AAV gene therapy for GBA1-related diseases

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Mutations in the GBA1 gene, encoding glucocerebrosidase (GCase), are a primary genetic risk factor for Parkinson's disease (PD).
• Deficiency in GCase activity leads to lysosomal dysfunction and lipid accumulation, characteristic of GBA-PD and Gaucher disease (GD).
• Current treatments do not fully address the underlying GCase deficiency in these genetic disorders.

Purpose of the Study:

• To develop and evaluate an adeno-associated virus (AAV)-mediated gene therapy strategy for GBA1-related disorders.
• To engineer a secreted form of human GCase for enhanced cross-correction of affected tissues.
• To assess the safety and efficacy of the gene therapy in preclinical models.

Main Methods:

• Engineered a secretable human GCase variant for AAV delivery.
• Utilized conduritol β-epoxide (CBE)-induced lipid accumulation models in mice and non-human primates (NHPs).
• Assessed GCase levels, lipid clearance, and safety in treated NHP brains compared to human donors.

Main Results:

• The lead candidate, AAV.GMU01 SS3-GBA1, demonstrated robust secretion and cross-correction across tissues, promoting lipid clearance.
• Gene therapy successfully restored GCase levels in NHP brains to near-physiological levels, addressing the deficit seen in GBA-PD.
• The AAV.GMU01 SS3-GBA1 treatment was well-tolerated with no observed adverse effects in NHP models.

Conclusions:

• AAV-mediated GBA1 replacement gene therapy is a viable strategy for treating Gaucher disease and GBA-associated Parkinson's disease.
• The engineered SS3-GCase is effectively secreted and cross-corrects cellular GCase deficiency.
• This single-gene therapy product shows promise for restoring GCase function and mitigating disease pathology.