AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Inherited GPI deficiency (IGD) results from defects in genes for glycosylphosphatidylinositol (GPI)-anchored protein biosynthesis.
• The PIGA gene, crucial for the first step of GPI synthesis, is X-linked, primarily affecting males and causing severe neurological abnormalities.

Purpose of the Study:

• To investigate the efficacy of gene replacement therapy using adeno-associated virus (AAV) in CNS-specific Piga knockout mouse models of IGD.
• To assess the therapeutic potential and identify potential risks, such as tumorigenesis, associated with AAV-mediated gene therapy.

Main Methods:

• Generation of CNS-specific Piga knockout mice by crossing Nestin-Cre with Piga-floxed mice.
• Administration of AAV vector for gene replacement therapy in Piga-deficient mice.
• Evaluation of survival rates, growth, and myelination, alongside long-term monitoring for adverse effects like cancer.

Main Results:

• CNS-specific Piga KO male mice exhibited early lethality (P10) with growth defects; female mice showed severe growth and myelination deficits, dying by P25.
• AAV gene therapy significantly extended survival in male mice (up to 3 weeks) and improved growth.
• Approximately 40% of treated female mice survived for a year with improved growth, but all developed liver cancer, likely due to the strong CAG promoter in the AAV vector.

Conclusions:

• Gene replacement therapy with AAV demonstrates therapeutic efficacy in mitigating the severe phenotypes of Piga deficiency in mice.
• The development of liver cancer in treated mice highlights a significant safety concern associated with the use of strong promoter-driven AAV vectors, necessitating further research into safer delivery systems.