Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy

Area of Science:

• Muscle Diseases
• Genetics
• Therapeutics

Background:

• Centronuclear myopathies (CNM) are severe genetic muscle disorders lacking effective treatments.
• Previous research demonstrated DNM2 reduction benefits X-linked CNM models.
• DNM2 mutations cause autosomal dominant CNM forms.

Purpose of the Study:

• To investigate if reducing dynamin 2 (DNM2) can rescue the pathology in a mouse model of dominant centronuclear myopathy (CNM) caused by a specific DNM2 mutation (p.R465W).
• To evaluate two distinct delivery methods for DNM2 knockdown: adeno-associated virus-shRNA and antisense oligonucleotides.

Main Methods:

• A knock-in mouse model (Dnm2RW/+) with a DNM2 mutation causing mild CNM was used.
• Adeno-associated virus-shRNA was administered intramuscularly to assess local DNM2 reduction.
• Antisense oligonucleotides were administered intraperitoneally weekly for five weeks to evaluate systemic DNM2 reduction.

Main Results:

• Intramuscular AAV-shRNA targeting DNM2 reduced protein levels, improving muscle mass, fiber size, and histopathology in Dnm2RW/+ mice.
• Systemic treatment with antisense oligonucleotides targeting DNM2 normalized muscle mass, histopathology, and ultrastructure in Dnm2RW/+ mice to wild-type levels.
• DNM2 knockdown via both methods effectively corrected the myopathy associated with DNM2 mutations.

Conclusions:

• DNM2 knockdown is an effective strategy for correcting dominant centronuclear myopathy caused by DNM2 mutations.
• This approach offers a potential common therapeutic strategy for multiple forms of centronuclear myopathy.
• Targeting both alleles in dominant diseases, as demonstrated here, may be applicable to other dominant genetic disorders.