A new MDA translational research grant for $476,465 over three years will allow Carmen Bertoni at the University of California, Los Angeles (UCLA) to develop RTC13, an experimental compound designed to treat Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) caused by a specific type of flaw in the gene for the muscle protein dystrophin.
A complete or partial lack of dystrophin protein is the cause of DMD and BMD, respectively.
Bertoni, an assistant professor of neurology at UCLA's David Geffen School of Medicine, has shown in laboratory experiments that RTC13 can cause muscle cells to "read through," or "ignore," erroneous stop signals in the dystrophin gene.
The experiments were conducted in dystrophin-deficient mice that have a DMD-like disease because of an erroneous genetic stop signal. RTC13 allowed the mice to produce dystrophin protein in their muscles and did not have any apparent ill effects.
It's been estimated that some 5 to 15 percent of boys with DMD or BMD develop their disease because of an erroneous stop signal in the dystrophin gene. This type of genetic mutation is known as a "premature stop codon" or a "nonsense" mutation.
By the end of the project, Bertoni expects to have an experimental drug that can be taken orally; can cause a lot of muscle cells to ignore premature stop codon (nonsense) mutations and produce dystrophin; and can improve symptoms in dystrophin-deficient mice with a DMD-like disease. She also expects to have identified any problems related to potential toxicity associated with the drug.
There are other compounds in development aimed at treating nonsense mutations, but they work via slightly different mechanisms, Bertoni notes. (See, for example, Low-Dose Ataluren Shows Some Benefit in DMD/BMD.)
RTC13, Bertoni notes, was first developed by Liutao Du, a postgraduate fellow in the Department of Pathology and Laboratory Medicine at UCLA's David Geffen School of Medicine, when he was working in the laboratory of Richard Gatti, professor of pathology and laboratory medicine and of human genetics.
Bertoni has received previous support from MDA for a different type of DMD treatment strategy involving repair of the dystrophin gene. (See DMD Gene Repair Strategy Takes a Big Step Forward.)
Bertoni's work is not expected to lead directly to a human clinical trial but to cover steps that are essential along the way to a trial.
"We're excited about this new research in the lab and trilled by the support received from MDA," Bertoni said. "We've established a cooperative team focused on developing a drug that can be moved forward into the clinic. The goal of the team now is to optimize the structure of RTC13 so as to obtain an oral read-through drug that can be efficiently distributed into muscles. This drug would avoid the need for invasive procedures to deliver the therapeutic agent into DMD/BMD patients."