By MedWire Reporters
A compound that results in a read-through on nonsense mutations in messenger RNA (mRNA) restores dystrophin expression in an animal model of Duchenne muscular dystrophy (DMD), research shows.
In addition, the molecule, called RTC13, improves muscle function.
"The use of RTC13 to suppress early termination of protein synthesis holds promise and could ultimately result in the development of an effective treatment for DMD," state Carmen Bertoni (University of California, Los Angeles, USA) and colleagues in Human Molecular Genetics.
DMD is a fatal X-linked recessive disorder that affects 1 in 3500 males, with muscle weakening and muscle wasting beginning early in childhood.
Death, frequently caused by respiratory or cardiac failure resulting from a breakdown of the diaphragm or heart, typically occurs between 20 and 30 years of age.
The disease is caused by mutations in the dystrophin gene. Of the mutations, 13% are nonsense mutations that result in a truncated, nonfunctional protein.
Molecules that would induce ribosomal read-through of nonsense mutations and allow for the full-length functional proteins to be created are a promising area of research in DMD.
The researchers screened approximately 35,000 small molecules in search of new compounds that would ignore, or "read-through," the nonsense mutations. Two candidates, RTC13 and RTC14, were identified.
Direct intramuscular injection of RTC14 did not result in significant read-through activity in vivo. In addition, there was no increase in measured dystrophin levels in the mouse model.
An intramuscular injection of RTC13, on the other hand, resulted in a significantly higher level of dystrophin. Given systemically, RTC13 also restored dystrophin in various muscles, such as the heart and diaphragm, and also improved muscle function.
"An increase in muscle strength was detected in all treated animals and was accompanied by a significant decrease in creatine kinase (CK) levels," comment the investigators.
The decrease in CK levels, they add, further demonstrates that RTC13 can slow myofiber degeneration and, consequently, myofiber turnover.
Bertoni and colleagues state that any drug that targets nonsense mutations is likely to have only a temporary effect and will likely require repeated administrations over a prolonged period of time, likely over the lifetime of the patient.
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