J 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

Štítky

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.