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New strategy for the treatment of myotubular myopathy

In mice with myotubular myopathy (XLCNM; lacking MTM1), also named centronuclear myopathy due to the central position of nuclei, muscle fibres are smaller, and contain unusually centralized proteins, nuclei and organelles (left). The decrease in dynamin (DNM2) reverts fiber size to normal and allows the correct positioning of muscle proteins, nuclei and organelles within the fibre (right).

Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice.

Tasfaout H(1), Lionello VM(1), Kretz C(1), Koebel P(2), Messaddeq N(3), Bitz D(4), Laporte J(5), Cowling BS(6).

Mol Ther April 4, 2018

Feb. 14, 2018

Characterized by severe muscle weakness, myotubular myopathy, the X-linked form of centronuclear myopathies represents a major burden for patients and their families, as no curative treatment is available. After identifying Dynamin 2 as a potential therapeutic target in congenital myopathies and having successfully modulated the level of this protein with antisense oligonucleotides to cure signs of myopathy, researchers from Jocelyn Laporte's team at the IGBMC (CNRS/Inserm/Unistra) developed an alternative strategy to modulate Dynamin 2 expression. These results, published on February 14 in the journal Molecular Therapy, confirms the relevance of targeting Dynamin 2 in the treatment of this diseas and provide an alternative treatment strategy.

Several genetic causes are at the origin of centronuclear myopathies, including mutations in genes coding for myotubularin (MTM1) or dynamin2 (DNM2), proteins that regulate the organization of muscle fibres.

Three years ago, researchers at Jocelyn Laporte's team showed that reducing Dynamin 2levels by genetic means improved lifespan and clinical signs of the disease in myopathic mice no longer expressing MTM1 (Cowling et al. 2014).
The researchers then demonstrated that injections of synthetic antisense oligonucleotide that can bind very specifically to Dynamin 2 messenger RNAs, effectively reduce the level of Dynamin 2 and restore muscle function in different types of Centronuclear Myopathies. Thanks to a dose-response study, the researchers were able to determine the level of dynamin 2 reduction required for optimal effectiveness of the treatment (Tasfaout et al. 2017).

In this new study, Hichem Tasfaout and Belinda Cowling from Jocelyn Laporte's team tested another approach to reduce Dynamin 2 expression based on the use of an adeno-associated virus (AAV), a small non-pathogenic DNA virus that penetrates easily into cells and introduces DNA molecules, allowing the expression or inhibition of target genes. A single intramuscular injection of this Dynamin-2 inhibiting vector resulted in a long-term reduction of the Dynamin-2 protein level and the prevention of myopathy progression in mice lacking MTM1 expression.

These results thus offer a therapeutic alternative in the treatment of myotubular myopathy and confirm the relevance of targeting Dynamin 2 for the treatment of different forms of centronuclear myopathies.

This study was funded by the ANR, Myotubular Trust and Sparks the Children's Medical Research Charity, the Association Française contre les Myopathies (AFM 20323), and the SATT Alsace Conectus.

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