In silico analysis and theratyping of an ultra-rare CFTR genotype (W57G/A234D) in primary human rectal and nasal epithelial cells

Kleinfelder, Karina; Lotti, Virginia; Eramo, Adriana; Amato, Felice; Lo Cicero, Stefania; Castelli, Germana; Spadaro, Francesca; Farinazzo, Alessia; Dell’Orco, Daniele; Preato, Sara; Conti, Jessica; Rodella, Luca; Tomba, Francesco; Cerofolini, Angelo; Baldisseri, Elena; Bertini, Marina; Volpi, Sonia; Villella, Valeria Rachela; Esposito, Speranza; Zollo, Immacolata; Castaldo, Giuseppe; Laudanna, Carlo; Sorsher, Eric J.; Hong, Jeong; Joshi, Disha; Cutting, Garry; Lucarelli, Marco; Melotti, Paola; Sorio, Claudio

doi:10.1016/j.isci.2023.108180

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…Altogether, the positive responses in both tissues, supported the claim that Trikafta was effective in the airways and in the colon of people bearing the major mutation or certain rare mutations. The group of Cutting and colleagues, also employed a multimodal approach to examine the efficacy of Trikafta in an ultra-rare CF-causing mutation (19). The positive response measured in 2D and 3D cultures, modeling airway and rectal epithelia, supported the potential efficacy in Trikafta in treating disease in both organs in people with this ultra-rare mutation.…”

Section: Discussionmentioning

confidence: 99%

Benchmarking organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs

Daoud,

Xia,

Laselva

et al. 2024

Preprint

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Cystic Fibrosis (CF) is a life-shortening disease that is caused by mutations in theCFTRgene, a gene that is expressed in multiple organs. There are several primary tissue models of CF disease, including nasal epithelial cultures and rectal organoids, that are effective in reporting the potential efficacy of mutation-targeted therapies called CFTR modulators. However, there is the well-documented variation in tissue dependent, therapeutic response amongst CF patients, even those with the same CF-causing mutation. Hence, there is an interest in developing strategies for benchmarking therapeutic efficacy in different organs relative to isogenic controls. In this study, we evaluated the CFTR chloride channel response to the highly effective CFTR modulator: Trikafta, in CF patient specific, iPSC-derived colonic and airway cultures relative to mutation-corrected (non-CF) tissues from that same individual. We measured pharmacological rescue in both tissues, but interestingly, Trikafta treatment resulted in different levels of functional rescue in the two tissues relative to the relevant isogenic control. This proof-of-concept study lays the groundwork for future comparisons of patient-specific CF therapeutic responses in both pulmonary and extra-pulmonary systems.

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Section: Discussionmentioning

confidence: 99%

Benchmarking organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs

Daoud,

Xia,

Laselva

et al. 2024

Preprint

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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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Identification of an ultra-rare Alu insertion in the CFTR gene: Pitfalls and challenges in genetic test interpretation

Esposito,

Zollo,

Villella

et al. 2024

Clinica Chimica Acta

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In silico analysis and theratyping of an ultra-rare CFTR genotype (W57G/A234D) in primary human rectal and nasal epithelial cells

Cited by 3 publications

References 51 publications

Benchmarking organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs

Benchmarking organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs

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

Identification of an ultra-rare Alu insertion in the CFTR gene: Pitfalls and challenges in genetic test interpretation

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