Bourdon and colleagues evaluated the therapeutic potential of the inclusion of the dystrophin carboxyl-terminal (CT) domain on ΔR4-23/ΔCT micro-dystrophin (MD1) and discovered new evidence that strengthens its relevance as a candidate for gene therapy in Duchenne muscular dystrophy (DMD), as published in Gene Therapy.

DMD is characterized by mutations in the gene encoding dystrophin, resulting in progressive muscle wasting. Increasingly, scientists are turning to gene therapy to treat this disease, employing the use of micro-dystrophin (MD) transgenes and recombinant adeno-associated virus (rAAV). 

The research team chose to investigate the effects of the inclusion of the dystrophin CT domain to MD1 using rAAV-based gene transfer technology in DMDmdx rats. They wanted to study its dystrophin-associated protein complex (DAPC) composition, as well as its therapeutic potential.

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To assess the impact of the dystrophin CT domain on the DAPC composition, they used 21 DMDmdx rats and 4 littermates (Sprague Dawley® wild-type rats). Micro-dystrophin 1 (MD1), micro-dystrophin 2, micro-dystrophin 3, and micro-dystrophin 4 (MD4) were each administered via intraperitoneal injection (without anesthesia) to 4 newborn DMDmdx rats.

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They were euthanized 4.5 months later. Three newborn DMDmdx rats were injected intramuscularly with the rAAV/MD4 vector (after anesthesia) and euthanized 7.5 months later.

To assess the impact of the coil-coiled motif of the CT domain of dystrophin in DMDmdx rats, Bourdon and colleagues used 40 DMDmdx rats and 10 littermates. They administered the rAAV vector or its vehicle to the rat models in their tail vein via the intravenous route. These animals were sacrificed after 3 months of follow-up.

The results demonstrated that MD1 expression was sufficient to restore the interactions of most DAPC partners at a physiological level in the skeletal and cardiac muscles. The inclusion of the CT domain managed to increase the recruitment of some DAPC partners at supraphysiological levels. Bourdon et al also discovered that the inclusion of the CT domain does not improve the therapeutic efficacy of MD1 on DMD muscle and cardiac disease. 

“Our work highlights new evidence of the therapeutic potential of MD1 and strengthens the relevance of this candidate for gene therapy of DMD,” the researchers concluded.


Bourdon A, François V, Zhang L, et al. Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat modelGene Ther. Published online February 1, 2022. doi:10.1038/s41434-022-00317-6