BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G

Participants in the publication
Iris A.L. Silva (Author)
BioISI
Tereza Doušová (Author)
Sofia Ramalho (Author)
BioISI - Biosystems & Integrative Sciences Institute
Raquel Centeio (Author)
BioISI - Biosystems & Integrative Sciences Institute
Luka A. Clarke (Author)
Dep. Química e Bioquímica
BioISI
Violeta Railean (Author)
Hugo M. Botelho (Author)
Dep. Química e Bioquímica
BioISI
Andrea Holubová (Author)
Iveta Valášková (Author)
Jiunn-Tyng Yeh (Author)
Tzyh-Chang Hwang (Author)
Carlos M. Farinha (Author)
Dep. Química e Bioquímica
BioISI
Karl Kunzelmann (Author)
UNIVERSITÄT REGENSBURG
Margarida D. Amaral (Author)
Dep. Química e Bioquímica
BioISI

Summary
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.\\\\n\\\\nMethods: 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.\\\\n\\\\nResults: 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.\\\\n\\\\nConclusion: This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.


Where published
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Publication Identifiers
ISSN - 0925-4439

Publisher
Elsevier BV



Document Identifiers
DOI - https://doi.org/10.1016/j.bbadis.2020.165905
URL - http://dx.doi.org/10.1016/j.bbadis.2020.165905

Rankings
Web Of Science Q1 (2018) - 4.328 - BIOCHEMISTRY & MOLECULAR BIOLOGY - SCIE
SCIMAGO Q1 (2019) - 1.649 - Molecular Medicine
SCOPUS Q1 (2019) - 7.7 - Molecular Medicine
Web Of Science Q1 (2019) - 4.352 - BIOPHYSICS - SCIE
Web Of Science Q1 (2020) - 5.187 - BIOPHYSICS - SCIE
SCIMAGO Q1 (2020) - 1.676 - Molecular Medicine
SCOPUS Q1 (2020) - 9.1 - Molecular Medicine
SCOPUS Q1 (2020) - 9.1 - Molecular Biology

Keywords
CFTR modulators Intestinal organoids Precision medicine Rare mutations Theranostics