DMD, BMD: Combining Gene Therapy and Stem Cell Transplantation

Mice with a disorder similar to Duchenne muscular dystrophy showed improved muscle strength and structure following treatment with genetically corrected cells derived from their own skin cells

Transplanting cells from the recipient's own body, after genetically altering them to produce more of a protein the recipient already produces, has the potential to overcome some of the immune system obstacles posed by gene therapy and cell transplantation.
Article Highlights:
  • In a new approach to treating Duchenne and Becker muscular dystrophies, research mice were treated with induced pluripotent stem cells that were genetically corrected to produce utrophin. (Utrophin is a naturally occurring protein that is similar to dystrophin and can partially compensate for its absence in muscle cells.)
  • The cells used in these experiments were derived from skin cells of the DMD mice; the cells were then induced to become stem cells, given utrophin genes, and coaxed to become muscle progenitor cells.
  • The strategy represents a new approach to treating DMD with self-derived, genetically corrected cells.
  • The strategy used in these experiments theoretically could be applied to DMD caused by any type of dystrophin mutation and possibly to other forms of muscular dystrophy.
by Margaret Wahl on March 21, 2013 - 5:00am

A therapeutic strategy that combines gene therapy and stem cell transplantation has shown encouraging results in mice with a disorder mimicking Duchenne muscular dystrophy (DMD).

"Our findings demonstrate for the first time proof of principle for the feasibility of combining induced pluripotent stem cell therapy in conjunction with genetic correction to treat muscular dystrophy," the authors say in a paper published March 5, 2013, in Nature Communications.

The treatment brought about improvements in the structure and function of the mouse muscles, despite the particularly severe type of muscular dystrophy that affected the mice in these experiments.

The mice were bred to lack two muscle proteins: dystrophin, the protein missing in people with DMD; and utrophin, which is not missing in people with DMD. (The absence of both proteins results in more severe DMD symptoms in mice. Mice that are missing only dystrophin generally show a milder form of DMD than do people missing dystrophin.)

The research team included investigators from the University of Minnesota, Twin Cities, and the University of Washington, Seattle. Although MDA did not fund this specific project, the team included several former or current MDA research grantees who have been working in related areas.

Skin cells converted, corrected, transplanted

The induced pluripotent stem cells used in these experiments were derived from early-stage skin cells (fibroblasts) taken from living DMD research mice, converted back to stem cells, and then converted into early-stage muscle cells — a technique that has the potential to be used in people with DMD and possibly other forms of muscular dystrophy, such as Becker MD (BMD), which is caused by partial dystrophin deficiency. The strategy does not target a specific dystrophin mutation.

The cells, which were missing utrophin and dystrophin, were given miniaturized utrophin genes to improve their structure and function. Utrophin, a protein closely related to dystrophin, can at least partially substitute for dystrophin.

Many researchers prefer using utrophin to treat dystrophin-deficient disorders because they predict it will be readily accepted by the recipient's immune system. Children with DMD given dystrophin gene therapy have shown unwanted immune responses to the newly synthesized dystrophin protein, perhaps because the protein is not recognized by their immune systems. (The mice in these experiments were given immunosuppressant medication since they were missing utrophin and therefore would not have been expected to tolerate that protein either.)

After being converted to muscle precursor cells, the utrophin-corrected stem cells were injected directly into a leg muscle or intravenously into a tail vein in the mice.

Improved muscle structure, strength, repair

The investigators found that:

  • the genetically corrected stem cells engrafted into living mice after either local or systemic injection;
  • the cells produced utrophin protein, which allowed several other proteins to take their usual positions in the muscle-fiber membrane;
  • some transplanted cells became muscle fibers and formed connections with nerve fibers;
  • other transplanted cells became muscle repair cells and contributed to the repair of muscle fibers; and
  • the strength of the mice significantly improved.

For more information

To learn more about gene therapy and stem cell transplantation in DMD and BMD, read:

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