Duchenne muscular dystrophy, a severe and progressive hereditary muscular dystrophy, is caused by mutations in the DMD gene leading to the loss of a protein essential for muscle function, dystrophin. There is currently no effective treatment, but gene therapy trials using micro-dystrophins have been underway for several years. These strategies, targeting both skeletal and cardiac muscle, are applicable to all DMD patients, regardless of the mutation they carry. One of them recently received conditional accelerated approval from the FDA. However, recent adverse cardiac events in treated patients have prompted scientists to investigate further to understand these side effects.
In this context, researchers at the Institute of Myology* have studied the long-term effect of the micro-dystrophin replacement strategy, in particular on cardiac tissue, in a severe model of DMD, dKO (Dys-/-;Utr-/-) mice pre- and/or post-treated with antisense oligonucleotides (PPMO)**.
The results show that, after one year of treatment, micro-dystrophin replacement therapy results in :
- restoration of normal mouse weight,
- a remarkable improvement in the survival of DMD mice,
- maintenance of normal cardiac function
- an increase in the thickness of the septum,
- cardiomyocyte hypertrophy.
The tissue remodelling observed in the heart corresponds to inflammation of the cardiac muscle, a consequence of the presence of inflammatory cells in dKO mice treated with AAV-micro-dystrophin.
In order to limit the inflammatory response, the researchers plan, in a future work, to establish more precisely the dose-response relationship by modulating the quantity of micro-dystrophin injected, by testing modulators of the Unfolded Protein Response, which is overactivated in the presence of malformed proteins, and by defining the inflammatory population involved in cardiac inflammation with the aim of reducing it by specific targeting.
This research opens up new prospects for both treatment, thanks to the monitoring of cardiac inflammation in patients, and therapy, the idea being to offer a gene therapy using micro-dystrophin combined with another therapy capable of counteracting cardiac inflammation.
* Anne Forand, Antoine Muchir and France Pietri-Rouxel, members of two teams from the Center of Research in Myology : Muscle mass and function maintenance & optimization of AAV-based gene therapies (MOOVE) led by France Pietri-Rouxel and Signaling pathways & striated muscles led by Antoine Muchir.
