Optimized AAV vector enables potent therapeutic rescue of inherited glycosylphosphatidylinositol deficiency in mice.

Thirty genes are involved in the biosynthesis and modification of glycosylphosphatidylinositol (GPI)-anchored proteins. Defects in these genes cause inherited GPI deficiency, whose main clinical features include intellectual disability, developmental delay, and intractable seizures, and sometimes hyperphosphatasia and multiple congenital anomalies. The mechanisms of its systemic, especially neurological, manifestations largely remain unclear, and no fundamental therapy has yet been established. In this study, we report the development of effective adeno-associated virus (AAV)-mediated gene therapy using a mouse model of inherited GPI deficiency caused by phosphatidylinositol glycan anchor biosynthesis class O (PIGO) mutations, with the aim of developing gene therapy applicable to human patients. By optimizing AAV vectors with the most effective and safest promoter, we achieved significant amelioration of neuronal phenotype and growth impairment, with no cases of liver cancer observed. We further determined the optimal administration route and therapeutic dose required for effective systemic delivery. These results provide proof of concept for the therapeutic efficacy of AAV-based gene replacement therapy for inherited GPI deficiency.