Rescue ofKnockout Mice with Human IQSEC2 Adeno-Associated Virus Mediated Gene Therapy.

Abstract

The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linkedgene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into thegene, resulting in little or no IQSEC2 protein being produced. Approximately 20% of cases are missense variants in the seven functional domains of the IQSEC2 protein. We sought to determine whether an adeno-associated virus (AAV) containing thegene could rescue abnormal phenotypes in mice in two differentmouse models with prematuretermination codons resulting in a knockout of thegene expression and in mice with an A350Vmissense mutation. In theknockout mice, the AAV significantly improved growth, corrected behavioral abnormalities, and normalized the seizure threshold. Behavioral abnormalities were partially rescued in A350V mice, which expression studies suggest may have been due to the feedback inhibition of the endogenousallele by viral. We propose that the success in theknockout mice warrants a proof-of-concept study for gene replacement therapy in boys withpremature termination variants.