Large1 gene transfer in older myd mice with severe muscular dystrophy restores muscle function and greatly improves survival.
Takahiro YonekawaAdam J RauckhorstSara El-HattabMarco A CuellarDavid VenzkeMary E AndersonHidehiko OkumaAlvin D PewaEric B TaylorKevin P CampbellPublished in: Science advances (2022)
Muscular dystrophy is a progressive and ultimately lethal neuromuscular disease. Although gene editing and gene transfer hold great promise as therapies when administered before the onset of severe clinical symptoms, it is unclear whether these strategies can restore muscle function and improve survival in the late stages of muscular dystrophy. Large myd /Large myd ( myd ) mice lack expression of like-acetylglucosaminyltransferase-1 ( Large1 ) and exhibit severe muscle pathophysiology, impaired mobility, and a markedly reduced life span. Here, we show that systemic delivery of AAV2/9 CMV Large1 (AAV Large1 ) in >34-week-old myd mice with advanced disease restores matriglycan expression on dystroglycan, attenuates skeletal muscle pathophysiology, improves motor and respiratory function, and normalizes systemic metabolism, which collectively and markedly extends survival. Our results in a mouse model of muscular dystrophy demonstrate that skeletal muscle function can be restored, illustrating its remarkable plasticity, and that survival can be greatly improved even after the onset of severe muscle pathophysiology.
Keyphrases
- muscular dystrophy
- skeletal muscle
- toll like receptor
- duchenne muscular dystrophy
- insulin resistance
- early onset
- mouse model
- high fat diet induced
- poor prognosis
- free survival
- multiple sclerosis
- drug induced
- immune response
- type diabetes
- randomized controlled trial
- adipose tissue
- physical activity
- inflammatory response
- copy number
- gene expression
- deep learning
- machine learning
- big data
- genome wide identification