Scholarlink

Background <p>Translational readthrough represents a promising therapeutic strategy for genetic disorders caused by nonsense mutations. Although multiple translational readthrough-inducing drugs (TRIDs) have been reported, their relative efficacy remains inconsistent across studies, likely due to differences in experimental systems and cellular contexts. A systematic comparison across complementary and clinically relevant models is therefore required to better define their therapeutic potential. This study aims to evaluate and compare the efficiency of different TRIDs used for nonsense mutation correction.</p> Methods <p>We performed a comparative evaluation of 12 TRIDs using a panel of cellular models encompassing increasing levels of physiological relevance. These included a firefly luciferase-based reporter assay, human cell lines harboring endogenous TP53 nonsense mutations, patient-derived intestinal organoids carrying CFTR nonsense variants, and Fischer rat thyroid (FRT) cells expressing homozygous CFTR nonsense mutations. Readthrough efficiency was assessed and compared across models.</p> Results <p>Across the different systems, 2,6-diaminopurine (DAP), clitocine, SRI-41315, and TLN468 consistently exhibited the highest readthrough activity. However, variations in relative efficacy were observed depending on the assay and cellular context, underscoring the influence of experimental conditions, amino acid incorporation profiles, and cell-specific determinants on readthrough outcomes.</p> Conclusions <p>Our findings demonstrate the necessity of evaluating candidate TRIDs across multiple complementary and patient-relevant models to accurately estimate their therapeutic potential. This study identifies several promising compounds for further preclinical development and provides a comparative framework to guide the rational selection of readthrough-inducing agents for translational applications.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Comparative evaluation of TRIDs : a strategy to improve treatments

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

查看全文
  • Fatima Hariss,
  • Sacha Spelier,
  • Louise Damy,
  • Carmen Sandoval Pacheco,
  • Luca Houpe,
  • Catherine Leroy,
  • Xavier Thuru,
  • Frédéric Becq,
  • Fabrice Lejeune

摘要

Background

Translational readthrough represents a promising therapeutic strategy for genetic disorders caused by nonsense mutations. Although multiple translational readthrough-inducing drugs (TRIDs) have been reported, their relative efficacy remains inconsistent across studies, likely due to differences in experimental systems and cellular contexts. A systematic comparison across complementary and clinically relevant models is therefore required to better define their therapeutic potential. This study aims to evaluate and compare the efficiency of different TRIDs used for nonsense mutation correction.

Methods

We performed a comparative evaluation of 12 TRIDs using a panel of cellular models encompassing increasing levels of physiological relevance. These included a firefly luciferase-based reporter assay, human cell lines harboring endogenous TP53 nonsense mutations, patient-derived intestinal organoids carrying CFTR nonsense variants, and Fischer rat thyroid (FRT) cells expressing homozygous CFTR nonsense mutations. Readthrough efficiency was assessed and compared across models.

Results

Across the different systems, 2,6-diaminopurine (DAP), clitocine, SRI-41315, and TLN468 consistently exhibited the highest readthrough activity. However, variations in relative efficacy were observed depending on the assay and cellular context, underscoring the influence of experimental conditions, amino acid incorporation profiles, and cell-specific determinants on readthrough outcomes.

Conclusions

Our findings demonstrate the necessity of evaluating candidate TRIDs across multiple complementary and patient-relevant models to accurately estimate their therapeutic potential. This study identifies several promising compounds for further preclinical development and provides a comparative framework to guide the rational selection of readthrough-inducing agents for translational applications.