An experimental drug called RTC13, designed to treat Duchenne muscular dystrophy (DMD) by restoring production of the muscle protein dystrophin, has shown promise in experiments in dystrophin-deficient mice that have a DMD-like disease.
RTC13's MDA-supported developers say they're optimistic about the compound but that refinement of its chemistry and further testing will be needed before it can be taken into clinical trials in people with DMD.
RTC13, which stands for read-through compound 13, is designed to bypass, or "read through," a flaw in the dystrophin gene that's known as a premature stop codon mutation or nonsense mutation.
Such mutations cause cells to stop making the muscle protein dystrophin too soon, resulting in synthesis of a nonfunctional protein.
RTC13 and other compounds that cause read-through of premature stop codons are designed to coax synthesis of full-length dystrophin protein despite the erroneous stop signal. (Drugs that cause read-through of stop codons also have potential in other genetic diseases in which premature stop codons play a role. An example is the lung disease cystic fibrosis.)
It's believed that about 10 to 15 percent of boys with DMD have the disease because of a premature stop codon.
RTC13 was first identified in 2009 by researchers in the laboratory of Richard Gatti, professor of pathology and laboratory medicine and of human genetics at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), and colleagues. Among the handful of promising read-through compounds discovered, two — RTC13 and RTC14— were shown to be promising candidates for treatment of DMD.
Carmen Bertoni, an assistant professor in the Department of Neurology at UCLA, began receiving funding in 2011 to develop RTC13 through MDA Venture Philanthropy, the drug development arm of MDA's translational research program.
Bertoni, with UCLA postdoctoral researcher Refik Kayali and other colleagues, now report a series of experiments in dystrophin-deficient mice that have a premature stop codon in the dystrophin gene and show a disease resembling human DMD.
The results, published online June 12, 2012, in Human Molecular Genetics, suggest that RTC13 may be superior to previously tested read-through compounds aimed at treating the disease. (However, only a clinical trial can demonstrate RTC13's efficacy in humans.)
Two weeks after the investigators injected RTC13 directly into the leg muscles of DMD-like mice, they saw dystrophin protein production along the whole length of the muscle. When they compared muscles injected with RTC13 to those injected with other compounds, they saw better dystrophin production with RTC13 than with any of the others.
Muscles injected with either RTC13 or ataluren produced dystrophin along the muscle, but the ataluren-injected muscles showed patchy dystrophin production, while the RTC13-injected muscles showed broad distribution of the protein.
The investigators compared systemically delivered RTC13 with systemically delivered ataluren in DMD-like mice, giving each mouse one of the compounds by injection into the abdomen every five days for four weeks.
Three weeks after the last injection of either compound, they saw dystrophin protein production in several muscles, including the diaphragm and heart. Dystrophin protein levels and numbers of dystrophin-producing fibers were higher in the RTC13-treated mice than in the ataluren-treated mice.
Tests of the dystrophin induced by RTC13 treatment showed it was full-length and functional. Tests of toxicity showed it had no apparent ill effects.
Mice given the same regimen of either systemic RTC13, systemic ataluren or no treatment were compared on tests of muscle function three weeks after the final injection.
In a test of overall strength and coordination, mice that received RTC13 or ataluren did equally better than untreated mice. Both groups of treated mice did better in a test of forelimb grip strength than untreated animals did, but the RTC13-treated mice performed better than mice that were treated with ataluren on this test.
In their June 12 paper, the investigators say the results of testing of RTC13 in the dystrophin-deficient mouse are encouraging, particularly because they saw production of the needed protein in the heart and diaphragm, which are critical muscles for survival.
"Challenges and caveats still remain," said Bertoni. "The development of this new drug will require a better understanding of the mechanisms by which RTC13 causes read-through of stop codons. Giving RTC13 orally instead of by injection, knowing how safe it is to use, and knowing how much protein can be produced after it is given repeatedly (every day over the course of several weeks) are the next goals."