Chromosome 15q, Trisomy

A groundbreaking study 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. 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."

When Takeda Pharmaceutical and Ovid Therapeutics began working together four years ago, the partners aimed to share in the development of a drug with the potential to treat rare forms of epilepsy. The partners are ending the alliance, but Takeda leaves with full rights to a Phase 3 ready compound while Ovid gains $196 million to support its own pipeline of neurological disease drugs. Under terms of a new agreement announced Wednesday, Takeda assumes responsibility for further clinical development and potential commercialization of the drug, soticlestat. Ovid stands to earn up to $660 million in milestone payments. If Tokyo-based Takeda succeeds in bringing the drug to the market, it will owe its former partner royalties from sales. The transaction is a homecoming for soticlestat, a small molecule that was originally discovered in Takeda’s labs. In 2017, Takeda licensed the drug to Ovid but arranged to remain part of the drug’s future. The agreement called for both companies to share equally in research and development expenses. If the drug reached the market, the partners agreed to split the profits equally. Ovid tested soticlestat in Dravet syndrome and Lennox-Gastaut syndrome, two rare forms of epilepsy. The drug is designed to block 24 hydroxylate (24HC), an enzyme found only in the brain. Elevated levels of this enzyme have been linked to activation of NMDA receptors, which play a role in epilepsy. By blocking the key enzyme, soticlestat is intended to reduce signaling from NMDA receptors. In 2020, Ovid reported Phase 2 results showing that the drug met the main study goal of reducing seizure frequency in children who have Dravet or Lennox-Gastaut. Last September, the company reported additional clinical data in CDKL5 deficiency disorder and 15q duplication syndrome, two other rare forms of epilepsy. The study was small and not designed to show statistical significance. But the results provided additional validation for the compound’s approach to treating seizures. Full control of soticlestat gives Takeda the opportunity to compete against other drugs that have reached the market for Dravet and Lennox-Gastaut. Cannabis-derived drug Epidiolex won FDA approval in 2018. Last month, Jazz Pharmaceuticals announced a $7.2 billion deal to acquire that drug’s maker, GW Pharmaceuticals. Last year, Zogenix won FDA approval for Fintepla, a drug developed to treat Dravet. The new agreement between Takeda and Ovid gives the small biotech an opportunity to recover from the failure of OV101, a drug candidate for Angelman syndrome, a rare inherited disorder that leads to developmental delays and cognitive difficulties. Last December, Ovid reported that the drug did not meet the main goal of a Phase 3 study. Ovid plans to move on to other drugs. Speaking on a conference call, CEO Jeremy Levin said that the upfront payment alone represents four times what his company spent on soticlestat’s development since beginning the collaboration. That payment, and plus the milestone payments tied to the compound’s progress, provide Ovid with the capital to support its drug pipeline, which Levin said has three compounds for rare neurological disorders on track to begin clinical testing in the next three years, starting in the first half of 2022. One of those compounds, OV882, is another potential Angelman treatment. Levin said that Ovid has learned a great deal from its neuroscience drug research to date, and the company will apply that knowledge to its current drug candidates and potential new assets. Levin left the door open for another deal like the one Ovid initially reached with Takeda in 2017. “We’re really interested in novel, first in class, genetically focused mechanisms,” Levin said. “Some of these are obviously in smaller biotechs, private companies. Others of them actually are in larger pharmaceutical companies. One of the struggles that these companies have is that they have these interesting constructs. They’re able to drive the early research but what they can’t do is understand how to translate that into a product that you can develop—and we really understand that.” Takeda and Ovid expect the new agreement will close by the end of this month. Public domain photo by Flickr user affen ajlfe