Assessing the feasibility of a new cell- and gene-based therapy for Duchenne muscular dystrophy

Professor Morgan and her team will develop and test a novel cell- and gene-based therapy for Duchenne muscular dystrophy. The approach is based on the theory that an individual’s own skin cells can be reprogrammed into induced pluripotent stem cells (iPSCs), the genetic mutation repaired, the cells developed into cells capable of muscle repair and transplanted back into damaged muscles. The efficacy of the approach will be tested by injecting the generated cells into a mouse model of Duchenne muscular dystrophy and measuring their ability to increase fully functional dystrophin protein.

This work will help to make cell-mediated gene therapies a viable option for people with Duchenne and Becker muscular dystrophies

What are the aims of the project?

In Duchenne muscular dystrophy, mutations in the dystrophin gene cause a lack of dystrophin protein, resulting in damage to and loss of muscle fibres. Satellite cells, the stem cells of muscle, work hard to repair and replace the damaged and lost muscle fibres. However, without any dystrophin in the new fibres, these too deteriorate and the cycle continues, leading to exhausted, ineffective stem cells and continued loss of muscle fibre.

Transplanting healthy satellite cells from a donor would boost the repair capacity of deteriorating muscle and allow the production of full length dystrophin protein. However, there is a risk of immune rejection of the transplanted cells, unless long-term immunosuppression is given.

To address the dystrophin mutation, a correct copy of the gene could be introduced, but this approach is limited by the size of the commonly used delivery vehicles, viral vectors, which are unable to hold the entire dystrophin gene, one of the largest genes in the human body. Shortened versions of the gene, micro-dystrophins, can be used instead. These appear to work well but are not expected to have full functionality as some parts of the gene, and therefore the protein, are missing.

This project aims to generate cells for transplantation that address these concerns.

Professor Morgan has access to iPSCs which have been generated from skin cells from a person with Duchenne muscular dystrophy. A full length version of the dystrophin gene will be introduced to these cells, using a lentivirus, which Professor Morgan and her team have recently shown is capable of carrying the entire dystrophin gene. Cells that have successfully taken up the dystrophin-containing lentivirus will be selected then grown and differentiated into satellite-like muscle cells.

Lentiviruses are particularly suitable for this kind of gene therapy as the gene will be inserted into the DNA of the iPS cells for a long-lasting effect; the gene will be replicated in all future cells as the iPS cells multiply in number.

These will then be transplanted into a mouse model of Duchenne muscular dystrophy, to test their ability to increase dystrophin protein and form new, healthy muscle fibres.

Why is this research important?

This project will address the challenges of a cell- and gene-based therapy for Duchenne muscular dystrophy, namely the difficulties of providing a fully functional dystrophin gene and generating a cell therapy with a low risk of immune rejection. The use of a lentivirus will allow the full length dystrophin gene to be delivered to cells and the use of iPSCs would allow people’s own skin cells to be used for the treatment, if the procedure is shown to be effective.

The approach would additionally be applicable for all people affected by Duchenne or Becker muscular dystrophy, whatever their mutation.

How will the outcomes of this research benefit people with Duchenne muscular dystrophy?

Although a long way from being tested in humans, this approach could eventually offer a corrective therapy for everyone with Duchenne or Becker muscular dystrophy, irrespective of their mutation.

How might this research impact on other neuromuscular conditions?

There is still a significant amount of work to be done before this approach can be tested in humans; the process of selecting genetically corrected, transplantable cells needs to be optimised and the safety of iPSCs for transplantation into humans needs to be proven. These will be the next steps of the research if this project is successful.

However, if the procedure was successfully developed for Duchenne muscular dystrophy, the process (of creating iPSCs from a person’s skin cells, correcting the mutation with a gene therapy and selecting the corrected cells to transplant back in to the body) could be applied to other muscle-wasting conditions with genetic causes.

Grant Information

Project leader: Professor Jenny Morgan
Institute: University College London (UCL)
Conditions: Duchenne muscular dystrophy, Becker muscular dystrophy
Duration: three years, starting 2017
Total cost (£): 225,000
Official title: Restoration of full length dystrophin in induced pluripotent stem cell derived muscle progenitor cells

Further information

Read about our other Duchenne muscular dystrophy research projects

Read our research news stories on Duchenne muscular dystrophy

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