Knowing exactly how rare mutations affect the CFTR gene in patients with cystic fibrosis (CF) is important to determining treatments of benefit to these people, according to a study of exactly such a mutation. Its researchers also argued for greater efforts to include CF patients with rarer mutations in clinical trials, so as to potentially expand existing therapies to this group.
The study, “Analysis Of Cystic Fibrosis–Associated P67L CFTR Illustrates Barriers To Personalized Therapeutics For Orphan Diseases,” published in the journal JCI Insight, looked at the abnormalities associated with the rare P67L mutation, and reported that already approved drugs can target this dysfunctional protein, improving its ability to work.
The CFTR gene encodes a protein channel that allows the conduction of chloride ions in cells. When it doesn’t work as intended, this protein contributes to the accumulation of mucus in several organs, including the lungs, leading to infections by bacteria that settle in the mucus.
The P67L mutation affects a small number of individuals with CF, which is why not much is known about its impact on the function of the CFTR protein and the consequences to patients. Knowing the specific defects it causes helps in understanding what a given treatment should be ‘addressing’ in patients with a P67L mutation.
Researchers used cultures of rat cells to compare the function of CFTR with the P67L mutation to the workings of normal CFTR. Their analysis showed that the mutation affects how the CFTR protein is produced, leaving it deficient in channel properties; it also has reduced maturation and trafficking ability within the cell.
Importantly, the team observed that these abnormalities can be treated with CFTR modulators already approved by the U.S. Food and Drug Administration as CF treatments, like Kalydeco (ivacaftor) and Orkambi (lumacaftor/ivacaftor), both of which are able to reactivate the CFTR channel. FDA approval, however, pertains to specific — and generally more common — CF mutations evaluated in clinical studies.
These findings support arguments that thorough evaluation of rare CFTR mutations offer detailed information that should be considered when developing clinical trials, so as to include individuals with rare CF forms.
“In summary, patients with rare CFTR mutations such as P67L often cannot gain access to leading edge CF compounds unless they possess an FDA-approved genotype, and third party payers have struggled with the complexity of providing reimbursement for individuals carrying uncommon alleles until FDA registration is available,” the authors wrote.
“The biochemical, monolayer, and single-channel findings shown here indicate that individuals with P67L CFTR could potentially benefit from ivacaftor or Orkambi [lumacaftor/ivacaftor], if in vivo confirmation and regulatory approval were in place. Thorough evaluation of rare CFTR alleles, together with an approach that allows physicians more opportunity to evaluate and treat patients based on well-validated preclinical or clinical endpoints and FDA approval, would serve many individuals with rare forms of the disease,” the team concluded.