2020
Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G
SILVA, I. A.L ., Tereza DOUSOVA, S. RAMALHO, R. CENTEIO, L. A. CLARKE et. al.Základní údaje
Originální název
Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G
Autoři
SILVA, I. A.L . (620 Portugalsko), Tereza DOUSOVA (203 Česká republika), S. RAMALHO (620 Portugalsko), R. CENTEIO (620 Portugalsko), L. A. CLARKE (620 Portugalsko), V. RAILEAN (620 Portugalsko), H. M. BOTELHO (620 Portugalsko), Andrea HOLUBOVA (203 Česká republika), Iveta VALÁŠKOVÁ (203 Česká republika, domácí), J. T. YEH (840 Spojené státy), T. C. HWANG (840 Spojené státy), C. M. FARINHA (620 Portugalsko), K. KUNZELMANN (276 Německo) a M. D. AMARAL (620 Portugalsko, garant)
Vydání
Biochimica et Biophysica Acta - Molecular Basis of Disease, Amsterdam, ELSEVIER SCIENCE BV, 2020, 0925-4439
Další údaje
Jazyk
angličtina
Typ výsledku
Článek v odborném periodiku
Obor
10601 Cell biology
Stát vydavatele
Nizozemské království
Utajení
není předmětem státního či obchodního tajemství
Odkazy
Impakt faktor
Impact factor: 5.187
Kód RIV
RIV/00216224:14110/20:00116370
Organizační jednotka
Lékařská fakulta
UT WoS
000561985900013
Klíčová slova anglicky
CFTR modulators; Theranostics; Rare mutations; Intestinal organoids; Precision medicine
Příznaky
Mezinárodní význam, Recenzováno
Změněno: 9. 9. 2020 08:08, Mgr. Tereza Miškechová
Anotace
V originále
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.