Cystic fibrosis: Advances, ongoing challenges
Mutation agnostic therapy
Unfortunately, CF mutants, outside the population eligible for Trikafta, are prodigious in number and do not fall into just a few major groups. “Furthermore, although CF is a monogenic disease, it has variable phenotypes even for two individuals with the same mutations,” Dr. Sala said. “Current CFTR modulators act on the dysfunctional CFTR protein (either as channel gating potentiators or molecular chaperones to improve misfolding). That leaves about 10% of the CF population, those with little to no protein production (such as in nonsense mutations) ineligible for treatment with CFTR modulators. “The ideal for efficacy and equity, given that some CFTR mutations only exist in a handful of people, would be to develop a ‘mutation agnostic’ strategy — such as with mRNA or gene delivery. Here you could imagine that regardless of the type of mutation, a patient would then be able to receive the technology to increase CFTR channel function,” Dr. Sala said. Many modifiable factors, including host immunity and non-CFTR genes that impact CFTR indirectly, may underlie the fact that one person has a worse trajectory than another. “New therapies may also be found in this area of research,” Dr. Sala said.
Strategies in testing phases
“For patients with class I (nonsense) mutations there is hope that small molecules will be identified that can facilitate premature truncation codon (PTC) read-through and/or impede mRNA decay allowing for clinically relevant levels of functional CFTR,” the researchers noted. While the most extensively developed, ataluren, an oxadiazole, failed in phase 3 trials after initial promise, other ribosomal read-through drugs are in preclinical and early phase clinical trials. Also, early encouraging results support an alternative strategy, engineered transfer RNAs (tRNAs) that introduce an amino acid to an elongating peptide in place of the termination codon.
While these will address specific mutations, DNA or mRNA replacement strategies would be “mutation agnostic,” the researchers stated. The major challenge: delivery to the respiratory epithelium. Approaches currently in early testing include an inhaled aerosolized, lipid-based nanoparticle carrier for mRNA delivery, viral and non-viral DNA transfer, lipid-mediated CFTR gene transfer, pseudotyped lentiviral vector and adeno-associated vector transfer of CFTR DNA.
Adult CF care
“Adult CF care in general is a completely new frontier,” Meilinh Thi, DO, director of the adult cystic fibrosis program and assistant professor at University of Texas Health at San Antonio, said in an interview. “It’s fairly new to have separate pediatric and adult CF centers. There’s been a shift,” she said. “We’re encountering diseases in CF that we have not in the past had to deal with: diabetes that has features of both type 1 and type 2, increased colon cancer risk, bone disease, and mental health issues. Also, while pregnancy was previously discouraged for women with CF because of lung disease, now many are giving birth without complications and living normal lives,” Dr. Thi said.
“We do encourage our patients to talk to us before becoming pregnant so we can discuss the risk of passing on the gene. And, we do encourage their significant others to get testing. Some patients and their others, however, do decline to get tested,” she added.
The lifetime health issues conferred by CF, Dr. Thi noted, include lung disease with chronic inflammation, infection, respiratory failure (still the most common cause of death), gastrointestinal disorders (including of the pancreas) , colon obstruction and colon cancer, sinus disease, and reproductive system effects. Their permanence, she said, depends on how far their disease has progressed. “So the earlier you can provide these newer therapies — the modulators, for example, or the gene therapy whenever that comes out, then the less damage these organ systems will have, and the patients, we hope, will then do better.”
