Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G.
Alleles
Aminophenols
/ therapeutic use
Aminopyridines
/ therapeutic use
Benzodioxoles
/ therapeutic use
Blotting, Western
Cystic Fibrosis
/ drug therapy
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Electrophysiology
Fluorescent Antibody Technique
Genotype
Humans
Indoles
/ therapeutic use
Mutation
/ genetics
Precision Medicine
/ methods
Quinolones
/ therapeutic use
CFTR modulators
Intestinal organoids
Precision medicine
Rare mutations
Theranostics
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 11 2020
01 11 2020
Historique:
received:
14
01
2020
revised:
07
07
2020
accepted:
22
07
2020
pubmed:
31
7
2020
medline:
15
12
2020
entrez:
31
7
2020
Statut:
ppublish
Résumé
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. 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 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. This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.
Sections du résumé
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.
Identifiants
pubmed: 32730979
pii: S0925-4439(20)30253-2
doi: 10.1016/j.bbadis.2020.165905
pmc: PMC7484254
mid: NIHMS1621804
pii:
doi:
Substances chimiques
Aminophenols
0
Aminopyridines
0
Benzodioxoles
0
Indoles
0
Quinolones
0
tezacaftor
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
ivacaftor
1Y740ILL1Z
lumacaftor
EGP8L81APK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
165905Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK055835
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Références
Pharmacol Res Perspect. 2015 Aug;3(4):e00152
pubmed: 26171232
J Gen Physiol. 2018 Apr 2;150(4):539-570
pubmed: 29581173
Hum Mutat. 2019 Mar;40(3):326-334
pubmed: 30488522
Hum Mutat. 2014 Oct;35(10):1249-59
pubmed: 25066652
J Cyst Fibros. 2019 Mar;18(2):182-189
pubmed: 30030066
J Physiol. 2020 Feb;598(3):517-541
pubmed: 31585024
Cell Rep. 2019 Feb 12;26(7):1701-1708.e3
pubmed: 30759382
J Cyst Fibros. 2019 Sep;18(5):693-699
pubmed: 31147302
PLoS One. 2012;7(10):e47708
pubmed: 23082198
J Cyst Fibros. 2013 Dec;12(6):737-45
pubmed: 23478129
Eur J Pediatr. 1997 Mar;156(3):212-3
pubmed: 9083763
Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G617-24
pubmed: 10762616
J Cyst Fibros. 2014 Jan;13(1):29-36
pubmed: 23891399
J Cyst Fibros. 2019 Jan;18(1):22-34
pubmed: 29934203
J Gen Physiol. 2015 Jan;145(1):47-60
pubmed: 25512598
J Cyst Fibros. 2019 Sep;18(5):677-684
pubmed: 31303382
J Biol Chem. 1999 Jul 30;274(31):21873-7
pubmed: 10419506
Nat Med. 2013 Jul;19(7):939-45
pubmed: 23727931
Gastroenterology. 2004 Oct;127(4):1085-95
pubmed: 15480987
Sci Transl Med. 2016 Jun 22;8(344):344ra84
pubmed: 27334259
Br J Pharmacol. 2013 Jan;168(1):253-65
pubmed: 22946960
Cell Mol Life Sci. 2018 Dec;75(24):4495-4509
pubmed: 30066085