The drug gentamicin increased dystrophin levels in boys with DMD due to a nonsense mutation, but didn't improve strength at the doses used
Results of the MDA-supported trial of gentamicin in Duchenne muscular dystrophy (DMD) were presented Wednesday, April 14, at the annual meeting of the American Academy of Neurology (AAN), held in Toronto.
Levels of the needed dystrophin protein increased in six out of 12 participants who received the drug for six months. No functional improvements were seen.
An unwanted immune response to the newly synthesized dystrophin was seen in one trial participant. (The reaction was determined by exposing immune-system cells to parts of the dystrophin molecule in the laboratory and by analysis of biopsy slides.)
The presentation contained similar information to a paper published online March 15, 2010, in Annals of Neurology, which was summarized on the MDA Web site March 23. (See Gentamicin Trial in DMD Shows Mixed Results.)
Meaning for people with DMD
The data from this latest gentamicin trial show that this drug can, in some cases, increase dystrophin production, but that still more dystrophin will be needed to improve muscle function than was produced in these trial participants.
The proposed mechanism for gentamicin in DMD is the coaxing of cells to ignore, or "read through," premature stop codons (erroneous early stop signs) in the dystrophin gene, so that functional dystrophin protein can be made. Premature stop codons are thought to affect some 13 percent to 15 percent of boys with DMD.
It's possible that higher gentamicin dosages would be more beneficial. However, problems with further increases in gentamicin dosing include: 1) the drug may be toxic in high doses or when given for prolonged periods of time; 2) it has to be given intravenously, which is inconvenient and expensive; 3) only some dystrophin-deficient patients respond to it; and 4) researchers don't yet know what all the factors are that determine this response.
It's plausible (although not yet established) that an immune response may be responsible for the failure of gentamicin — and perhaps other stop codon read-through drugs — to sustain enhanced levels of dystrophin and therefore to improve function. If this proves to be the case, it may be possible to manipulate the immune system to overcome this barrier to treatment.