Rescue of Iqsec2 Knockout Mice with Human IQSEC2 Adeno-Associated Virus Mediated Gene Therapy

The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked <i>IQSEC2</i> gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the <i>IQSEC2</i> gene, 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 the <i>IQSEC2</i> gene could rescue abnormal phenotypes in mice in two different <i>Iqsec2</i> mouse models with premature <i>Iqsec2</i> termination codons resulting in a knockout of the <i>Iqsec2</i> gene expression and in mice with an A350V <i>Iqsec2</i> missense mutation. In the <i>Iqsec2</i> knockout 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 endogenous <i>Iqsec2</i> allele by viral <i>IQSEC2</i>. We propose that the success in the <i>Iqsec2</i> knockout mice warrants a proof-of-concept study for gene replacement therapy in boys with <i>IQSEC2</i> premature termination variants.