Dr. Ryszard Kole from AVI Biopharma and PPMD President Pat Furlong further reflect on recent findings that Duchenne is a stem cell disease. Read the discussion below, as well as, Pat’s previous blog.
I read with interest your blog yesterday regarding the Cell paper on Duchenne that came out on Monday. I can very well understand the excitement, as well as some possible confusion, that the paper generated among PPMD members and the Duchenne community in general. I believe that your comments helped put the publication in the right perspective.
To characterize Duchenne as only a stem cell disease is not entirely correct. Without dystrophin, a very large structural protein, muscle cells struggle and eventually die. Without dystrophin, there is no shock absorber to protect cell membrane from tearing when muscle does its work. Without it the muscle membrane is vulnerable and the repeated contraction and relaxation of the muscles results in small tears in the muscle membrane. (That’s why the boys should not lift weights, do steps, etc – eccentric exercise increases injury). These small tears (think of holes in the roof of your home) cause extracellular calcium to leak into the muscle cell. The muscle cell is unable to handle the overload and a cascade of biochemical events occurs with the end result, the muscle cell dies. The body tries very hard to repair the damage, recruiting satellite cells also called stem cells, to replace the damaged muscle cells and help with repair. Because the satellite cells have no dystrophin, they are unable to repair the damage and are subject to the same series of events. Eventually, they run out and the muscles deteriorate irreversibly.
If we think about treating Duchenne, it is reasonable to imagine that by interfering at any step along the way, it should be possible to slow the degradation process. It might be worth thinking about it in terms of a base hit in baseball. If you target one or more pathways – you might have a single, a double, or a triple. Replacing dystrophin restores stability to the muscle membrane – a home run. When this happens the muscle cell survives longer and stem cells do not need to step in and are used up more slowly. So it’s at least a double.
There is an excellent mouse model of severe Duchenne developed previously by Dr. Kay Davies and her group at Oxford that offers additional color on this issue (http://www.ncbi.nlm.nih.gov.libproxy.lib.unc.edu/pubmed/19844193; Goyenvalle A, Babbs A, Powell D, Kole R, Fletcher S, Wilton SD, Davies KE. Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping. Mol Ther. 2010 Jan;18(1):198-205. PubMed PMID:19844193).
In mice, if only the dystrophin gene is defective, the disease is mild, animals move around well, and have close to normal lifespan. In Dr. Davies’ mouse, a gene for utrophin, which can compensate for lack of dystrophin, is also knocked out. These double knockout mice have very severe muscular dystrophy, are barely mobile, and survive for no longer than 20 weeks. Healthy mice live for about two years.
This paper, published a year ago, also shows that the treatment of double knockout mice with an oligomer that causes exon skipping in dystrophin mRNA restores production of dystrophin. The presence of this protein restored mobility of these severely affected animals to almost normal levels and extended their lifespan. These effects were achieved with exon skipping, a method that does not affect the stem cells. There is also a variety of published and unpublished data showing that restoration of dystrophin by exon skipping promotes muscle regeneration and inhibits degeneration, which in turn should reduce pressure on stem cells and regenerative capacity of affected muscles. On the basis of these findings I agree with you and respectfully differ with Dr. Blau and colleagues. In my opinion, in Duchenne muscular dystrophy, dystrophin restoration is essential to enable muscle function and to protect stem cells from early depletion. Duchenne is ultimately and certainly a dystrophin disease.
With Best Wishes,
Ryszard Kole, Ph.D.
Senior VP, Distinguished Scientist
3450 Monte Villa Parkway
Bothell, WA 98021