Genetic therapies in cystic fibrosis

Taylor-Cousar, Jennifer L.; Boyd, A. Christopher; Alton, Eric W.F.W.; Polineni, Deepika

doi:10.1097/mcp.0000000000001019

Cited by 4 publications

(1 citation statement)

References 29 publications

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“…Both various genetic therapies and small-molecule pharmacophores are pursued to alleviate the cellular phenotype of PTCs in various model systems ( Taylor-Cousar et al, 2023 ). Significant progress has been made by using gene editing, engineered nonsense suppressor tRNA, and CFTR gene or mRNA delivery approaches ( Marquez Loza et al, 2021 ; Ko et al, 2022 ; Albers et al, 2023 ; Graeber and Mall, 2023 ; Kulhankova et al, 2023 ; Walker et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations

Premchandar,

Ming,

Baiad

et al. 2024

Front. Pharmacol.

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Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Premature termination codons (PTCs) represent ∼9% of CF mutations that typically cause severe expression defects of the CFTR anion channel. Despite the prevalence of PTCs as the underlying cause of genetic diseases, understanding the therapeutic susceptibilities of their molecular defects, both at the transcript and protein levels remains partially elucidated. Given that the molecular pathologies depend on the PTC positions in CF, multiple pharmacological interventions are required to suppress the accelerated nonsense-mediated mRNA decay (NMD), to correct the CFTR conformational defect caused by misincorporated amino acids, and to enhance the inefficient stop codon readthrough. The G418-induced readthrough outcome was previously investigated only in reporter models that mimic the impact of the local sequence context on PTC mutations in CFTR. To identify the misincorporated amino acids and their ratios for PTCs in the context of full-length CFTR readthrough, we developed an affinity purification (AP)-tandem mass spectrometry (AP-MS/MS) pipeline. We confirmed the incorporation of Cys, Arg, and Trp residues at the UGA stop codons of G542X, R1162X, and S1196X in CFTR. Notably, we observed that the Cys and Arg incorporation was favored over that of Trp into these CFTR PTCs, suggesting that the transcript sequence beyond the proximity of PTCs and/or other factors can impact the amino acid incorporation and full-length CFTR functional expression. Additionally, establishing the misincorporated amino acid ratios in the readthrough CFTR PTCs aided in maximizing the functional rescue efficiency of PTCs by optimizing CFTR modulator combinations. Collectively, our findings contribute to the understanding of molecular defects underlying various CFTR nonsense mutations and provide a foundation to refine mutation-dependent therapeutic strategies for various CF-causing nonsense mutations.

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Section: Introductionmentioning

confidence: 99%

Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations

Premchandar,

Ming,

Baiad

et al. 2024

Front. Pharmacol.

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Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases

Kim,

Plate

2024

Israel Journal of Chemistry

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Cystic Fibrosis (CF) is a genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to a faulty CFTR protein. Dysfunctional CFTR causes chloride ion imbalance, resulting in dense mucus accumulation in various organs, particularly the lungs. CF treatments focus on symptom management and addressing CFTR′s functional defects. Notably, development of CFTR modulator therapies has significantly advanced CF treatment. These drugs target CFTR protein structural defects induced by mutations, restoring its function and improving CF symptoms. VX‐770, a CFTR potentiator, and CFTR correctors like VX‐809, VX‐661, and VX‐445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. However, some CFTR mutations lack effective targeted therapies, leaving approximately 6 % of CF patients without suitable options. CFTR modulator therapies have proven essential for combating the underlying causes of protein misfolding diseases, serving as a blueprint for similar treatments in other membrane protein misfolding diseases. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases.

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Traitements de la mucoviscidose

Bardin,

Pranke,

Hinzpeter

et al. 2024

Med Sci (Paris)

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Avec le temps, la mucoviscidose est devenue un exemple de synergie entre la recherche en biologie cellulaire et les progrès cliniques. Les thérapies protéiques ont enfin apporté l’espoir d’une vie normale aux patients, bouleversant ainsi les statistiques épidémiologiques établies. Néanmoins, les patients ne guérissent pas, et l’évolution épidémiologique de la maladie ouvre de nouveaux défis pour la prise en charge des malades. Par ailleurs, environ 10 % des patients demeurent sans solution thérapeutique. De nouvelles stratégies sont ainsi envisagées et la communauté des chercheurs, industriels, patients et autorités de santé reste mobilisée pour suivre les effets à long terme de ces nouveaux traitements et explorer de nouvelles approches pharmacologiques.

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Genetic therapies in cystic fibrosis

Cited by 4 publications

References 29 publications

Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations

Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations

Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases

Traitements de la mucoviscidose

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