How to determine the mechanism of action of CFTR modulator compounds: A gateway to theranostics

Personalized Medicine Based on Nasal Epithelial Cells: Comparative Studies with Rectal Biopsies and Intestinal Organoids

“…As highly effective CFTR modulator therapies (HEMT) emerge, there is an unmet need to find effective drugs for individuals with CF with ultra-rare mutations, for whom there are no dedicated drug discovery programs [ 3 , 40 , 41 , 42 , 43 , 44 ]. Therefore, the development of techniques and models that reliably predict the clinical benefit from CFTR modulator therapies are required for these individuals through personalized approaches termed theranostics [ 41 ]. Here, we assess CFTR basal function and the individual responses to CFTR modulators in primary human nasal epithelial (pHNE) cells from PwCF carrying rare mutations and compare these measurements with those in native rectal biopsies and intestinal organoids.…”

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

“…The CF drug development pipeline has been expanding with the discovery of novel small molecules from a diversity of chemical series that are able to correct specific cellular/functional defect(s) generated by CF-causing mutations. 17 , 30 Accordingly, CFTR modulator drugs may be grouped into five main types according to their actions on CFTR mutations: read-through agents, correctors, potentiators, amplifiers and stabilizers ( Figure 2 ). Examples of promising CFTR modulators that are under both experimental and clinical investigation are described in the following sub-sections.…”

“…Several HTS have been performed over the last few years in an attempt to identify novel read-through agents for CFTR PTC mutations. 11 , 30 A library containing ~85,000 molecules was screened by the CF Foundation Therapeutics laboratory and some promising hits were found to rescue the Y122X and W1282X mutations, including CFFT-0182812 and CFFT-0176974, which were able to increase both CFTR PM expression and transepithelial conductance. 51 Notably, the five leading hits of W1282X increased CFTR PM expression to more than 20% of the WT-CFTR levels, which makes it encouraging to conclude that these hit compounds may yield full-length functional CFTR protein.…”

“…Overall, all these compounds provide a good resource to further explore their mechanisms of action and pharmacophore structural space by medicinal chemistry to identify novel and more potent correctors. 11 , 30 …”

“…Although all CF-causing mutations result in CFTR-dependent Cl – /HCO 3 – defective transport, these are due to distinct cellular/functional defects. Accordingly, CFTR mutations have been grouped into functional classes/theratypes, 11 , 12 , 17 , 30 characterized by: (I) no production of full-length protein, (II) defective folding and trafficking, (III) defective gating, (IV) reduced anion conductance, (V) reduced protein production, (VI) reduced stability at the PM, and (VII) no mRNA production. Despite not all CFTR gene variants have been characterized according to their respective cellular/functional defect(s), this classification has been useful as mutations within the same group are expected to be treated by the same therapeutic strategy if not by the same drug.…”