Table 1.

CFTR mutation class and current modulator therapeutic approach.

Mutation class	Molecular defect	Type of mutation	Therapeutic approach	Approved or drugs in clinical trial	Mutation examples
IA~	No mRNA synthesis	Large deletions	Bypass therapies (Activate alternative Cl− channels)	–	Dele2, 3(21 kb) 1717-1G->A 621+1G->T
IB~	Protein synthesis	Nonsense (PTC), Frame-shift, Splicing	Read-through compounds	Phase 2: QBW276, SPX-101 Phase 1: AZD5634, BI443651	G542X, W1282X
II	Trafficking	Missense	Correctors and potentiators	Approved: Orkambi, Symdeko Phase 3: VX-445#, VX-659# Phase 2: VX-152#, VX-440#, GLPG2222, GLPG2737, FDL169 Phase 1: PTI-801	F508del, R560T, A561E
III	Channel Gating	Missense	Potentiators	Approved: Ivacaftor Phase 2: VX-561, QBW251, GLPG1837, GLPG2451, GLPG3067 Phase 1: PTI-808	G551D, S1251N, G178R
IV	Conductance	Missense	Potentiators	Approved: Ivacaftor	R334W, R347P, R117H
V	Protein synthesis	Missense, Alternative splicing	Correctors, Potentiators, Antisense Oligonucleotides	Approved: Ivacaftor	3849+10kbC>T, 3272-26A>G, 2789+5G>A
VI	Reduced CFTR stability at PM	Missense, Frameshift	Stabilizers	–	120del23, N287Y, Q1412X

Compounds starting with VX are developed by Vertex Pharmaceuticals, GLPG by Galapagos NV and AbbVie, FDL, Flatley discovery lab; QBW, Novartis pharmaceuticals; PTI, Proteostasis therapeutics; SPX, Spyryx biosciences; AZD, AstraZeneca; BI, Boehringer ingelheim; Orkambi, VX-809+VX-770; Symdeko, VX-661+VX-770; Ivacaftor, VX-770;

^#Triple combination therapy with VX-661 and VX-770.

PTC, Premature termination codons; PM, Plasma membrane; ~, classification is based on (Marson et al.,2016).