#apaperaday: Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy

Today’s pick is from Cernisova et al on assessing the effects of micro-dystrophin on fibrosis formation in diaphragm in d2/mdx mice. DOI: 10.3390/ijms24098174.

Micro-dystrophin gene therapy is delivered with adeno associated viruses (currently combinations of 3 types of micro-dystrophin and 3 types of AAV are in clinical development by Sarepta, Solid BioSciences, Pfizer and Genethon.

The FDA verdict on the Sarepta micro-dystrophin gene therapy was expected for later this month, but the decision has been postponed to June 22nd. Likely the label will be for 4-5 year olds if it is approved (yesterday’s news). Back to the paper:

Authors outline that micro-dystrophin treatment has been studied primarily in mdx mice, which do not have a lot of fibrosis. Here they want to study micro-dystrophin treatment in d2/mdx mice which have more fibrosis arguing that Duchenne patients have more fibrosis.

Notably, adding a micro-dystrophin gene in fibrotic tissue will not revert the fibrotic tissue back to muscle. Once the muscle is gone it is gone. So mdx mice (with little fibrosis) will respond better to gene therapy than patients.

Here authors treated d2/mdx mice which have more fibrosis at an early age with a micro-dystrophin that is evaluated in clinical trial and AAV8, a serotype that is also in clinical trials. Mice were treated at 6 weeks of age with 2.5.10(14) viral genomes per kg.

This is slightly more than used in clinical trials. Authors included control groups: saline treated d2/mdx & wild type references. The treated d2/mdx mice showed improved strength, reduced fatigue and improved resistance to eccentric exercise compared to untreated mice.

Authors focused on the diaphragm – the most severely affected muscle. Micro-dystrophin was expressed in >75% of fibers at >70% of normal in treated animals. Histology improved compared to untreated with less fibrosis, less centrally located nuclei and normalized fiber size.

Authors studied mRNA markers for fibrosis & inflammation showing levels normalized in treated d2/mdx mice. Authors discuss the treatment with the micro-dystrophin is able to prevent fibrosis formation. However, we know d2/mdx model can restore muscle after pathology.

This process is not well understood and at the time point the authors analyze the treated d2/mdx mice this process is not yet started. As such a more likely explanation is that the fibrosis formation was prevented IN MICE.

If and to which extend this extrapolates to humans is something that we do not know yet but that will become apparent from the patients who have been treated with micro-dystrophin gene therapy (some more than 4 years ago).