BIN1 gene replacement reverses BIN1-related centronuclear myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Centronuclear myopathies (CNMs) are severe genetic muscle disorders.
• Mutations in the BIN1 gene are a common cause of CNM.
• Current treatments are lacking, and disease mechanisms are poorly understood.

Purpose of the Study:

• To investigate adeno-associated virus (AAV)-based gene replacement therapy for BIN1-related CNM.
• To evaluate the efficacy of BIN1 gene therapy in a mouse model of CNM.
• To identify optimal AAV constructs for therapeutic delivery.

Main Methods:

• Adeno-associated virus (AAV) vector delivery of the BIN1 gene into Bin1-CNM mice.
• Assessment of disease progression and reversal of symptoms.
• Analysis of muscle function, histology, and molecular markers.
• Evaluation of different BIN1 isoforms and protein domains.

Main Results:

• Systemic BIN1 gene expression prevented disease progression when administered early.
• BIN1 gene therapy reversed established CNM signs, including muscle weakness and organelle mispositioning.
• The optimal construct combined a myotropic AAV serotype with the muscle BIN1 isoform.
• Therapeutic effects correlated with normalized autophagy and excitation-contraction coupling.

Conclusions:

• BIN1 gene replacement is a promising therapeutic strategy for BIN1-related CNM.
• Both early and late administration of BIN1 gene therapy can be effective.
• The muscle-specific BIN1 isoform is crucial for full functional recovery.