This study will evaluate the antibiotic gentamicin for treating patients with muscular
dystrophy caused by a specific genetic abnormality known as a nonsense mutation. In studies
of mice with this type of muscular dystrophy, gentamicin treatment produced positive changes
in muscle tissue.
Patients with Duchenne or Becker muscular dystrophy caused by nonsense mutations by may be
eligible for this 2-week study. Before starting treatment, patients will have evaluations
of muscle strength and general well being. Two muscle tissue samples will be taken by
needle biopsy, under local anesthetic and sedation. Because of potential risks of hearing
loss and kidney toxicity associated with gentamicin, patients will also have a hearing test
and blood and urine tests for kidney function before starting treatment. (Currently,
gentamicin is commonly prescribed for serious infections of the lungs, heart, and digestive
and urinary tracts; adverse effects of hearing loss and kidney toxicity can occur with
excessively high drug doses.)
Patients will be hospitalized during drug treatment. Gentamicin will be given intravenously
(through a vein) once a day for 14 days. Blood samples will be collected daily to monitor
drug levels and determine dosage adjustments, if necessary. Urine samples will be collected
to assess kidney function. Hearing tests will be done on days 7 and 10.
On the last day of the study, hearing, kidney function, and muscle strength will be tested
and the results compared with pre-treatment levels. Blood and muscle samples will also be
taken again for pre-treatment comparison. Hearing, blood, urine, and muscle strength tests
will be repeated one month after treatment ends for comparison with previous results.
Duchenne muscular dystrophy (DMD) is a fatal disease of progressive muscular weakness for
which there is currently no effective treatment. The disease is caused by mutations in the
gene for dystrophin. A subset of these mutations includes nonsense mutations, i.e.,
premature stop codons. Previous studies have shown that aminoglycosides are effective in
allowing translation through stop codons. Recently, gentamicin was shown to restore
functional dystrophin in a mouse model of DMD. The objective of this protocol is to
determine if gentamicin is also an effective treatment in patients with DMD caused by
nonsense mutations. This will be a preliminary, non-blinded study in which levels of
intravenous gentamicin previously established to be safe, will be administered to identified
patients meeting inclusion criteria over a two-week period. These patients will have CLIA
approved laboratory documented stop codon mutations in the dystrophin gene. Quantitative
dystrophin expression will be the primary outcome. Strength measurements will also be
assessed before and immediately after the two-week treatment period. Follow-up evaluations
will be made at one month. For this subset of patients with DMD it is anticipated that
there will be a transient increase in dystrophin expression with a possible corresponding
transient improvement in strength. Subsequent blinded studies to evaluate the most
effective dose and dosing intervals would then be pursued.
Diagnosis of DMD or Becker muscular dystrophy with confirmed dystrophin nonsense mutation.
Measurable limb or pulmonary weakness.
Must not have a history of hypersensitivity reaction to an aminoglycoside.
Must not have abnormal baseline hearing.
Must not have abnormal baseline kidney function or serum creatinine level.
Must not be currently enrolled in another clinical trial.
Must not have recent (within past 3 months) initiation of prednisone or creatinine
Must not have a history of significant concomitant illness.
Must not have concomitant use of aminoglycoside or other nephrotoxic agent.