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Pharmacological approaches for targeting cystic fibrosis nonsense mutations
Jyoti Sharma1, Kim M Keeling2, Steven M Rowe3
1Department of Medicine, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA.
Abstract:
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.
Insights
This review explores readthrough agents for cystic fibrosis (CF) nonsense mutations. Combining therapies like readthrough agents and NMD inhibitors shows promise for improving CFTR protein function and patient outcomes.
Area of Science:
- Genetics and Molecular Biology
- Pharmacology and Therapeutics
- Medical Genetics
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- Over 2,000 CFTR mutations exist, necessitating diverse therapeutic strategies.
- Current precision medicines target specific CFTR mutations but may not address all defects.
Purpose of the Study:
- To review translational readthrough approaches for CFTR nonsense mutations.
- To evaluate the efficacy and limitations of current readthrough/nonsense suppression therapies.
- To explore combination strategies for enhanced CF treatment.
Main Methods:
- Review of existing literature on translational readthrough and nonsense suppression therapies for CF.
- Analysis of limitations including non-native amino acid incorporation and nonsense-mediated mRNA decay (NMD).
- Discussion of combination approaches involving readthrough agents, NMD inhibitors, and potentiators/correctors.
Main Results:
- Translational readthrough therapies offer a promising avenue for treating CFTR nonsense mutations.
- Limitations such as off-target effects and NMD need to be addressed for improved efficacy.
- Combination therapies have the potential to enhance the effectiveness and safety of suppression strategies.
Conclusions:
- Targeted, mutation-specific strategies are crucial for addressing the basic defects in CF.
- Combining readthrough agents with other therapeutic modalities can improve outcomes for CF patients with nonsense mutations.
- This approach represents a significant advancement in precision medicine for cystic fibrosis.
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