Preclinical Autism Research | Icahn School of Medicine

SEAVER AUTISM CENTER FOR RESEARCH AND TREATMENT

Preclinical Research

The Seaver Autism Center for Research and Treatment’s preclinical research team employs innovative molecular, cellular, and model systems approaches to unravel the complex pathobiology of autism. Our studies are firmly grounded in genetic and genomic discoveries, seamlessly coordinated with our clinical research efforts to ensure a comprehensive understanding of autism spectrum disorder. Central to our approach is the "genetics-first" methodology, leveraging the identification of several hundred high-risk autism genes to create model systems with strong construct validity for autism. This unique opportunity allows us to deploy high-throughput methods to examine common pathways shared across these genes, focusing on high-confidence autism risk genes such as ADNP, ARID1B, CACNA1, CHAMP1, CHD8, DDX3X, DYRK1A, FOXP1, NF1/2, and SHANK2/3, among others.

A cornerstone of our preclinical research is the use of induced pluripotent stem cells. These patient-derived or engineered stem cells provide an invaluable platform for mechanistic studies of autism genes on human neural development. By allowing us to study human nerve and glial cell function in the context of autism genetic variation, these models offer unprecedented insights into the cellular basis of autism. Our researchers utilize both two-dimensional cultures and three-dimensional organoid cultures, subjecting them to extensive molecular characterization. This approach not only helps us evaluate cellular phenotypes associated with autism-related mutations but also facilitates drug screening and validation. Additionally, we are deploying large-scale CRISPR approaches to identify convergent pathways dysregulated by mutations in diverse autism genes, further expanding our understanding of the disorder's underlying mechanisms.

Complementing our in vitro studies, we also conduct in-depth characterizations of mouse and rat models with mutations in several autism risk genes, including ADNP, DDX3X, FOXP1, and SHANK3. These in vivo models provide objective measures of how the loss of these genes affects nerve cell connectivity, synaptic plasticity, and cognitive, motor, and social behavior. Importantly, these models serve as platforms for drug efficacy studies, bridging the gap between basic science and clinical applications. A prime example of this translational approach is our work with SHANK3-deficient mice, where treatment with Insulin-Like Growth Factor-1 (IGF-1) showed promising results in ameliorating synaptic plasticity and motor deficits. These preclinical findings have directly led to clinical trials testing the effects of IGF-1 and Growth Hormone in individuals carrying SHANK3 mutations or individuals with idiopathic autism, exemplifying our commitment to translating laboratory discoveries into potential treatments for individuals with autism.