Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

Area of Science:

• Gene Therapy
• Molecular Biology
• Pediatric Metabolic Disorders

Background:

• Glycogen storage disease type Ia (GSD-Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency.
• G6Pase deficiency leads to severe hypoglycemia, growth retardation, and hyperlipidemia.
• Current treatments for GSD-Ia manage symptoms but do not address the underlying enzyme defect.

Purpose of the Study:

• To evaluate the efficacy of adeno-associated virus serotype 8 (AAV8) vector-mediated G6Pase gene therapy in a mouse model of GSD-Ia.
• To assess the impact of AAV8-G6Pase gene therapy on survival, growth, and metabolic parameters in GSD-Ia mice.

Main Methods:

• Adeno-associated virus (AAV) vector encoding G6Pase, pseudotyped as AAV8, was administered to 2-week-old GSD-Ia mice.
• Survival rates, body weight, blood glucose, blood cholesterol, liver G6Pase activity, and liver glycogen storage were monitored.
• Vector genome persistence and liver immune cell infiltration were also analyzed.

Main Results:

• AAV8-G6Pase gene therapy significantly prolonged median survival of GSD-Ia mice to 7 months, compared to 2 weeks in untreated mice.
• Treated mice showed a fourfold increase in weight, normalizing growth, and partial correction of blood glucose and liver glycogen.
• Blood cholesterol levels normalized, and partial G6Pase activity was sustained up to 7 months post-treatment, despite some immune infiltrates.

Conclusions:

• AAV vector-mediated G6Pase gene therapy demonstrates significant therapeutic potential for GSD-Ia.
• This approach can alleviate critical GSD-Ia complications, including hypoglycemia, hyperlipidemia, and growth failure.
• Further development of efficacious AAV gene therapy could substantially improve long-term outcomes for GSD-Ia patients.