Health
Grant funds research to identify drug targets for autism and schizophrenia using human stem cell models
The research aims to uncover the molecular and cellular mechanisms underlying autism and schizophrenia and to identify drug targets for both conditions.
Mohammed Mostajo-Radji.
Photo by Carolyn Lagattuta.
Mohammed Mostajo-Radji, a research scientist at the University of California, Santa Cruz, will serve as an investigator for a $13.9 million grant from the California Institute for Regenerative Medicine (CIRM). The research, led by scientists at UC Los Angeles, will use human stem cell-based models to uncover the molecular and cellular mechanisms underlying autism and schizophrenia and to identify drug targets for both conditions.
Mostajo-Radji is a researcher at the UC Santa Cruz Genomics Institute and a member of the Braingeneers group. The campus will receive around $1.2 million for this effort.
Autism and schizophrenia affect tens of millions of people in the U.S., yet no drugs exist that target their underlying biology—largely because researchers don’t yet know precisely how brain cells from people with these conditions differ, at the molecular level, from those of neurotypical individuals, leaving nothing concrete against which to screen drugs.
“Right now, there’s virtually no roadmap for developing treatments for these conditions,” said Daniel Geschwind, a distinguished professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA. “This work is focused on solving that problem by studying many variants in parallel, which will provide an initial roadmap for our lab, for other researchers, and for the pharmaceutical companies that could eventually take these findings into the clinic.”
Both conditions are thought to have strong genetic components that emerge as early as prenatal brain development, but those early molecular differences have never been systematically characterized across a representative patient population—leaving the drug development pipeline effectively stalled before it starts. To address this gap, the multidisciplinary team will pursue two parallel scientific strategies, each targeting a different dimension of genetic risk.
The first focuses on specific, well-documented genetic variants already known to raise the risk of autism or schizophrenia. The team will introduce autism- and schizophrenia-linked variants into human stem cell models, then coax those cells to grow into miniature, brain-like structures. By studying the molecular, structural and electrical properties of these models, the team aims to pinpoint exactly how each genetic variant alters brain development.
As part of this, Mostajo-Radji’s will focus on understanding how different genetic mutations underlying neuropsychiatric disorders show up at the electrophysiological, or “circuit” level, in the brain. Recent research out of UCLA has demonstrated that mutations come together at a common point early in brain development, so Mostajo-Radji will build upon these findings to investigate how different mutations might create common circuit-level changes.
“Neuropsychiatric disorders are linked to hundreds of different genetic mutations, and so one of the big questions is how changes in so many different parts of a cell can lead to similar conditions,” Mostajo-Radji said. “This work asks whether these different mutations can lead to similar changes in how brain cells communicate and function as a network. We are aiming to understand how mutations affect brain circuits, and ultimately create better ways to study and treat these conditions.”
The second strategy addresses a harder and more common problem: in the vast majority of autism and schizophrenia cases, no single genetic variant can be identified as the cause.
To address this, the researchers will use an approach called “cell villages,” in which they will grow and examine stem cell-derived brain cells from more than 100 people with autism, more than 100 people with schizophrenia and more than 100 people without either condition together in a single shared dish. This enables them to evaluate the cells without interference from the subtle variations in temperature, oxygen levels and evaporation that occur when cells are grown in separate dishes.
“By putting everyone’s cells together in the same dish, we improve our ability to detect meaningful biological differences between patients and neurotypical controls,” said Michael F. Wells, a co-investigator on the grant and an assistant professor of human genetics at UCLA. “We also reduce costs dramatically: what might otherwise require tens of thousands of sequencing samples can be done with dozens to hundreds.”
If successful, the work could open the door to something that doesn’t yet exist: a reliable way to screen drug compounds against autism and schizophrenia in the lab. In the final phase of the project, the team will test up to ten compounds in models of these conditions to see which, if any, can reverse the cellular differences observed. Those that do would represent strong candidates for further clinical investigation.
Throughout the research, the team is committed to ensuring the findings from this work can benefit all patients with these conditions, regardless of their background. Studies to date have primarily relied on cell lines derived from individuals of European ancestry. In contrast, the studies supported by this grant will include cell lines from donors of Hispanic/Latino, African American and European backgrounds.
“For us it’s all about representation,” Wells said. “Many drugs that work in one ancestral population do not work as well in others because those individuals were not included in the preclinical studies. At least here, we can ensure a broad array of genetic variation is included from the start.”
CIRM was created by the people of California to fund stem cell and gene therapy research with the goal of accelerating treatments for patients with unmet medical needs. With $8.5 billion in funding allocated through both Proposition 71 in 2004 and Proposition 14 in 2020, CIRM supports stem cell and gene therapy discoveries from inception through clinical trials, trains a workforce in California to fill jobs in the state’s thriving biotech and biomedical research industry, and creates infrastructure to make clinical trials accessible for people throughout California.