A UC San Francisco–led research team, supported by a $12.2 million grant from the California Institute for Regenerative Medicine (CIRM), is exploring how stem cell and gene therapies could help treat neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism.
The project is led by Alex Pollen, PhD, of UC San Francisco. His team aims to identify the genetic roots of autism spectrum disorder (ASD) and develop new diagnostic tools. The group includes UCSF researchers Martin Kampmann, PhD, and Elliott Sherr, MD, PhD; UC Berkeley’s Saul Kato, PhD, and Helen Bateup, PhD; and UC Santa Cruz investigators Sofie Salama, PhD, Mircea Teodorescu, PhD, Mohammed Mostajo‑Radji, PhD, and David Haussler, PhD.
This work is part of CIRM’s Research using Multidisciplinary, Innovative approaches in Neuro Diseases (ReMIND) program. ReMIND supports large collaborative teams that use advances in stem cell and genetic research to address major gaps in the study of neuropsychiatric disorders.
CIRM spoke with Dr. Pollen about the project. His responses have been edited for clarity and brevity.
What are the questions that this project is hoping to address?
Dr. Pollen: This project will identify the genetic foundations of ASD and create new diagnostic tools. The team will use patient‑derived neural organoids—clusters of neurons and other cell types—to pinpoint “ASD phenotypes in a dish.” Researchers will then confirm these lab‑based phenotypes using MRI scans and clinical data from the same patients.
We will use these validated phenotypes to test new drug candidates, identified through diversity analysis of human brain samples linked to ASD risk. Some genetic backgrounds show lower rates of ASD, and secondary genetic mutations can influence disease severity. We will identify these secondary mutations, known as genetic modifiers, and develop gene therapy strategies to adjust their activity in ASD cells.
Our research will produce a set of clinically validated ASD phenotypes for laboratory studies, early tests of gene therapy targeting genetic modifiers, an ASD classification tree, and potentially new biomarkers.
What are some research challenges you’d like to overcome through this project?
Dr. Pollen: We hope to identify gene therapy targets for ASD that are based on genetic disease modifiers rather than a correction of the ASD genes themselves. Additionally, we hope to identify new ASD biomarkers and build a decision tree that doctors can use to diagnose patients early and treat patients based on their genetic background.
With expertise spanning from molecular biologists, bioengineers, clinicians, computational biologists, geneticists, and individuals with previous expertise in clinical translation, we believe we are in the perfect position to translate research from the bench to industry in a short time frame.
What are some ways this research project can positively impact patients across California and the world?
Dr. Pollen: ASD affects one in 22 children in California. It has no cure and causes social, cognitive, motor, and sensory challenges. The estimated lifetime social cost is $3.6 million per patient.
People with ASD often struggle in the workplace because multitasking and maintaining focus can be difficult. Communication challenges and repetitive or inflexible behaviors can also lead to unemployment and social isolation.
The neurobiology of ASD is still unclear. Understanding how ASD‑related mutations disrupt biological pathways will reveal new therapeutic targets. Although hundreds of genes are linked to ASD, patients with the same mutation can show very different symptoms.
Some gene variants also show variable effects across populations. We will take advantage of these differences by identifying beneficial genetic modifiers that delay or reduce disease severity. We will then explore gene therapy approaches to target these modifiers as a potential treatment for ASD.
CIRM: In your words, can you share why research for neuropsychiatric disorders and diseases affecting the Central Nervous System (CNS) is so important?
Dr. Pollen: Research for neuropsychiatric disorders and diseases affecting the CNS is important because of the high prevalence and, therefore, the large burden it poses on society. In the United States, mental and neurological conditions collectively cost the economy over $1.5 trillion annually, accounting for approximately 8.8% of the nation’s gross domestic product.
Despite advancements in neuroscience, many mechanisms underlying CNS and, specifically, neuropsychiatric disorders remain poorly understood. Research can provide insights into the molecular and genetic factors contributing to these conditions and help identify pathways to target for disease treatment.
The ReMIND program is a pilot for collaborative, multi-investigator funding for foundational basic discovery research. What sort of impact might it have?
Dr. Pollen: Many pressing scientific and societal challenges, such as understanding neuropsychiatric and CNS disorders, require large-scale, multi-faceted approaches. Multi-investigator funding facilitates interdisciplinary collaboration, therefore making it feasible to tackle complex scientific questions that require expertise in various fields, from biology to engineering.
Multi-investigator funding can also lead to innovative solutions that may not emerge from single-investigator efforts. Different perspectives often challenge conventional thinking, leading to breakthroughs that may not arise in single-investigator projects.
On an educational level, large research teams provide opportunities for trainees and junior scientists to be mentored by investigators other than their main supervisor, exposing them to various methodologies and perspectives.
We believe that multi-investigator funding has the potential to revolutionize academic research by enabling teams to address large, complex questions, promoting interdisciplinary collaboration, driving innovation, and enhancing the mentoring of the next generation of scientists.
Can you describe CIRM’s impact over the last 20 years?
Dr. Pollen: CIRM has made a great impact in facilitating and enhancing the use of stem cells and gene therapy in biomedical research, from basic science to clinical translations of therapies and tools. From my perspective as a basic scientist, the CIRM funding has made California a worldwide center of excellence in stem biology across institutions, and the CIRM Bridges program, combined with PhD and postdoc training grants, has supported a new generation of stem cell biologists poised to make a big impact in the field. With respect to translation, it is exciting to see California-based companies fueled by this talent now making progress in the clinic.
Learn more about the ReMIND program at cirm.ca.gov/remind.