Exploring the Genetic Foundations of Autism and Gene Therapy Treatments

As outlined in Proposition 14, one of the goals of the California Institute for Regenerative Medicine (CIRM) is to help accelerate discoveries that enhance our understanding of central nervous system (CNS) disorders. As part of this goal, CIRM launched the Research using Multidisciplinary, Innovative approaches in Neuro Diseases (ReMIND) Program in 2023 with the ReMIND-L (DISC4) awards.

Through the 2024 ReMIND-L awards, CIRM is supporting large, collaborative research teams conducting expansive, integrated research projects, utilizing recent advancements in stem cell and genetic research, to address critical gaps in the study of neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and other conditions that significantly affect patients and caregivers throughout California.

Alex Pollen, PhD, of UC San Francisco (UCSF) and a team of co-investigators were awarded $12.2 million for basic research that aims to uncover the genetic foundations of autism spectrum disorder (ASD or Autism) and develop innovative diagnostic tools.

Co-investigators in the project include Martin Kampmann, PhD; Elliott Sherr, MD, PhD, also from UCSF; Saul Kato, PhD; Helen Bateup, PhD, of UC Berkeley; Sofie Salama, PhD; Mircea Teodorescu, PhD; Mohammed Mostajo-Radji, PhD; and David Haussler, PhD of UC Santa Cruz.

CIRM connected with Dr. Pollen to learn more about the project and how the team will use patient-derived neural organoids to identify ASD phenotypes in the lab, validate them with MRI and clinical data, and test potential drug candidates.

Some responses have been edited for clarity and brevity:

CIRM: Please share a summary of your research project. Is there a particular disease focus? Is there a broader question that this project is hoping to address?

Dr. Pollen: This project will uncover the genetic underpinnings of ASD and develop new diagnostic tools. The team will employ patient-derived neural organoids - complex assemblies of neurons and other cell types - to identify "ASD phenotypes in a dish." Researchers will then validate these "lab" phenotypes with MRI brain scans and clinical data from the patients.

We will use these clinically validated phenotypes to test new drug candidates, which we will identify through diversity analysis in human brain samples for ASD risk. Certain genetic backgrounds show a reduced prevalence of ASD, and secondary genetic mutations can modify disease severity. We will identify these secondary genetic mutations, called genetic modifiers, and develop gene therapy approaches to modulate their expression in ASD cells.

The outcome of our research will be a set of clinically validated ASD phenotypes for research in the lab, an initial testing of gene therapy for genetic modifiers to rescue clinically validated ASD phenotypes, an ASD classification tree, and potentially new biomarkers.

CIRM: What are some of the discoveries you're hoping to achieve through this research project? Can you please tell us about them? 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.

CIRM: What are some ways this research project can positively impact patients across California and the world? Alternatively, what are the ways in which this research could change the way this disease is considered or studied by other scientists?

Dr. Pollen: ASD affects one in 22 children in California, is untreatable, and is characterized by social, cognitive, motor, and sensory deficits.The estimated social cost is $3.6 million per patient.

Individuals affected with ASD can be challenged at work because of their difficulty in balancing multitasking and focus. Additionally, challenges with communication and repetitive or inflexible behaviors often result in unemployment and isolation.

The neurobiology of ASD remains unresolved. Understanding the pathways through which ASD mutations cause disease will uncover new therapeutic targets. And while hundreds of genes have been linked to ASD, across patients with the same ASD mutation, diverse symptoms develop.

Additionally, certain gene variants show variable expressivity across populations. We will exploit this aspect of ASD genetics by identifying genetic modifiers that are beneficial and delay or inhibit disease development and severity. We will then target these genetic modifiers with gene therapy for ASD treatment.

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.

CIRM: The ReMIND program is a pilot for collaborative, multi-investigator funding for foundational basic discovery research. Could you speak to the timeliness and impact of such funding structures more broadly and why you think such funding structures will be impactful for CIRM's mission?

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.

CIRM: CIRM is celebrating its 20-year anniversary this year. In your words, 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.