Report for Parent Project for Muscular Dystrophy USA
Drug screening in mdx mice opens new therapeutic perspectives for children with muscular dystrophy
The major long-term goal of the Duchenne Muscular Dystrophy Research Center (DMDRC) is to facilitate rational therapies for Duchenne muscular dystrophy (DMD) through the integration of basic science with animal and human clinical trials. As all components are now in place, it is critical to fully implement this interactive/synergistic model through the rapid translation of research advances to the patient. Within this scope both researchers and clinicians gathered in Buffalo NY on February 12 1999. The goal of this meeting was to decide whether the potential therapeutic agents discovered in mdx mice required further studies in animals (mice, dogs) or whether they could be directly applied to human clinical trials. Attendants of the meeting were Drs. J. Granchelli, M. Hudecki and C. Pollina from Buffalo NY, R. Leshner from Richmond VA, and G. Buyse and E. Hoffman from Washington DC.
The DMDRC Mouse Pharmacology Core at SUNY in Buffalo New York is currently evaluating the potential of approved drugs on muscle function as well as histology in the exercised mdx mice model. The goal of these studies is to identify and characterize novel potential drugs that prevent or diminish muscle breakdown and improve muscle strength, and thus may be eligible for treating muscular dystrophy in humans. Using prednisone (widely known to prolong ambulation in DMD children albeit at the potential cost of several adverse effects) as a control, their recent completion of a 40-drug screening provided a series of 5 drug 'hits' that significantly improved muscle strength.
At the Buffalo meeting each of these agents was placed in the context of skeletal muscle breakdown and synthesis, trying to clarify the biological basis for their action in muscular dystrophy. Bearing in mind the safety issue of possibly using these compounds in children, available data on previous use in humans (for other indications) were reviewed. For some of the drug 'hits', it was decided that further mouse and/or dog trials are indicated before human trials can be considered. In addition, as a result of our discussions another 'battery' of drugs will be screened in the mdx mice model. And most importantly, some of the drug hits were judged to be ready for direct application in human clinical trials. This was decided because there is a considerable body of data which suggests that they target a number of processes involved in muscle breakdown in DMD, and because of their established safety profile in humans. The implementation of these trials is currently under investigation, and will be coordinated in Washington DC by Drs. Buyse, Escolar, Hoffman and Leshner.
It should be noted that we do not wish to mention the names of the 'hits' at this time, as it is important to realize that further studies need to be done. First, human clinical trials need to be done because mice are mice and some drugs may not have the same effects in humans. Second, such results should be reviewed by other scientists to make sure that our conclusions are valid (this review is currently underway).
Clearly, the development of new drug therapies for muscular dystrophy such as described above should be seen separate from the ongoing intensive efforts to enable gene therapy for muscular dystrophy. By definition, drug therapies are not 'curing' the disease, which gene therapy eventually will do by restoring in muscle cells the defective dystrophin gene that is causing the disease. In the best scenario, drugs would be able to prevent muscle breakdown by blocking a crucial step in the initial events leading to muscle cell death. The other scenario is that the drug (prednisone as an example) is able to slow down the progressive evolution of the disease, thus maintaining patients in a better functional state until gene therapy will be available to cure the disease. Finally, it may very well be the case that ultimately a combination of both gene and drug therapy is needed to cure Duchenne children. It is therefore justified and important to further investigate in developing better drug therapies for DMD in parallel with the ongoing gene therapy efforts.
Gunnar M. Buyse, M.D., Ph.D., Diana M. Escolar, M.D., and Eric P. Hoffman, Ph.D.
Children's National Medical Center, Center for Genetic Medicine Washington, D.C., U.S.A.
