Gene replacement therapy for Piga GPI-anchor deficiency in the developing nervous system

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Glycosylphosphatidylinositol (GPI) anchors are crucial post-translational modifications for over 150 proteins.
• Pathogenic variants in the GPI biosynthesis enzyme PIGA cause severe brain anomalies and mortality in humans.
• Existing treatments for PIGA patients are palliative, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To evaluate the efficacy of AAV9-mediated PIGA gene replacement therapy in a mouse model of PIGA deficiency.
• To assess the impact of gene therapy on survival, brain structure, and neurological function in PIGA-mutant mice.

Main Methods:

• Genetic deletion of Piga in embryonic mouse brains to model human PIGA variants.
• Single intracerebroventricular administration of AAV9-hPIGA on the first day of life.
• Mass spectrometry to quantify GPI-anchored proteins in treated and untreated mice.

Main Results:

• AAV9-hPIGA treatment significantly improved survival rates in PIGA-mutant mice.
• Gene therapy corrected structural brain malformations and neurological impairments.
• Mass spectrometry confirmed restoration of GPI-anchored protein levels post-treatment.

Conclusions:

• AAV9-mediated PIGA gene replacement is a promising therapeutic strategy for PIGA-related disorders.
• This approach offers a potential intervention for improving brain development and function in affected individuals.
• The study advances understanding of GPI-anchored protein regulation during brain development.