Pathophysiology and therapeutic approaches for centronuclear myopathies

Description

Abstract Centronuclear and myotubular myopathies (CNM) are severe congenital myopathies linked to muscle weakness and often respiratory distress. A main histopathological hallmark is the centralized localization of nuclei in muscle fibers. There is an urgent unmet need for therapy. Most CNM are caused by mutations in either the lipid phosphatase myotubularin (MTM1), the membrane remodeling protein amphiphysin (BIN1), or the mechanoenzyme dynamin (DNM2)(Gomez-Oca 2021).

We found MTM1, BIN1 and DNM2 interact and function together in skeletal muscle. Moreover, modulation of their levels in mouse models of CNM ameliorate the motor defects and histopathology, highlighting the concept of cross-therapy, where modulation of one CNM gene can rescue defects linked to mutations in the other genes (Lionello 2019; Giraud 2023). Adeno-associated virus (AAV), antisense oligonucleotides or drugs can be used to modulate the function of the CNM proteins. In addition, we repurposed tamoxifen, previously used in breast cancer, to ameliorate different genetic forms of CNM in mouse models (Gineste 2023).

Overall, the CNM pathway is a key pathway for controlling organelle positioning and function in muscle, and a therapeutic target amenable to clinical development.

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