About gentamicin and MD
Gentamicin is an aminoglycoside antibiotic, normally used for fighting infections. Several years ago, it was found that gentamicin is among the compounds that can cause "stop codon read-through," allowing cells to ignore (read through) a stop codon and synthesize a complete and functional protein.
In 1999, MDA-supported studies showed that mice missing dystrophin because of a stop codon began producing the protein after treatment with gentamicin. (See Antibiotic Shows Promise as Systemic Treatment for Muscular Dystrophy.) In these mice, the investigators saw some protection against contraction-induced muscle injury and a reduction of serum creatine kinase (CK), an enzyme that leaks out of damaged muscle cells. A reduction in serum CK is generally considered an indication that muscle destruction has slowed.
Investigators began to plan studies in humans, but they had to exercise extreme care, because long-term or high-dose gentamicin can cause kidney damage, hearing loss and impairment of balance. (A blood test before gentamicin treatment can reduce the incidence of side effects, Mendell said.)
Starting about 2000, investigators cautiously infused the drug in two small, two-week studies in people with DMD, BMD and limb-girdle muscular dystrophy (LGMD), announcing results in 2001. The results of both small studies were confusing: There was no evidence that dystrophin or the targeted LGMD protein increased, but both studies saw marked decreases in blood CK levels, indicating possible slowing of muscle damage. (See "Gentamicin Studies Yield Confusing Results," in Research Updates, Quest, June 2001.)
An Italian study of the drug in DMD patients, for which results were announced in 2003, found three out of four participants began producing dystrophin after receiving gentamicin for two six-day periods seven weeks apart.
These early results prompted Mendell and others to continue studying gentamicin as a possible therapy for DMD or BMD. They speculated that a longer course of treatment, accompanied by careful monitoring for drug toxicity, could result in significant dystrophin production.
Meaning for people with DMD and BMD
The data from this latest gentamicin trial show that this stop codon read-through drug can, in some cases, increase dystrophin production, but still more dystrophin will be needed to improve muscle function.
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.
Recently, the oral drug ataluren (PTC124), an experimental stop codon read-through compound, failed to increase the distance people with DMD or BMD could walk in six minutes (see Ataluren Results Disappointing). Detailed analyses of those trial results are not yet available.
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 in DMD and BMD. If this proves to be the case, it may be possible to manipulate the immune system to overcome this barrier to treatment.
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