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The American Academy of Neurology (AAN) recently released a report on the use of corticosteroids (prednisone or deflazacort) in Duchenne muscular dystrophy (DMD). In a review of relevant literature published from 1966 to 2004 the group concluded that corticosteroids provide a benefit in DMD, but that there are drawbacks to their use. Prednisone and deflazacort were included in the studies, but there is not a comparison of the two drugs. A summary of the report with recommendations and a discussion of the drawbacks to this treatment is on the website of the Musclar Dystrophy Associaton. The original paper is published in Neurology, 2005, 65, Jan (1 of 2)13-20.
The January-February 2005 issue of “Quest” magazine, published by the Muscular Dystrophy Association (MDA), has an excellent article, “Bridge over Troubled Waters,” that discusses the progress and challenges being encountered in gene therapy research in the United States. For a thorough look at the current status of gene therapy for DMD and a presentation of the process involved in the translation of basic science research to the clinic, where it will benefit the patient, go to the “Quest” article on the MDA web site at: http://www.mdausa.org/publications/Quest/q121genetherapy.cfm
Also reported is the progress being made toward gene therapy for Duchenne muscular dystrophy (DMD) by each of the research programs that are studying the possibility of gene therapy for DMD. The featured investigators are Jeffrey Chamberlain, PhD, Richard Jude Samulski, PhD, Jon Wolff, MD, and Xiao Xiao, PhD .
In January-February 2005 issue of “Quest” there is also a review of a book, Duchenne MD: a Family Legacy, by Christine Kehl O’Hagan that explores the impact of DMD on five generations of a family. It can be found at: http://www.mdausa.org/publications/Quest/q121kehls.cfm.
On December 16, 2004 the Muscular Dystrophy Association (MDA) announced that the Recombinant DNA Advisory Committee of the U.S. National Institutes of Health (NIH) voted to allow the first American study of gene therapy in boys with Duchenne muscular dystrophy to move on to the next step toward clinical testing of the proposed gene therapy treatment. The Food & Drug Administration (FDA) must also approve the proposal before the trial can begin. The FDA review of this project may come as early as next summer. When final approval of the study is received, the clinical testing and monitoring will be conducted at Columbus Children’s Research Institute, part of Ohio State University. A more detailed description of the study may be found on the web site of the MDA at:
http://www.mdausa.org/research/041216genetherapy.html
The progress being made in using various methods of gene therapy for Duchenne muscular dystrophy was discussed in the Jan-Feb 2005 issue of Quest, published by the Muscular Dystrophy Association see article above. In the March-April 2005 issue of Quest another approach to solving the problem of a lack of dystrophin in DMD is discussed. This is the concept of modifying a faulty gene to correct an error rather than replacing the entire gene, as is attempted in gene therapy. This genetic engineering or gene modification may repair the gene, modify the way the cell interprets the gene or it may change the activity of another gene that codes for a dystrophin-like molecule.
The DNA in the gene is comprised of four compounds (nucleic acids) that are held together by a backbone of sugar and phosphate molecules and maintained in specific sequences in the gene. The information in these sequences is exactly transcribed to RNA, which is then responsible for translating the message into the proteins that are used in the cell. Errors can occur at each of these steps, resulting, in the case of DMD, in the lack of production of dystrophin. The order of the nucleic acids may be altered. The transcription to the RNA may not be correct or the translation to from the RNA to the protein may have an error. The “Changing the Code” article by Margaret Wahl has an excellent, understandable discussion of these processes and the errors that can occur. Following the discussion of the genetic process is a series of articles on several research projects that are attempting to overcome the errors that may occur.
The laboratory of Thomas Rando, M.D., Ph.D., at Stanford University is studying the gene repair approach. His method repairs those mutations that are due to an error in the nucleic acid code. In preliminary work his laboratory has proved that the principle will work. These preliminary studies using the mdx mouse (a model for DMD) did not provide an efficient repair, but there was evidence that the repair worked. Dr. Rando feels that this method of gene repair “avoids many disadvantages of other forms of gene therapy” because it is likely to be a permanent change in the DNA and it does not require the use of viruses as gene therapy does. A more thorough discussion of Dr. Rando’s work is in the March-April 2005 Quest.
A different gene repair approach is being studied in the laboratory of Lee Sweeney, Ph.D., at the University of Pennsylvania, Philadelphia. He is using a drug, which permits normal dystrophin formation in situations where the dystrophin is too short because the gene sends the message to stop forming the protein before the entire protein is produced. The drug being studied prevents this early stoppage of the transcription of the gene and allows the production of the full dystrophin molecule. This compound, PTC124, is currently in a Phase I clinical trial and will soon be in a Phase 2 trial. If effective, this drug could possibly help 10-15% of boys with DMD. A more thorough discussion of this approach is also in March- April 2005 Quest.
Stephen Wilton, Ph.D., at the University of Western Australia, Perth, is studying ways to make the repair, not at the DNA level as Drs. Rando and Sweeney are, but at the RNA level. His method is compared to a “Band Aid” approach. Where there is a problem identified in the RNA code, he uses a short group of the nucleic acid-phosphate-sugar molecules (nucleotides) to repair the RNA error. This method allows the skipping of the erroneous information (antisense) to allow correct reading of the RNA and the formation of dystrophin. A preliminary study using this approach in mdx mice has been successful, allowing the production of normal levels of dystrophin in a large number of fibers. A much more complete discussion of this is in the March-April 2005 Quest.
Bernard Jasmin, Ph.D. at the University of Ottawa, Canada, is studying the method of genetic repair that is accomplished by having the cell produce increased amounts of a protein that is similar in structure to the dystrophin molecule. Although this doesn’t actually change the DNA or RNA that is abnormal, it achieves the effect of replacing the missing dystrophin with a protein of similar structure, utrophin. They are accomplishing this by preventing the action of the protein that tells the cells to stop producing utrophin, which results in the production of abnormally high amounts of the protein, utrophin. When this was done in mdx mice, utrophin appeared around the muscle cells that were lacking dystrophin and the fiber damage was reduced. For a further discussion of this method check the article in Quest.
The studies discussed here and those in the January-Feruary 2005 issue of Quest illustrate that there are many possible ways being studied in an attempt to solve the problems that are present in the boys with DMD. Small steps of progress are being made that may ultimately prolong the active life of the boys and, perhaps, achieve success in mitigating the disease.
Last updated: March 28, 2005 4:27 PM
