Duchenne Muscular Dystrophy Calls Stem Cells
Milan, Italy -
Duchenne Muscular Dystrophy is a lethal genetic condition, characterized by progressive muscle weakness caused by mutations in the dystrophin gene. Approaches to treatment of this condition have included the use of cord blood stem cells, however little functional improvement is seen, even in animal models. US patent 7,229,963 provides histone deacetylase inhibitors that may be useful for treatment of this condition, however clinical trials have yet to begin.
In various disease situations, stem cells from the bone marrow seem to be mobilized to go and try to heal the damaged/degenerating tissue. For example, in stroke, better prognosis is associated with increased number of circulating stem cells after the stroke. This is the same for patients after a heart attack. What drives stem cells to mobilized to damaged tissue? Well in some situations where the damage is associated with hypoxia, the ischemic tissue releases stromal derived factor-1, (SDF-1) which promotes homing. This is the same cytokine that attracts bone marrow stem cells into the bone marrow, allowing for intravenous administration of bone marrow stem cells during bone marrow transplant. There are, of course, other homing signals such as VEGF, inflammatory signals such as TWEAK, and various degradation products of the extracellular matrix.
A recent study (Marchesi et al. Correlation of circulating CD133+ progenitor subclasses with a mild phenotype in Duchenne muscular dystrophy patients. PLoS. One 2008 May 21;3(5):e2218) demonstrated that circulating stem cells have a correlation with better prognosis in patients with Duchenne Muscular Dystrophy.
The investigators assessed 70 patients with Duchenne Muscular Dystrophy that were between 2-20 years of age. Circulating levels of CD133 positive, CXCR4 (the receptor for SDF-1) positive, and CD34 negative were studied. What was found:
1. As compared to age-matched controls, patients with Duchenne Muscular Dystrophy had much higher levels of circulating CD133 positive, CXCR4 positive, and CD34 negative cells.
2. Patients with a slower disease progression had higher levels of the stem cells as compared to pateints with a faster disease progression.
This is very interesting since the same group has previously published that autologous stem cell transplant may be useful in this condition (Torrente Y et al. Autologous transplantation of muscle-derived CD133+ stem cells in Duchenne muscle patients. Cell Transplant. 2007;16(6):563-77).
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jonnyboy said...
Christine good question. I wish that I knew the answer to this but i dont.
For allo-transplantation good results are being seen in dogs using tolerance inducing protocols. See the abstract below
Mol Ther. 2008 May 13. [Epub ahead of print]
Hematopoietic Cell Transplantation Provides an Immune-tolerant Platform for Myoblast Transplantation in Dystrophic Dogs.
1Program in Transplantation Biology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Duchenne Muscular Dystrophy (DMD) is the most common and severe form of muscular dystrophy in humans. The goal of myogenic stem cell transplant therapy for DMD is to increase dystrophin expression in existing muscle fibers and to provide a source of stem cells for future muscle generation. Although syngeneic myogenic stem cell transplants have been successful in mice, allogeneic transplants of myogenic stem cells were ineffective in several human trials. To determine whether allogeneic muscle progenitor cells can be successfully transplanted in an immune-tolerant recipient, we induced immune tolerance in two DMD-affected (cxmd) dogs through hematopoietic cell transplantation (HCT). Injection of freshly isolated muscle-derived cells from the HCT donor into either fully or partially chimeric xmd recipients restored dystrophin expression up to 6.48% of wild-type levels, reduced the number of centrally located nuclei, and improved muscle structure. Dystrophin expression was maintained for at least 24 weeks. Taken together, these data indicate that immune tolerance to donor myoblasts provides an important platform from which to further improve myoblast transplantation, with the goal of restoring dystrophin expression to patients with DMD.
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Christineball33 said...
I am having trouble understanding how the autologous cells would actually be useful. If there is a mutation that is genetic in Duchenne, then the mutation should still be present in the cells that are bone marrow as well. The stem cells from the bone marrow, even if they could make muscle would still be making muscle that has the mutation? no? maybe im missing something