Several forms of syndromic autism have as a common feature changes in N-methyl-D-aspartate (NMDA) receptors. Most notably, GRIN disorder is a rare genetic disorder caused by de novo missense mutations in the NMDA receptor-encoding GRIN genes (GRIN1, GRIN2A, GRIN2B and GRIN2D). People with GRIN disorder have autism-related symptoms that include differences in speech and communication, repetitive movements, movement disorders, intellectual challenges, epilepsy, behavioral symptoms and sensory deficits (cortical visual impairment and acoustic hypersensitivity).
The current project, led by Amy Ramsey, brings together NMDA receptor neuroscientists with a pediatric neurologist (who is leading a clinical trial for GRIN disorder) and with biotech researchers who specialize in gene therapy. The goal is to test the efficacy and tolerability of gene replacement as a strategy to treat GRIN disorder.
The research team plans to study three mouse models of GRIN disorder with loss- or gain-of-function variants in GRIN1 and GRIN2B. Three cargo genes will be tested in two adeno-associated virus (AAV) capsids using two different routes of administration. Autism-relevant behavioral outcomes, electrophysiological phenotypes, and histological measures of efficacy and toxicity will be assessed. Partnerships between physicians, industry, and patient advocacy groups will ensure that these research studies have the best possible chance of being translated into medical practice.
- Development of CRISPR activation therapeutics to rescue SCN2A function
- CRISPR/Cas9-based early intervention for Angelman syndrome
- Leveraging systemic adeno-associated viral vectors to ameliorate autism-associated phenotypes in a mouse model of neurofibromatosis type 1
- Development of genetic therapies for STXBP1 haploinsufficiency