Fusion of T Cells to Muscles to Alleviate Dystrophies – TFUSE

Cell therapies that have been tested for decades on myopathies have all proven disappointing. While stem cells of the adult (satellite cells -SC) are extremely efficient at repairing damaged muscles in normal conditions, they poorly engraft when locally injected into normal, diseased or regenerating muscles. Immune rejection of SCs, massive cell death, and limited spread at the injection sites have hindered their practical application to patients. Moreover, since dystrophies generally affect many if not all muscles of the body, local delivery is hardly an acceptable mode of therapy for those diseases. Significant headways were made using exon-skipping gene therapy technologies but substantial drawbacks have so far limited their generalized use for patients with dystrophies. Blood cells (i.e. myeloid and lymphoid cells) are particularly interesting for cell therapies, since they home injured tissues during inflammatory responses. This is important since muscles affected by inherited myopathies are undergoing chronic inflammation. However, endogenous blood cells never fuse to muscle cells. In this context, the discovery of Myomaker and Myomixer (Mymk, Mymx), two muscle-specific transmembranal proteins that display the property of promoting the fusion of heterologous cells to muscle cells in vitro, may represent a paradigm shift in the possibility of fusing circulating cells to muscles. The first premise of this project is that we can manipulate the muscle cell fusion machinery to provoke the fusion of genetically modified blood cells to Duchenne Muscle Dystrophy muscles. The second premise of this study is that we can couple cell therapy approaches with gene-engineering tools to amplify the impact of heterologous cell fusion to muscles and achieve functional improvement of the disease.