2. Academic Validation
  3. CFTR modulator therapy for cystic fibrosis caused by the rare c.3700A>G mutation

CFTR modulator therapy for cystic fibrosis caused by the rare c.3700A>G mutation

  • J Cyst Fibros. 2021 May;20(3):452-459. doi: 10.1016/j.jcf.2020.07.003.
Puay-Wah Phuan 1,  Peter M Haggie 2,  Joseph A Tan 1,  Amber A Rivera 1,  Walter E Finkbeiner 3,  Dennis W Nielson 4,  Merlin M Thomas 5,  Ibrahim A Janahi 6,  Alan S Verkman 7
Affiliations

Affiliations

  • 1 Department of Medicine, University of California San Francisco, CA 94143, USA.
  • 2 Department of Medicine, University of California San Francisco, CA 94143, USA. Electronic address: Peter.haggie@ucsf.edu.
  • 3 Department of Pathology, University of California San Francisco, CA 94143, USA.
  • 4 Department of Pediatrics, University of California San Francisco, CA 94143, USA.
  • 5 Department of Chest, Hamad General Hospital, PO Box 3050, Doha, Qatar.
  • 6 Pediatric Pulmonary, Pediatric Medicine, Sidra Medicine, PO Box 26999, Doha, Qatar.
  • 7 Department of Medicine, University of California San Francisco, CA 94143, USA; Department of Physiology, University of California San Francisco, CA 94143, USA.
PMID: 32674984 DOI: 10.1016/j.jcf.2020.07.003
Abstract

Background: The c.3700A>G mutation, a rare cystic fibrosis (CF)-causing CFTR mutation found mainly in the Middle East, produces full-length transcript encoding a missense mutation (I1234V-CFTR), and a cryptic splice site that deletes 6 Amino acids in nucleotide binding domain 2 (I1234del-CFTR).

Methods: FRT cell models expressing I1234V-CFTR and I1234del-CFTR were generated. We also studied an I1234del-CFTR-expressing gene-edited human bronchial (16HBE14o-) cell model, and primary cultures of nasal epithelial cells from a c.3700A>G homozygous subject. To identify improved mutation-specific CFTR modulators, high-throughput screening was done using I1234del-CFTR-expressing FRT cells. Motivated by the in vitro findings, Trikafta was tested in two c.3700A>G homozygous CF subjects.

Results: FRT cells expressing full-length I1234V-CFTR had similar function to that of wildtype CFTR. I1234del-CFTR showed reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, and low-temperature incubation. Screening identified novel arylsulfonyl-piperazine and spiropiperidine-quinazolinone correctors, which when used in combination with VX-445 increased current ~2-fold compared with the VX-661/VX-445 combination. The combination of VX-770 with arylsulfonamide-pyrrolopyridine, piperidine-pyridoindole or pyrazolo-quinoline potentiators gave 2-4-fold greater current than VX-770 alone. Combination potentiator (co-potentiator) efficacy was also seen in gene-edited I1234del-CFTR-expressing human bronchial epithelial cells. In two CF subjects homozygous for the c.3700A>G mutation, one subject had a 27 mmol/L decrease in sweat chloride and symptomatic improvement on Trikafta, and a second subject showed a small improvement in lung function.

Conclusions: These results support the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A>G mutation.

Keywords

C.3700A>G; CFTR modulators; Co-potentiators; Cystic fibrosis; I1234V; N-of-1 clinical trials.

Figures
Products