Gene therapy for IQSEC2 disease

Mutations in the IQSEC2 gene account for 2-5% of children presenting with intellectual disability, autism and drug resistant seizures. Gene therapy using adeno-associated virus (AAV) is a promising strategy to provide a good copy of a gene mutated in disease in order to treat affected children. However, the IQSEC2 gene is too big to fit into the virus. In this proposal, we provide preliminary data and an algorithm for the design of an IQSEC2 “minigene” that will work with AAV gene therapy. Our algorithm for designing the minigene is based on clinical, biochemical and computer-based modeling of the IQSEC2 gene. Using this algorithm, we have screened several hundred thousand potential permutations of deletions of IQSEC2 to create an IQSEC2 minigene. The specific aims of this proposal will assess if this approach can prevent abnormal activity in brain cells derived from children with diverse IQSEC2 mutations, rescue mice with IQSEC2 mutations from having seizures and behavioral abnormalities, and identify the developmental window when this therapy must be performed to be therapeutic.