings.

Systematic review registration

https://doi.org/10.17605/OSF.IO/7JRWD (OSF registration DOI).

Peer Review reports

In recent years, innovative health research has moved quickly towards a new paradigm. The ability to analyse and process previously unseen sources and amounts of data, e.g. environmental, clinical, socio-demographic, epidemiological, and ‘omics-derived, has created opportunities in the understanding and prevention of chronic diseases, and in the development of targeted therapies that can cure them. This paradigm has come to be known as “personalised medicine”. According to the European Council Conclusion on personalised medicine for patients (2015/C 421/03), this term defines a medical model which involves characterisation of individuals’ genotypes, phenotypes and lifestyle and environmental exposures (e.g. molecular profiling, medical imaging, lifestyle and environmental data) for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease and/or to deliver timely and targeted prevention [ 1 , 2 ]. In many cases, these personalised health strategies have been based on advances in fields such as molecular biology, genetic engineering, bioinformatics, diagnostic imaging and new’omics technologies, which have made it possible to identify biomarkers that have been used to design and adapt therapies to specific patients or groups of patients [ 2 ]. A biomarker is defined as a substance, structure, characteristic, or process that can be objectively quantified as an indicator of typical biological functions, disease processes, or biological reactions to exposure [ 3 , 4 ].

Adopting a public health perspective within this framework, one of the most relevant areas that would benefit from these new opportunities is the personalisation of disease prevention. Personalised prevention aims to delay or avoid the occurrence, progression and recurrence of disease by adopting targeted interventions that take into account biological information, environmental and behavioural characteristics, and the socio-economic and cultural context of individuals. These interventions should be timely, effective and equitable in order to maintain the best possible balance in lifetime health trajectory [ 5 ].

Among the main diseases that merit specific attention are chronic noncommunicable diseases, due to their incidence, their mortality or disability-adjusted life years [ 6 , 7 , 8 , 9 ]. Within the European Union (EU), in 2021, one-third of adults reported suffering from a chronic condition [ 10 ]. In addition, in 2019, the leading causes of mortality were cardiovascular disease (CVD) (35%), cancer (26%), respiratory disease (8%), and Alzheimer's disease (5%) [ 11 ]. For all of the above, in 2019, the PRECeDI consortium recommended the identification of biomarkers that could be used for the prevention of chronic diseases to integrate personalised medicine in the field of chronicity. This will support the goal of stratifying populations by indicating an individuals’ risk or resistance to disease and their potential response to drugs, guiding primary, secondary and tertiary preventive interventions [ 12 ]; understanding primary prevention as measures taken to prevent the occurrence of a disease before it occurs, secondary prevention as actions aimed at early detection, and tertiary prevention as interventions to prevent complications and improve quality of life in individuals already affected by a disease [ 4 ].

The “Personalised Prevention roadmap for the future HEalThcare” (PROPHET) project, funded by the European Union’s Horizon Europe research and innovation program and linked to ICPerMed, seeks to assess the effectiveness, clinical utility, and existing gaps in current personalised preventive approaches, as well as their potential to be implemented in healthcare settings. It also aims to develop a Strategy Research and Innovation Agenda (SRIA) for the European Union. This protocol corresponds to one of the first steps in the PROPHET, namely a review that aims to map the evidence and highlight the evidence gaps in research or the use of biomarkers in personalised prevention in the general adult population, as well as their integration with digital technologies, including wearable devices, accelerometers, and other appliances utilised for measuring physical and physiological functions. These biomarkers may be already available or currently under development in the fields of cancer, CVD, and neurodegenerative diseases.

There is already a significant body of knowledge about primary and secondary prevention strategies for these diseases. For example, hypercholesterolemia or dyslipidaemia, hypertension, smoking, diabetes mellitus and obesity or levels of physical activity are known risk factors for CVD [ 6 , 13 ] and neurodegenerative diseases [ 14 , 15 , 16 ]; for cancer, a summary of lifestyle preventive actions with good evidence is included in the European code against cancer [ 17 ]. The question is whether there is any biomarker or combination of biomarkers that can help to better identify subgroups of individuals with different risks of developing a particular disease, in which specific preventive strategies could have an impact on clinical outcomes. Our aim in this context is to show the available research in this field.

Given the context and time constraints, the rapid scoping review design is the most appropriate method for providing landscape knowledge [ 18 ] and provide summary maps, such as Campbell evidence and gap map [ 19 ]. Here, we present the protocol that will be used to elaborate three rapid scoping reviews and evidence maps of research on biomarkers investigated in relation to primary or secondary prevention of cancer, cardiovascular and neurodegenerative diseases, respectively. The results of these three rapid scoping reviews will contribute to inform the development of the PROPHET SRIA, which will guide the future policy for research in this field in the EU.

Review question

What biomarkers are being investigated in the context of personalised primary and secondary prevention of cancer, CVD and neurodegenerative diseases in the general adult population in clinical or public health settings?

Three rapid scoping reviews are being conducted between February and June 2023, in parallel, one for each disease group included (cancer, CVD and neurodegenerative diseases), using a common framework and specifying the adaptations to each disease group in search terms, data extraction and representation of results.

This research protocol, designed according to Joanna Briggs Institute (JBI) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist [ 20 , 21 , 22 ] was uploaded to the Open Science Framework for public consultation [ 23 ], with registration DOI https://doi.org/ https://doi.org/10.17605/OSF.IO/7JRWD . The protocol was also reviewed by experts in the field, after which modifications were incorporated.

Eligibility criteria

Following the PCC (population, concept and context) model [ 21 , 22 ], the included studies will meet the following eligibility criteria (Table  1 ):

Rationale for performing a rapid scoping review

As explained above, these scoping reviews are intended to be one of the first materials produced in the PROPHET project, so that they can inform the first draft of the SRIA. Therefore, according to the planned timetable, the reviews should be completed in only 4 months. Thus, following recommendations from the Cochrane Rapid Review Methods Group [ 24 ] and taking into account the large number of records expected to be assessed, according to the preliminary searches, and in order to meet these deadlines, specific restrictions were defined for the search—limited to a 3-year period (2020–2023), in English only, and using only MEDLINE and EMBASE as possible sources—and it was decided that the title-abstract and full-text screening phase would be carried out by a single reviewer, after an initial training phase with 10% of the records assessed by two reviewers to ensure concordance between team members. This percentage could be increased if necessary.

Rationale for population selection

These rapid scoping reviews are focused on the general adult population. In addition, they give attention to studies conducted among populations that present specific risk factors relevant to the selected diseases or that include these factors among those considered in the study.

For cancer, these risk (or preventive) factors include smoking [ 25 ], obesity [ 26 ], diabetes [ 27 , 28 , 29 ], Helicobacter pylori infection/colonisation [ 30 ], human papillomavirus (HPV) infection [ 30 ], human immunodeficiency virus (HIV) infection [ 30 ], alcohol consumption [ 31 ], liver cirrhosis and viral (HVB, HVC, HVD) hepatitis [ 32 ].

For CVD, we include hypercholesterolemia or dyslipidaemia, arterial hypertension, smoking, diabetes mellitus, chronic kidney disease, hyperglycaemia and obesity [ 6 , 13 ].

Risk groups for neurodegenerative diseases were defined based on the following risk factors: obesity [ 15 , 33 ], arterial hypertension [ 15 , 33 , 34 , 35 ], diabetes mellitus [ 15 , 33 , 34 , 35 ], dyslipidaemia [ 33 ], alcohol consumption [ 36 , 37 ] and smoking [ 15 , 16 , 33 , 34 ].

After the general search, only relevant and/or disease-specific subpopulations will be used for each specific disease. On the other hand, pregnancy is an exclusion criterion, as the very specific characteristics of this population group would require a specific review.

Rationale for disease selection

The search is limited to diseases with high morbidity and mortality within each of the three disease groups:

Cancer type

Due to time constraints, we only evaluate those malignant neoplasms with the greatest mortality and incidence rates in Europe, which according to the European Cancer Information System [ 38 ] are breast, prostate, colorectum, lung, bladder, pancreas, liver, stomach, kidney, and corpus uteri. Additionally, cervix uteri and liver cancers will also be included due to their preventable nature and/or the existence of public health screening programs [ 30 , 31 ].

We evaluate the following main causes of deaths: ischemic heart disease (49.2% of all CVD deaths), stroke (35.2%) (this includes ischemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage), hypertensive heart disease (6.2%), cardiomyopathy and myocarditis (1.8%), atrial fibrillation and flutter (1.7%), rheumatic heart disease (1.6%), non-rheumatic valvular heart disease (0.9%), aortic aneurism (0.9%), peripheral artery disease (0.4%) and endocarditis (0.4%) [ 6 ].

In this scoping review, specifically in the context of CVD, rheumatic heart disease and endocarditis are not considered because of their infectious aetiology. Arterial hypertension is a risk factor for many cardiovascular diseases and for the purposes of this review is considered as an intermediary disease that leads to CVD.

• Neurodegenerative diseases

The leading noncommunicable neurodegenerative causes of death are Alzheimer’s disease or dementia (20%), Parkinson’s disease (2.5%), motor neuron diseases (0.4%) and multiple sclerosis (0.2%) [ 8 ]. Alzheimer’s disease, vascular dementia, frontotemporal dementia and Lewy body disease will be specifically searched, following the pattern of European dementia prevalence studies [ 39 ]. Additionally, because amyotrophic lateral sclerosis is the most common motor neuron disease, it is also included in the search [ 8 , 40 , 41 ].

Rationale for context

Public health and clinical settings from any geographical location are being considered. The searches will only consider the period between January 2020 and mid-February 2023 due to time constraints.

Rationale for type of evidence

Qualitative studies are not considered since they cannot answer the research question. Editorials and opinion pieces, protocols, and conference abstracts will also be excluded. Clinical practice guidelines are not included since the information they contain should be in the original studies and in reviews on which they are based.

Pilot study

We did a pilot study to test and refine the search strategies, selection criteria and data extraction sheet as well as to get used to the software—Covidence [ 42 ]. The pilot study consisted of selecting from the results of the preliminary search matrix 100 papers in order of best fit to the topic, and 100 papers at random. The team comprised 15 individual reviewers (both in the pilot and final reviews) who met daily to revise, enhance, and reach consensus on the search matrices, criteria, and data extraction sheets.

Regarding the selected databases and the platforms used, we conducted various tests, including PubMed/MEDLINE and Ovid/MEDLINE, as well as Ovid/Embase and Elsevier/Embase. Ultimately, we chose Ovid as the platform for accessing both MEDLINE and Embase, utilizing thesaurus Mesh and EmTrees. We manually translated these thesauri to ensure consistency between them. Given that the review team was spread across the UK and Spain, we centralised the search results within the UK team's access to the Ovid license to ensure consistency. Additionally, using Ovid exclusively for accessing both MEDLINE and Embase streamlined the process and allowed for easier access to preprints, which represent the latest research in this rapidly evolving field.

Identification of research

The searches are being conducted in MEDLINE via Ovid, Embase via Ovid and Embase preprints via Ovid. We also explored the feasibility of searching in CDC-Authored Genomics and Precision Health Publications Databases [ 43 ] . However, the lack of advanced tools to refine the search, as well as the unavailability of bulk downloading prevented the inclusion of this data source. Nevertheless, a search with 15 records for each disease group showed a full overlap with MEDLINE and/or Embase.

Search strategy definition

An initial limited search of MEDLINE via PubMed and Ovid was undertaken to identify relevant papers on the topic. In this step, we identified keytext words in their titles and abstracts, as well as thesaurus terms. The SR-Accelerator, Citationchaser, and Yale Mesh Analyzer tools were used to assist in the construction of the search matrix. With all this information, we developed a full search strategy adapted for each included database and information source, optimised by research librarians.

Study evidence selection

The complete search strategies are shown in Additional file 3. The three searches are being conducted in parallel. When performing the search, no limits to the type of study or setting are being applied.

Following each search, all identified citations will be collated and uploaded into Covidence (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org ) with the citation details, and duplicates will be removed.

In the title-abstract and full-text screening phase, the first 10% of the papers will be evaluated by two independent reviewers (accounting for 200 or more papers in absolute numbers in the title-abstract phase). Then, a meeting to discuss discrepancies will lead to adjusting inclusion and exclusion criteria and to acquire consistency between reviewers’ decisions. After that, the full screening of the search results will be performed by a single reviewer. Disagreements that arise between reviewers at each stage of the selection process will be resolved through discussion, or with additional reviewers. We maintain an active forum to facilitate permanent contact among reviewers.

The results of the searches and the study inclusion processes will be reported and presented in a flow diagram following the PRISMA-ScR recommendations [ 22 ].

Expert consultation

The protocol has been refined after consultation with experts in each field (cancer, CVD, and neurodegenerative diseases) who gave input on the scope of the reviews regarding the diverse biomarkers, risk factors, outcomes, and types of prevention relevant to their fields of expertise. In addition, the search strategies have been peer-reviewed by a network of librarians (PRESS-forum in pressforum.pbworks.com) who kindly provided useful feedback.

Data extraction

We have developed a draft data extraction sheet, which is included as Additional file 4, based on the JBI recommendations [ 21 ]. Data extraction will include citation details, study design, population type, biomarker information (name, type, subtype, clinical utility, use of AI technology), disease (group, specific disease), prevention (primary or secondary, lifestyle if primary prevention), and subjective reviewer observations. The data extraction for all papers will be performed by two reviewers to ensure consistency in the classification of data.

Data analysis and presentation

The descriptive information about the studies collected in the previous phase will be coded according to predefined categories to allow the elaboration of visual summary maps that can allow readers and researchers to have a quick overview of their main results. As in the previous phases, this process will be carried out with the aid of Covidence.

Therefore, a summary of the extracted data will be presented in tables as well as in static and, especially, through interactive evidence gap maps (EGM) created using EPPI-Mapper [ 44 ], an open-access web application developed in 2018 by the Evidence for Policy and Practice Information and Coordinating Centre (EPPI-Centre) and Digital Solution Foundry, in partnership with the Campbell Collaboration, which has become the standard software for producing visual evidence gap maps.

Tables and static maps will be made by using R Studio, which will also be used to clean and prepare the database for its use in EPPI-Mapper by generating two Excel files: one containing the EGM structure (i.e. what will be the columns and rows of the visual table) and coding sets, and another containing the bibliographic references and their codes that reviewers had added. Finally, we will use a Python script to produce a file in JSON format, making it ready for importation into EPPI-Reviewer.

The maps are matrixes with biomarker categories/subcategories defining the rows and diseases serving as columns. They define cells, which contain small squares, each one representing each paper included in it. We will use a code of colours to reflect the study design. There will be also a second sublevel in the columns, depending on the map. Thus, for each group of diseases, we will produce three interactive EGMs: two for primary prevention and one for secondary prevention. For primary prevention, the first map will stratify the data to show whether any or which lifestyle has been considered in each paper in combination with the studied biomarker. The second map for primary prevention and the map for secondary prevention will include, as a second sublevel, the subpopulations in which the biomarker has been used or evaluated, which are disease-specific (i.e. cirrhosis for hepatic cancer) researched. The maps will also include filters that allow users to select records based on additional features, such as the use of artificial intelligence in the content of the papers. Furthermore, the EGM, which will be freely available online, will enable users to view and export selected bibliographic references and their abstracts. An example of these interactive maps with dummy data is provided in Additional file 5.

Finally, we will elaborate on two scientific reports for PROPHET. The main report, which will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) recommendations, will summarise the results of the three scoping reviews, will provide a general and global interpretation of the results and will comment on their implication for the SRIA, and will discuss the limitations of the process. The second report will present the specific methodology for the dynamic maps.

This protocol summarises the procedure to carry out three parallel rapid scoping reviews to provide an overview of the available research and gaps in the literature on biomarkers for personalised primary and secondary prevention for the three most common chronic disease groups: cancer, CVD and neurodegenerative diseases. The result will be a common report for the three scoping reviews and the online publication of interactive evidence gap maps to facilitate data visualisation.

This work will be complemented, in a further step of the PROPHET project, by a subsequent mapping report on the scientific evidence for the clinical utility of biomarkers. Both reports are part of an overall mapping effort to characterise the current knowledge and environment around personalised preventive medicine. In this context, PROPHET will also map personalised prevention research programs, as well as bottlenecks and challenges in the adoption of personalised preventive approaches or in the involvement of citizens, patients, health professionals and policy-makers in personalised prevention. The overall results will contribute to the development of the SRIA concept paper, which will help define future priorities for personalised prevention research in the European Union.

In regard to this protocol, one of the strengths of this approach is that it can be applied in the three scoping reviews. This will improve the consistency and comparability of the results between them, allowing for better leveraging of efforts; it also will facilitate the coordination among the staff conducting the different reviews and will allow them to discuss them together, providing a more global perspective as needed for the SRIA. In addition, the collaboration of researchers with different backgrounds, the inclusion of librarians in the research team, and the specific software tools used have helped us to guarantee the quality of the work and have shortened the time invested in defining the final version of this protocol. Another strength is that we have conducted a pilot study to test and refine the search strategy, selection criteria and data extraction sheet. In addition, the selection of the platform of access to the bibliographic databases has been decided after a previous evaluation process (Ovid-MEDLINE versus PubMed MEDLINE, Ovid-Embase versus Elsevier-Embase, etc.).

Only 10% of the papers will undergo screening by two reviewers, and if time permits, we will conduct kappa statistics to assess reviewer agreement during the screening phases. Additionally, ongoing communication and the exchange and discussion of uncertainties will ensure a high level of consensus in the review process.

The main limitation of this work is the very broad field it covers: personalised prevention in all chronic diseases; however, we have tried to maintain decisions to limit it to the chronic diseases with the greatest impact on the population and in the last 3 years, making a rapid scoping review due to time constraints following recommendations from the Cochrane Rapid Review Methods Group [ 24 ]; however, as our aim is to identify gaps in the literature in an area of growing interest (personalisation and prevention), we believe that the records retrieved will provide a solid foundation for evaluating available literature. Additionally, systematic reviews, which may encompass studies predating 2020, have the potential to provide valuable insights beyond the temporal constraints of our search.

Thus, this protocol reflects the decisions set by the PROPHET's timetable, without losing the quality and rigour of the work. In addition, the data extraction phase will be done by two reviewers in 100% of the papers to ensure the consistency of the extracted data. Lastly, extending beyond these three scoping reviews, the primary challenge resides in amalgamating their findings with those from numerous other reviews within the project, ultimately producing a cohesive concept paper in the Strategy Research and Innovation Agenda (SRIA) for the European Union, firmly rooted in evidence-based conclusions.

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Acknowledgements

We are grateful for the library support received from Teresa Carretero (Instituto de Salud Carlos III, ISCIII) and, from Concepción Campos-Asensio (Hospital Universitario de Getafe, Comité ejecutivo BiblioMadSalud) for the seminar on the Scoping Reviews methodology and for their continuous teachings through their social networks.

Also, we would like to thank Dr. Héctor Bueno (Centro Nacional de Investigaciones Cardiovasculares (CNIC), Hospital Universitario 12 de Octubre) and Dr. Pascual Sánchez (Fundación Centro de Investigación de Enfermedades Neurológicas (CIEN)) for their advice in their fields of expertise.

The PROPHET project has received funding from the European Union’s Horizon Europe research and innovation program under grant agreement no. 101057721. UK participation in Horizon Europe Project PROPHET is supported by UKRI grant number 10040946 (Foundation for Genomics & Population Health).

Author information

Plans-Beriso E and Babb-de-Villiers C contributed equally to this work.

Kroese M and Pérez-Gómez B contributed equally to this work.

Authors and Affiliations

Department of Epidemiology of Chronic Diseases, National Centre for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain

E Plans-Beriso, C Barahona-López, P Diez-Echave, O R Hernández, E García-Ovejero, O Craciun, P Fernández-Navarro, N Fernández-Larrea, E García-Esquinas, M Pollan-Santamaria & B Pérez-Gómez

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain

E Plans-Beriso, D Petrova, C Barahona-López, P Diez-Echave, O R Hernández, N F Fernández-Martínez, P Fernández-Navarro, N Fernández-Larrea, E García-Esquinas, V Moreno, F Rodríguez-Artalejo, M J Sánchez, M Pollan-Santamaria & B Pérez-Gómez

PHG Foundation, University of Cambridge, Cambridge, UK

C Babb-de-Villiers, H Turner, L Blackburn & M Kroese

Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain

D Petrova, N F Fernández-Martínez & M J Sánchez

Escuela Andaluza de Salud Pública (EASP), Granada, Spain

Cambridge University Medical Library, Cambridge, UK

National Library of Health Sciences, Instituto de Salud Carlos III, Madrid, Spain

V Jiménez-Planet

Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, 08908, Spain

Colorectal Cancer Group, ONCOBELL Program, Institut de Recerca Biomedica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08908, Spain

Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, Spain

F Rodríguez-Artalejo

IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain

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Contributions

BPG and MK supervised and directed the project. EPB and CBV coordinated and managed the development of the project. CBL, PDE, ORH, CBV and EPB developed the search strategy. All authors reviewed the content, commented on the methods, provided feedback, contributed to drafts and approved the final manuscript.

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Correspondence to E Plans-Beriso .

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Additional file 1: glossary., additional file 2: glossary of biomarkers that may define high risk groups., additional file 3: search strategy., additional file 4: data extraction sheet., additional file 5: example of interactive maps in cancer and primary prevention., rights and permissions.

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Plans-Beriso, E., Babb-de-Villiers, C., Petrova, D. et al. Biomarkers for personalised prevention of chronic diseases: a common protocol for three rapid scoping reviews. Syst Rev 13 , 147 (2024). https://doi.org/10.1186/s13643-024-02554-9

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DOI : https://doi.org/10.1186/s13643-024-02554-9

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