U.S. Department of Health and Human Services

An Important Proof of Principle for the “Combination Therapy” Approach to Treating the Most Common Cystic Fibrosis Mutation

New research has shown that it may one day be possible to treat people with cystic ibrosis (CF) using a combination of medicines that work cooperatively to stabilize an aberrant form of CFTR, the protein that is defective in CF. Among people with CF, the most common genetic mutation causing the disease is designated cftr‑ΔF508. The U.S. Food and Drug 
Administration recently approved a “small molecule corrector” drug that alleviates CF when it is caused by a less common CFTR mutation (found in roughly ive percent of CF patients), allowing patients with the rarer mutation to lead their lives with far fewer symptoms of the disease. However, researchers have not yet been successful in taking a similar approach  to ind small molecule correctors for the cftr‑ΔF508 mutation. While several candidate small molecule drugs have been found to improve stability of the cftr‑ΔF508 protein in the laboratory, clinical trials are still under way with people with this mutation, so their therapeutic value is not yet known. Previous NIDDK‑supported research identiied a possible explanation: ΔF508 destabilizes multiple “domains” of the protein (distinct sections of the protein which 
fulill speciic biological roles). In particular, ΔF508 disrupts two “nucleotide binding domains” (designated NBD1 and NBD2), as well as the interaction of NBD1 with critical regions that connect parts of the protein that are inside the cell with a portion that is outside the cell, termed “membrane spanning” domains. The new study characterizes the existing candidate drugs in terms of which domain they stabilize, effectively deining three classes of corrector compounds. 
Existing correctors stabilize the interaction of NBD1 with the irst and second membrane spanning domains (class I) or stabilize NBD2 (class II). Also necessary is stabilization of NBD1 itself (class III), achieved in this study by using the chemical glycerol or other “chemical chaperones.” In a key test on human lung cells grown in the laboratory that harbored the cftr‑ΔF508 mutation, they found that using only one or two classes of correctors resulted in very little CFTR activity; but combined treatment with all three classes of correctors achieved almost normal levels of CFTR function. The chemical chaperones that serve as class III correctors in this study are unlikely themselves to be medicinally useful. For example, because glycerol is a naturally occurring compound that is freely metabolized by the body, it would not reach target tissues in suficient concentration to function as a therapeutic agent. However, these results strongly suggest a potential 
beneit for focusing efforts on inding compounds that stabilize the NBD1 domain of the cftr‑ΔF508 protein. The research suggests that if a compound that can do so proves safe in combination with existing class I and class II correctors, the approach may greatly improve treatment for the majority of people with CF.

Okiyoneda T, Veit G, Dekkers JF, et al. Mechanism‑based 
corrector combination restores ΔF508‑CFTR folding and 
function. Nat Chem Biol 9: 444‑454, 2013.