Recently, MDA researchers at the University of Pennsylvania in Philadelphia announced a startling finding in Duchenne muscular dystrophy (DMD): The well-known antibiotic gentamicin has the potential to allow a small percentage of people with DMD to begin making dystrophin, a necessary muscle protein not made by people with DMD. (See the press release.)
Frequently Asked Questions (FAQ)
About Gentamicin Studies in Duchenne
Questions:
Q1 What led researchers to study an antibiotic normally used to treat infections as a potential treatment for a genetic disorder such as DMD?
A It's been known for some time that gentamicin (an aminoglycoside antibiotic) affects the way bacteria process their genetic material. Perhaps because of this knowledge, researchers began to take a look at whether gentamicin could affect the way human cells manufacture proteins from the genetic code (DNA and RNA).
More recently, investigators studying cystic fibrosis, a genetic disorder of the respiratory and digestive systems, found that when gentamicin was added to cultured cells from people with CF, the drug enabled the cells to "read through" a type of genetic defect known as a "premature stop codon." Premature stop codons tell cells to stop making a protein from a gene before the protein is fully formed. Normally, stop codons tell a cell when a protein is "finished" and ready to be released into the cell.
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Q2 What did the researchers do to test the effects of gentamicin in Duchenne dystrophy?
A First, researcher H. Lee Sweeney and colleagues at the University of Pennsylvania added gentamicin to muscle cells taken from mice with DMD (mdx mice) and found it had the same effect in these cells as it did on the CF cells that had premature stop codons. It allowed the cells to ignore the stop codons and make the whole protein. Mdx mice all have DMD because of a premature stop codon in the dystrophin gene. Dystrophin made from a gene with a premature stop codon is too small to be useful and is quickly destroyed by the cell.
Next, the researchers tested the drug in living mdx mice. They found that, as they expected, it allowed the mdx mice to start producing dystrophin and reversed the signs of DMD in these mice.
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Q3 Is gentamicin likely to have this effect in children with DMD?
A The researchers estimate that between 5 percent and 15 percent of children with DMD have the disorder because of a premature stop codon in the dystrophin gene. Most people with DMD have other kinds of genetic mutations, such as deletions (pieces missing) in the dystrophin gene. For the 5 percent to 15 percent of boys with DMD due to a premature stop codon, gentamicin could have the same beneficial effects on the disease as it had in the mdx mice. This, however, remains to be demonstrated in a clinical trial. MDA is supporting such a trial at Ohio State University in Columbus.
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Q4 How do you know who has a premature stop codon and who has another type of genetic mutation?
A A very careful type of genetic testing must be done to determine precisely what type of mutation a person has in the dystrophin gene (or any gene). The vast majority of children and young people with DMD haven't had this type of testing, which is different from the usual kind of test available through commercial laboratories and is estimated to cost about $1,000. At this time, researchers tell us it also requires a muscle biopsy, while the usual type of test can be done from blood cells.
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Q5 Should I get this type of test for my child?
A This is a very specialized type of test and we've been advised by researchers that it isn't yet commercially available. The test is currently done only as part of a research study.
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Q6 Who can participate in the clinical trial of gentamicin?
A As of February 2000, researchers at Ohio State University are conducting a pilot study of gentamicin in boys with DMD. Participants have already been selected for this pilot study. There are plans to enroll a new group of people to participate in an expanded follow-up trial in the future.
Candidates for the future trial will be limited to those with DMD who have a premature stop codon mutation in the dystrophin gene. The test for this mutation isn't presently commercially available and will require travel to Ohio State University in Columbus. Those eligible will be the 30 percent who have no deletion in the dystrophin gene (coding sequence). The test will require a muscle biopsy.
As a first step in the process, those interested in participating in a study should have the standard genetic test to determine whether there is any deletion, which is the case with most people with DMD. For people having no deletion, investigators at Ohio State may consider further testing to determine eligibility for the trial.
Because the expanded trial is in its initial planning stage, at the present time, families would be expected to cover all costs relating to genetic testing and initial screening for the trial.
Those meeting the initial eligibility criteria (no deletion) who wish to travel to Columbus, Ohio, may contact:
Clinical Trial Coordinator
Ohio State University
Department of Neurology
(614) 293-9016
(If you call and get an answering machine, please leave your name and phone number. Someone will return your call at the earliest opportunity.)
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Q7 Should I try to secure gentamicin treatment for my child in the meantime?
A Absolutely not. Gentamicin, which has to be injected, is a dangerous drug. It can cause hearing loss and serious kidney damage. The correct dosage and timing of the doses hasn't yet been determined. If the patient doesn't have a premature stop codon, the drug is likely to do much more harm than good. Even if he does, significant harm could come from the wrong dosage or the wrong timing of doses.
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Q8 Does gentamicin have any potential for treating Becker muscular dystrophy?
A The researchers say that, to their knowledge, people with Becker muscular dystrophy who have undergone genetic testing so far have been found to have a deletion in the dystrophin gene. However, it's possible that there are people with BMD who have a premature stop codon that occurs "late" in the dystrophin gene and, therefore, leads to production of a small but partially functional dystrophin protein. (People with BMD have a less severe disease than those with DMD and have some functional dystrophin in their muscle cells.) Therefore, there is some potential for gentamicin in the treatment of BMD.
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Q9 What about other genetic diseases in MDA's program?
A Research on the presence of premature stop codons in genetic diseases is limited but expanding. Preliminary information suggests that there are many diseases, including, but not limited to, spinal muscular atrophy, Charcot-Marie-Tooth disease, at least some mitochondrial disorders and probably various forms of muscular dystrophy, in which premature stop codons play a role. Premature stop codons probably account for a small percentage of disease-causing genetic mutations in most genetic disorders and in some forms of cancer.
As of March 2000, the Ohio State research team is planning to expand the trial to include people with premature stop codons in sarcoglycan genes in limb-girdle muscular dystrophy.
If you have a family member with LGMD, you may call the trial coordinator listed above and discuss testing for premature stop codons in any of four sarcoglycan genes and eligibility for the gentamicin trial in LGMD.
As research results concerning premature stop codons and their relevance to treatment of genetic disorders become available, MDA will keep you informed via its Web site and its publications, such as Quest magazine.
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