Gene-replacement therapy in neurodevelopmental disorders: progress and challenges

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Loss-of-function variants in the SLC6A1 gene, encoding the GAT1 GABA transporter, cause severe neurodevelopmental disorders.
• Gene replacement therapy is a potential treatment strategy for these disorders, requiring precise delivery of therapeutic genes.

Purpose of the Study:

• To evaluate different strategies for AAV-mediated GAT1 gene replacement in mouse models of SLC6A1 deficiency.
• To determine optimal promoters, injection methods, and timing for effective gene delivery and therapeutic outcomes.

Main Methods:

• Adeno-associated virus type 9 (AAV9) vectors with two different promoters were tested.
• Three injection modalities (intrathecal, intracerebroventricular, intraparenchymal) and various administration timings were assessed.
• Gene expression, tolerability, and therapeutic efficacy were evaluated in heterozygous and homozygous GAT1 knockout mice.

Main Results:

• Intrathecal administration of AAV9 vectors at postnatal day 5 resulted in high GAT1 expression and was well-tolerated.
• Gene replacement therapy was ineffective when administered at later disease stages.
• Early gene reconstitution is crucial for therapeutic success, underscoring the importance of GABA metabolism during early brain development.

Conclusions:

• Intrathecal AAV9 delivery at an early developmental stage is a promising strategy for GAT1 gene replacement therapy.
• The timing of gene therapy is critical, with early intervention being essential for treating SLC6A1-related disorders.
• These findings emphasize the vital role of GABAergic neurotransmission in early brain development and the potential of gene therapy for related neurodevelopmental conditions.