Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy

Inherited glycosylphosphatidylinositol (GPI) deficiency (IGD) is caused by mutations in GPI biosynthesis genes. The mechanisms of its systemic, especially neurological, symptoms are not clarified and fundamental therapy has not been established. Here, we report establishment of mouse models of IGD caused by PIGO mutations as well as development of effective gene therapy. As the clinical manifestations of IGD are systemic and lifelong lasting, we treated the mice with adeno-associated virus for homology-independent knock-in as well as extra-chromosomal expression of Pigo cDNA. Significant amelioration of neuronal phenotypes and growth defect was achieved, opening a new avenue for curing IGDs. Inherited GPI deficiency (IGD) is caused by PIGO mutations. Here, the authors generate a mouse model of IGD and show that AAV-mediate gene therapy, for knock-in as well as extra-chromosomal expression of Pigo cDNA, ameliorates pathology in the mice.