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.
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.
The investigators found that:
To learn more about gene therapy and stem cell transplantation in DMD and BMD, read: