Investigating the therapeutic potential of miR-29c therapies

Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency resulting in progressive muscle weakness and fibrotic scarring. Muscle fibrosis impairs blood flow, hampering muscle repair and regeneration. Irrespective of the success of gene restoration, functional improvement is limited without reducing fibrosis. The levels of miR-29c, a known regulator of collagen, are reduced in DMD. The aim of this study was to develop translational, antifibrotic therapy by overexpressing miR-29c.

The authors provide evidence for the use of AAV-mediated overexpression of miR-29c, codelivered with micro-dystrophin, as a potential therapeutic approach for the treatment of DMD. They compared multiple paradigms to suppress skeletal muscle fibrosis in an animal model suitable to test and compare modes of treatment. The animal model used for proof of principle was the mdx/utrn+/– mouse, known for the extent of fibrosis found in the GAS muscle as early as 3 months of age. Combinatorial gene delivery in 3-month-old mdx/utrn+/- mice further decreased fibrosis, and showed a reduction of transcript levels for Col1A, Col3A, fibronectin, and Tgfb1. In addition, absolute and specific force was normalized and equivalent to WT. However, protection against eccentric contraction fell short of WT levels at this time point. When this same mouse model was treated with miR-29c/micro-dystrophin combinatorial therapy at 1 month of age, there was complete normalization of specific and absolute force and protection against eccentric contraction-induced injury was comparable to WT.

These findings highlight the potential for miR-29c as an important addition to the armamentarium for https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414552/translational gene therapy, especially when used in combination with micro-dystrophin in DMD.

Heller KN, Mendell JT, Mendell JR, Rodino-Klapac LR. MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle  function in combination with micro-dystrophin. JCI Insight. 2017 May 4;2(9).