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Nonsense Mutations in Genetic Disease - A Novel Treatment« Back to Volume 23, Issue 3, November 2007 - Table of Contents Nonsense mutations are a common cause of human genetic disease. They give rise to in-frame premature translation termination or stop codons within the coding regions of genes and lead to truncated protein translation products that are typically nonfunctional and also promote mRNA destruction by so-called nonsense-mediated mRNA decay (NMD). The idea of developing pharmacologic means to induce a cell’s translation machinery to readthrough premature termination codons (PTCs) has been around for some time, and there is evidence that the antibiotic gentamicin prompts ribosomes to readthrough PTCs to generate full-length proteins (Figure). In fact, gentamicin has received attention in this context and preliminary trials have been carried out in patients with Duchenne muscular dystrophy (DMD) and cystic fibrosis due to mutations that introduce PTCs. However, the high doses that are required, potential for renal and otic toxicity and need for intravenous or intramuscular administration of gentamicin have limited its potential usefulness for treatment of human diseases. A new compound has now been identified that appears to suppress PTCs with fewer potential problems.
Welch et al utilized high-throughput screening of ~800,000 compounds to identify small molecules that would suppress PTCs. One compound designated PTC124 promoted dose-dependent readthrough of PTCs, including human and mouse nonsense alleles of the dystrophin gene. Compared to gentamicin, PTC124 was effective at much lower doses and it could be delivered orally. After documenting an increase in dystrophin protein levels in primary muscle cell cultures, they then treated mdx mice, a mouse model of DMD due to a mutation-induced PTC in the dystrophin gene. PTC124 treatment led to partial rescue of the muscle disturbance in the mdx mice. The most notable functional result was protection against susceptibility to contraction-induced injury. This injury, which is a typical feature of the mdx mouse and most likely occurs in DMD patients, involves repeated cycles of degeneration—regeneration, inflammation, and necrosis that eventually leads to muscle destruction. Susceptibility to this injury for mice treated with PTC124 was no different than for wild-type mice. Mdx mice treated with PTC124 for 8 weeks showed significant decreases in serum creatinine kinase levels compared to untreated controls. Their muscle tissues displayed increased levels of dystrophin protein as well as g-sarcoglycan consistent with production and stabilization of the dystrophin-associated membrane complex that is missing in the absence of dystrophin. Drug treatment also led to a partial restoration of dystrophin to the membrane of skeletal muscles, although the relative amount appeared to be less than in wild-type mice. The authors concluded that PTC124 is a more potent nonsense mutation suppressing agent than gentamicin. They attribute its effect to directly suppressing premature termination during translation rather than to interference with NMD. Importantly, they also provided evidence that it does not affect the function of normal termination codons. The authors suggested that through increasing the efficiency of translation, PTC124 may benefit patients with genetic diseases due to nonsense mutations. An accompanying news and views comment indicated that Phase II clinical trials are underway for PTC124 in DMD and cystic fibrosis. Schmitz A, Famulok M. Chemical biology: ignore the nonsense. Nature. 2007;447:42-3. Editor’s CommentThe research described in this paper could have significant impact on the treatment of a subset of genetic disease. It reflects a marriage between so called chemical biology, which seeks to identify small molecules that produce desired therapeutic effects on disesase processes, and continued efforts to understand the molecular consequences of mutations. It underscores an importance of DNA diagnoses. The paper raises the concern that suppressing PTCs would lead to synthesis of mutant proteins. In many instances such as enzymopathies and disorders in which structural proteins serve as platforms for or link together cellular machinery, such as in DMD, having more protein even if it harbors a mutation, would seem beneficial. However, there may also be instances where having no protein is better for a cell or a tissue than having a mutant protein that adversely affects other normal molecules. William A. Horton, MD
« Back to Volume 23, Issue 3, November 2007 - Table of Contents
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
