| SILVA, I. A.L ., Tereza DOUSOVA, S. RAMALHO, R. CENTEIO, L. A. CLARKE, V. RAILEAN, H. M. BOTELHO, Andrea HOLUBOVA, Iveta VALÁŠKOVÁ, J. T. YEH, T. C. HWANG, C. M. FARINHA, K. KUNZELMANN and M. D. AMARAL. Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G. Biochimica et Biophysica Acta - Molecular Basis of Disease. Amsterdam: ELSEVIER SCIENCE BV, 2020, vol. 1866, No 11, p. 1-10. ISSN 0925-4439. Available from: https://dx.doi.org/10.1016/j.bbadis.2020.165905. |
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@article{1677936,
author = {Silva, I. A.L . and Dousova, Tereza and Ramalho, S. and Centeio, R. and Clarke, L. A. and Railean, V. and Botelho, H. M. and Holubova, Andrea and Valášková, Iveta and Yeh, J. T. and Hwang, T. C. and Farinha, C. M. and Kunzelmann, K. and Amaral, M. D.},
article_location = {Amsterdam},
article_number = {11},
doi = {http://dx.doi.org/10.1016/j.bbadis.2020.165905},
keywords = {CFTR modulators; Theranostics; Rare mutations; Intestinal organoids; Precision medicine},
language = {eng},
issn = {0925-4439},
journal = {Biochimica et Biophysica Acta - Molecular Basis of Disease},
title = {Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G},
url = {https://www.sciencedirect.com/science/article/pii/S0925443920302532},
volume = {1866},
year = {2020}
}
TY - JOUR
ID - 1677936
AU - Silva, I. A.L . - Dousova, Tereza - Ramalho, S. - Centeio, R. - Clarke, L. A. - Railean, V. - Botelho, H. M. - Holubova, Andrea - Valášková, Iveta - Yeh, J. T. - Hwang, T. C. - Farinha, C. M. - Kunzelmann, K. - Amaral, M. D.
PY - 2020
TI - Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
VL - 1866
IS - 11
SP - 1-10
EP - 1-10
PB - ELSEVIER SCIENCE BV
SN - 09254439
KW - CFTR modulators
KW - Theranostics
KW - Rare mutations
KW - Intestinal organoids
KW - Precision medicine
UR - https://www.sciencedirect.com/science/article/pii/S0925443920302532
L2 - https://www.sciencedirect.com/science/article/pii/S0925443920302532
N2 - Background: For most of the > 2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine. Methods: Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators. Results: Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating < 1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels. Conclusion: This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.
ER -
SILVA, I. A.L ., Tereza DOUSOVA, S. RAMALHO, R. CENTEIO, L. A. CLARKE, V. RAILEAN, H. M. BOTELHO, Andrea HOLUBOVA, Iveta VALÁŠKOVÁ, J. T. YEH, T. C. HWANG, C. M. FARINHA, K. KUNZELMANN and M. D. AMARAL. Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A \&{}gt; G. \textit{Biochimica et Biophysica Acta - Molecular Basis of Disease}. Amsterdam: ELSEVIER SCIENCE BV, 2020, vol.~1866, No~11, p.~1-10. ISSN~0925-4439. Available from: https://dx.doi.org/10.1016/j.bbadis.2020.165905.
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