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Published on: May 24, 2016
Readthrough strategies for stop codons in Duchenne muscular dystrophy
Abstract:
Duchenne muscular dystrophy is due to mutations of the dystrophin gene. These are large deletions or duplications in 80% of cases, while premature stop codons (nonsense point mutations) account for 7% of cases. This subgroup of patients may take advantage of the properties of the antibiotic gentamicin to suppress stop codons (readthrough). The efficiency of the readthrough varies inversely to the efficiency of a stop codon and is also affected by the different components of the drug. Following gentamicin treatment of mdx mice, dystrophin was re-expressed up to 20% of normal level, albeit with variability among animals. Human trials with gentamicin have so far obtained doubtful results. PTC124 belongs to a new class of small molecules that mimics at lower concentrations the readthrough activity of gentamicin. The administration of PTC124 resulted in the production of full-length and functionally active dystrophin both in vitro and in mdx mice. A Phase II clinical trial is now in course and will be terminated at the end of 2006.
Insights
Gentamicin can help some Duchenne muscular dystrophy patients by suppressing stop codons. A new drug, PTC124, shows promise for restoring dystrophin protein in preclinical models.
Area of Science:
- Genetics
- Pharmacology
- Molecular Biology
Background:
- Duchenne muscular dystrophy (DMD) results from dystrophin gene mutations.
- Nonsense mutations causing premature stop codons affect 7% of DMD patients.
- Gentamicin antibiotic shows potential for stop codon readthrough therapy.
Purpose of the Study:
- To investigate the efficacy of gentamicin and PTC124 in treating Duchenne muscular dystrophy.
- To evaluate the potential of readthrough-inducing drugs for nonsense mutation-mediated DMD.
Main Methods:
- Treatment of mdx mice with gentamicin.
- In vitro and in vivo studies with PTC124.
- Assessment of dystrophin re-expression and functionality.
Main Results:
- Gentamicin treatment re-expressed dystrophin in mdx mice (up to 20%), with variable results.
- PTC124 induced full-length, functional dystrophin in vitro and in mdx mice.
- Human trials with gentamicin yielded uncertain outcomes.
Conclusions:
- Gentamicin shows limited efficacy and variability in DMD treatment.
- PTC124 represents a promising therapeutic strategy for DMD caused by nonsense mutations.
- Further clinical trials are warranted to confirm PTC124's efficacy in human patients.
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