Duchenne muscular dystrophy (DMD) is caused by a mutation in DMD, a gene encoding for dystrophin, a protein that stabilizes the sarcolemma. The absence of dystrophin leads to widespread myonecrosis; death typically results from cardiopulmonary complications. Despite our advanced understanding of DMD pathophysiology, treatment remains largely palliative. Stem cell transplantation has long been considered a potential treatment for DMD but has not been thoroughly investigated. Now, researchers report results of stem cell transplantation in a young boy with a diagnosis of chronic granulomatous disease (CGD) in infancy and, subsequently, a diagnosis of DMD. (Genes for each of these conditions are located on the X chromosome.)

Starting at age 16 months, the boy received two allogeneic stem cell transplantations from umbilical-cord donors, which cured him of CGD. At age 4 years he was diagnosed with DMD. To determine whether any donor dystrophin was being expressed in his cells, researchers examined his muscle tissue and DNA from skin fibroblasts, and they cultured myoblasts derived from his muscle tissue. The analyses revealed a large-scale deletion on the X chromosome that spanned the loci for both CGD and DMD. The absence of dystrophin led to muscle histology characteristic of DMD. Analysis of myofibers indicated no definite donor cell engraftment.

Comment: Regrettably, this case shows that umbilical cord–derived hematopoietic, allogeneic stem cell transplantation is not efficacious in treating DMD. Clearly, other strategies are needed to induce engraftment of donor cells in skeletal muscle. Even though transplanted cells can survive, improving muscle function remains elusive. Functional success will require highly efficient engraftment of transplanted cells.

The loss of pluripotentiality as the cells differentiate along specific cell lineages may account for lack of efficient engraftment of blood-derived stem cells in skeletal muscle in this case. As the authors note, certain stem cell subpopulations likely have better myogenic potential than others. Discovering novel, multipotent cell lineages that possess enhanced ability to engraft in muscle would markedly improve the efficacy of stem cell therapy in DMD. However, there are other hurdles to overcome, including the development of more-efficient delivery methods and management of immune-rejection events that can complicate any cell-based therapy.

Published in Journal Watch Neurology August 31, 2010