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Potential schizophrenia treatment, discovered at Vanderbilt and being developed by Neumora Therapeutics, entering Phase 1 clinical trial 

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Dec 4, 2023, 12:49 PM

A potential schizophrenia treatment discovered through the Warren Center for Neuroscience Drug Discovery has been cleared by the U.S. Food and Drug Administration for use in phase 1 clinical trials—the third WCNDD therapeutic to reach that benchmark.  

“Vanderbilt is proud that a discovery by our researchers at the Warren Center is now a significant step closer to helping improve the lives of people with schizophrenia,” Chancellor Daniel Diermeier said. “Our work with Neumora is the very definition of translational research and the work we aim to do every day, which is applying innovation and discovery to help address the world’s most complex challenges.”   

The clinical trial has been initiated by Neumora Therapeutics Inc. , a clinical-stage biopharmaceutical company founded to confront the global brain disease crisis by taking a fundamentally different approach to the way treatments are developed. Vanderbilt and Neumora signed an exclusive, worldwide license and a research collaboration agreement for two novel series of M4 receptor modulator compounds, including NMRA-266, in February 2022.  

Vanderbilt’s agreement with Neumora was centered around the M 4 muscarinic receptor, which NMRA-266 targets through positive allosteric modulation. In preclinical studies conducted by Conn and Lindsley, NMRA-266 was found to be highly selective to the M 4 receptor, the area of the brain that regulates neurotransmission of dopamine. Overactive transmission of dopamine is connected to the positive, negative and cognitive symptoms of schizophrenia.   

“The M 4 PAM story has been a Homer-style Odyssey to get to this point and represents almost 20 years of research funded by National Institutes of Health, the William K. Warren Foundation and pharmaceutical companies,” said Lindsley, also a University Professor of pharmacology, biochemistry and chemistry who holds the William K. Warren, Jr. Chair in Medicine. “This mechanism and NMRA-266 represent a potential game-changer for schizophrenic patients and their families. Moreover, this success is a testament to the virtue of academic drug discovery and Vanderbilt’s commitment to supporting the WCNDD, a clinical-stage biotech enterprise within the university.”  

For the WCNDD to have such regular production of clinical assets when up against diverse neuroscience pipeline is unprecedented among academic drug discovery centers, according to Lindsley.  

“NMRA-266 entering phase 1 trials highlights the complementary relationship between university researchers and industry partners,” said Vice Provost for Research and Innovation Padma Raghavan. “By pairing our faculty’s ingenuity with the private sector’s commercialization know-how, we are able to bring life-changing discoveries to patients in need faster.”  

Schizophrenia spectrum disorders affect 3.7 million U.S. adults, a figure up to three times higher than previously understood, according to a recent study . This fundamentally different mechanism that NMRA-266 acts through is very selective for brain circuits involved in schizophrenia, which means in is unlikely to have the adverse effects of current dopamine antagonists—resulting in an improved standard of care for people with schizophrenia.  

“The initiation of this phase 1 study is an important step in the development of NMRA-266. In pre-clinical studies NMRA-266 demonstrated a favorable pharmacologic profile that includes high potency and selectivity for the M 4  receptor subtype, meriting its advancement into the clinic,” Dr. Robert Lenz, executive vice president and head of research and development at Neumora, said in a  release . “With its pre-clinical profile and clinical validation of the M 4  muscarinic receptor class in treating schizophrenia, we believe that NMRA-266 has strong potential as a treatment for neuropsychiatric disorders.”  

Human clinical trials are a significant advancement in a five-step  drug development process . Drug discovery research begins in the lab and is followed by preclinical research to answer basic questions about safety. Then there is clinical research to ensure that the treatment is safe and effective. The FDA then reviews all submitted data. If approved, the therapeutic will be made available for use by the public and be monitored for safety by the FDA for as long as it is available.  

The Vanderbilt-Neumora collaboration was facilitated by the   Center for Technology Transfer and Commercialization . Vanderbilt researchers who contributed to research around NMRA-266 and the power of academic drug discovery include Darren W. Engers , Aaron Bender ,  Olivier Boutaud ,  Thomas Bridges , Julie Engers ,  Alison Gregro , Carrie Jones ,  Colleen Niswender ,  Jerri Rook and Kayla Temple .  

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Schizophrenia articles from across Nature Portfolio

Schizophrenia is a severe and debilitating psychiatric disorder that involves psychotic symptoms such as hallucinations and delusions, accompanied with regressive behaviour.

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Chronic social stressors and striatal dopamine functioning in humans: A systematic review of SPECT and PET studies

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Combination of UGT1A1 polymorphism and baseline plasma bilirubin levels in predicting the risk of antipsychotic-induced dyslipidemia in schizophrenia patients

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Behavioral evidence of impaired self-referential processing in patients with affective disorders and first-episode schizophrenia

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Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

Schizophrenia research has traditionally overlooked sex differences. Here, the authors show the importance of sex-based analysis across multi-brain regions by identifying sex-specific genes and genetic interactions in schizophrenia and sex-specific risk.

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Bridging cholinergic signalling and inflammation in schizophrenia.

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Support for network theories of schizophrenia

A computational neuroimaging study has shed new light on the relationship between morphological changes in the brain in schizophrenia and the network architecture of the brain, providing evidence to support two network theories of the disorder.

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The relationship between prefrontal cortex gray matter volume and subcortical dopamine release - an addendum

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Newly identified structures of trace-amine associated receptor-1 (TAAR1) will aid discovery of next generation neuropsychiatric drugs

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A New Drug Compound Shows Promise for Schizophrenia

F or people with schizophrenia, treatment is an ongoing, life-long process of antipsychotic medications and psychotherapy. Medications are key to controlling episodes, but most have serious enough side effects—including uncontrolled muscle movements, gaining weight and drowsiness—that people skip doses or decide not to take them.

In a study published Dec. 14 in the Lancet , researchers report on a promising new treatment for the psychiatric disorder that could give patients better options. KarXT, developed by biotech company Karuna Therapeutics, targets a different brain chemical than most existing schizophrenia treatments and appears to have fewer side effects.

The study involved 252 people who were hospitalized with schizophrenia and randomly assigned to receive two capsules of KarXT, or a placebo, per day for five weeks. Those taking the drug showed fewer extremes of positive and negative symptoms associated with acute psychosis than those on placebo. Both groups has similar rates of side effects, including constipation, diarrhea, reflux and hypertension.

“This represents a new option, and a new approach in an area where there is still substantial need for advances in treatments,” says Andrew Miller, chief operating officer of Karuna.

Unlike existing schizophrenia treatments, which target the brain chemical dopamine, KarXT targets the muscarinic neurotransmitter system in the brain, which is involved in cognition. The muscarinic receptors on brain cells bind with the brain chemical acetylcholine, which is the target of certain cognition-related treatments for Alzheimer’s disease. In studies that Karuna conducted in these patients, its scientists found that patients with Alzheimer’s-related psychoses seemed to benefit as well. “By targeting a completely different neurotransmitter system, through completely different receptors, clinical data uncovered novel benefits without the problematic side effects of existing treatments,” he says.

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But because muscarinic receptors are found widely throughout the body, creating a drug that targets them was challenging, since it would trigger serious side effects. To solve the problem, Karuna scientists combined its compound with another that blocked the drug from acting outside of the brain. “That enabled the development of KarXT,” Miller says.

Karuna has submitted the results of this trial as part of it request to the U.S. Food and Drug Administration for approval; the agency will make a decision by Sept. 2024.

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Landmark study implicates specific genes in schizophrenia

Scientists analysed dna from more than 300,000 people with and without the psychiatric disorder.

The largest ever genetic study of schizophrenia has identified large numbers of specific genes that could play important roles in the psychiatric disorder.

A group of hundreds of researchers across 45 countries analysed DNA from 76,755 people with schizophrenia and 243,649 without it to better understand the genes and biological processes underpinning the condition.

The Psychiatric Genomics Consortium study, led by scientists at Cardiff University, found a much larger number of genetic links to schizophrenia than ever before, in 287 different regions of the genome, the human body's DNA blueprint.

Furthermore, they showed that genetic risk for schizophrenia is seen in genes concentrated in brain cells called neurons, but not in any other tissue or cell type, suggesting it is the biological role of these cells that is crucial in schizophrenia.

The research team say this global study sheds the strongest light yet on the genetic basis of schizophrenia. It is published today in the journal Nature .

"Previous research has shown associations between schizophrenia and many anonymous DNA sequences, but rarely has it been possible to link the findings to specific genes," said co-lead author Professor Michael O'Donovan, from the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University.

"The present study not only vastly increased the number of those associations, but we have now been able to link many of them to specific genes, a necessary step in what remains a difficult journey towards understanding the causes of this disorder and identifying new treatments."

Schizophrenia is a serious psychiatric disorder that starts in late adolescence or early adulthood and at any one time affects around one in 300 people worldwide, according to the World Health Organization.

In the largest genome-wide association study to date, the research team identified a "substantial increase" in the number of genomic regions associated with schizophrenia. Within these regions, they then used advanced methods to identify 120 genes likely to contribute to the disorder.

As well as being the largest study of its kind, the researchers included more than 7,000 people with either African American or Latino ancestries in what they say is a small step towards making sure advances that come from genetic studies can benefit people beyond those of European ancestries.

Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons, pointing to these cells as the most important site of pathology. The findings also suggest abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms, which can include hallucinations, delusions and problems with thinking clearly.

The team's ability to link to specific genes and areas of biology was enhanced by co-ordinating their work with a companion study involving many of the same scientists, including those from Cardiff University, led by the Broad Institute of Harvard and MIT, and published in Nature in parallel.

That study looked at mutations that, while very rare, have large effects on the small proportion of people that carry them, and found overlapping genes and overlapping aspects of biology.

Professor James Walters, co-lead author on the Cardiff-led paper and Director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University, said: "Whilst people with schizophrenia can recover, many do not respond well to treatments, experience long-term problems with their mental and physical health, as well as impacts on relationships, education and work.

"We hope the findings in this, and the companion studies, can be used to advance our understanding of the disorder and facilitate the development of radically new treatments. However, those processes are often not straightforward, and a lot of work by other neuroscientists is needed to translate the genetic findings into a detailed understanding of disease mechanisms."

The Psychiatric Genomics Consortium is funded by the National Institute of Mental Health (NIMH) of the USA and work in Cardiff was additionally supported by the Medical Research Council.

Dr Joshua Gordon, Director of NIMH, said: "These results, achieved through a global collaboration unprecedented in scope, mark an important step forward in our understanding of the origins of schizophrenia. The findings will allow researchers to focus on specific brain pathways in the ongoing hunt for novel therapies for this serious mental illness."

This study has demonstrated the importance and power of large samples in genetic studies to gain insights into psychiatric disorders. The team are now seeking to recruit more research participants and build larger, more diverse datasets to further advance our understanding of schizophrenia.

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Materials provided by Cardiff University . Note: Content may be edited for style and length.

Journal Reference :

• Vassily Trubetskoy et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia . Nature , 2022; DOI: 10.1038/s41586-022-04434-5

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December 8, 2021

A potential new approach for the treatment of schizophrenia

by Wendy Bindeman , Vanderbilt University

A new study led by Jeff Conn, Lee E. Limbird Chair in Pharmacology, James Maksymetz, a former graduate student in the Conn laboratory, and other collaborators at the Warren Center for Neuroscience Drug Discovery has identified a protein in the central nervous system, known as mGlu1, as a potential target for novel treatments of schizophrenia.

Schizophrenia, which affects approximately 1 percent of the global population, has been historically difficult to treat. Current clinically approved antipsychotics are effective at reducing "positive symptoms" like hallucinations and delusions in some patients, but they fail to treat "negative symptoms," such as social withdrawal, lack of motivation and cognitive deficits associated with the disease. The new research focused on identifying a new approach that would treat positive and negative symptoms, Maksymetz said.

Schizophrenia is thought to occur when a region of the brain called the prefrontal cortex becomes abnormally active because interneurons, which connect neuron circuits or neuron groups, become dysfunctional and stop regulating neuronal activity. Conn's team sought to modulate the activity of those cells.

After identifying mGlu1—an abbreviation of metabotropic glutamate receptor subtype 1—as a potentially druggable target, they tested it with a compound that enhances its function: a positive allosteric modulator. The PAM was previously developed by Conn in close collaboration with other labs in the WCNDD, including those of Craig Lindsley, University Professor of Chemistry and Pharmacology, and Colleen Niswender, associate professor of pharmacology. Using this compound, they found that enhancing the activity of mGlu1 selectively increased the activity of specific inhibitory interneurons, restoring their ability to inhibit the neuronal circuits they control.

Further, the researchers saw that by working with the PAM, symptoms characteristic of schizophrenia in human patients were reversed. These results suggest that using a PAM to enhance mGlu1 activity is an effective treatment for schizophrenia.

Why it matters

Schizophrenia is an important clinical and societal concern. "Inadequate treatment responses and failures to address 'negative symptoms' and cognitive deficits result in poor patient outcomes," Maksymetz said. "And they incur a huge financial burden on the U.S. and global economies."

Researchers hope that this novel treatment strategy "may eventually provide relief for patients, allow them to reintegrate into and contribute to society, and diminish the burden on our health care systems." The results of this research are particularly exciting because the drug reverses working memory deficits, a hallmark of schizophrenia for which there is currently no treatment.

Today's pharmaceutical schizophrenia treatments were serendipitously discovered half a century ago and were not derived from good understanding of disease biology. Decades of clinical findings have improved researchers' understanding of the biological basis of the disease, opening the door for the development of better-targeted, more efficacious drugs. "We reasoned that if we addressed the underlying disease biology by boosting the function of these interneurons, then we might be able to rescue cognitive deficits associated with prefrontal cortex dysfunction," Maksymetz said.

What's next

The results of this study raise a number of questions about mGlu1 biology. Ongoing studies in the Conn lab are investigating the role and effects of mGlu1 in various regions within the brain.

To translate these findings to the clinic, scientists will need to investigate the efficacy of PAMs when used chronically rather than in the short term, evaluate potential side-effects, and determine whether enhancing mGlu1 reduces other symptoms in schizophrenia, especially "negative symptoms" like a lack of motivation and social withdrawal, which are frequently treatment -resistant.

"We think this study is a good foundation to build upon," Maksymetz said. "Hopefully we will be able to test the hypothesis that mGlu1 PAMs can actually treat patients with schizophrenia someday soon. I truly believe that understanding how neural circuits function and dysfunction will lead to a revolution in treating neuroscience-related diseases, and I'm excited to be a part of it."

The research was published in Cell Reports .

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