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Cell therapy as a possible approach to Duchenne muscular dystrophy treatment

16 June 2022

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What is Duchenne muscular dystrophy?

Duchenne muscular dystrophy is a serious genetic condition that causes progressive muscle wasting. Duchenne is caused by genetic changes in the DMD gene (the gene that provides cellular instructions for producing dystrophin).

Dystrophin is a protein that is important for maintaining the integrity, structure and function of cells during contraction and relaxation of skeletal (the muscles involved in body movement) and heart muscles. A lack of dystrophin causes muscle cells to weaken and break down over time. This leads to an accumulation of fat and scar tissue, further weakening the muscle and its ability to contract.

Duchenne muscular dystrophy mainly affects young boys (although, very occasionally it affects girls), with the first symptoms appearing as young as two to three years old. Currently, there are over 2,500 people in the UK living with Duchenne muscular dystrophy.

How is Duchenne muscular dystrophy treated?

There is no cure for Duchenne muscular dystrophy, and current therapies, such as corticosteroids, mainly aim to slow down and delay muscle weakening.

Given that Duchenne muscular dystrophy is a genetic condition, therapies such as exon-skipping, represent a promising approach. Exon-skipping uses molecular patches that mask the changed part of the gene, allowing the protein production to proceed by skipping the affected part of the gene. However, Duchenne is known to be caused by several different DMD gene changes and as exon-skipping can only cover up one specific gene variant at a time not every patient can benefit from it.

What is the current state of the art for gene therapy research in Duchenne muscular dystrophy?

There are several clinical trials for micro-dystrophin gene therapy. In these studies, a shortened variant of the DMD gene is packaged into vectors, which are small adeno-associated viruses (AAVs) that do not cause infection in humans, and injected into patients. This approach could lead to the reduction of muscle weakening, allowing for a slightly improved lifestyle for people with Duchenne. A drawback to this approach is that AAVs only have the capacity to package approximately half of the length of the dystrophin gene.

Efforts are being made to find alternative ways of packaging the full-length dystrophin gene, to further improve the longevity and quality of life of Duchenne patients. This is where Professor Morgan and her team come in.

What did the study aim to do?

Recent work by the Morgan group at Dubowitz Neuromuscular Centre, University College London, aimed to find a way to transfer the full-length dystrophin into mice lacking dystrophin, and therefore restore its function.

The overall aim was to restore 5-30% of fully functional dystrophin in as many muscle cells as possible. This is because having lower amounts of dystrophin in lots of cells is more beneficial than having more dystrophin in fewer cells.

To be able to package the full-length dystrophin, a different viral vector is required – here they used a virus called lentivirus. Lentiviruses can hold a longer length of dystrophin gene than AAVs, but this comes at the price of them being bigger and therefore the transfer into muscle tissue could be compromised.

What did the study show?

Promoters are often added to regulate when and where the gene will be translated. Excitingly, the researchers in this study found the optimal conditions for packaging the full-length dystrophin within the lentivirus. They used a specific promoter to transfer the viruses directly into the muscle tissue of the mice, using the cell-based therapy approach.

In cell therapy, cells are modified outside of the body and injected into the recipient. In this study, stem cells, modified to contain lentivirus with full-length dystrophin, were transplanted into the muscle tissue of mice lacking dystrophin.

The results showed a significant increase in dystrophin production in these mice compared to control mice. Furthermore, the restored full-length dystrophin appeared to function similarly to the healthy dystrophin.

What does this mean for people with Duchenne muscular dystrophy?

Professor Morgan says,

Thanks to the support from MDUK, these exciting results open new areas of research and represent a promising step towards finding a therapy that can be applicable to the majority of people living with Duchenne muscular dystrophy.

While this study shows promising and exciting results for the future, it is still only in its pre-clinical phase. It is hard to tell when it could reach clinical application but we do know that this will take many years.

Nevertheless, when available, this approach could potentially be used in combination with other therapies for Duchenne, and in that way provide longer and more durable protection of the muscle tissue.

The full research article can be found here.

Our position on animal research can be found here

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