- Cystic Fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene which causes the CFTR protein to become dysfunctional. Over 30,000 children and adults in the U.S. have CF (70,000 globally)
- CFTR modulators, small molecules that either correct protein misfolding and misprocessing or improve channel gating, enhance an array of clinical outcomes in CF from improved lung function, to increased BMI, to better quality of life outcomes
- For a minority of CF patients with rare and nonsense mutations, preclinical research into treatments such as read-through, gene editing, gene therapy, and ASOs offer continuing hope
According to the National Heart, Lung, and Blood Institute’s website, cystic fibrosis (CF) is a progressive, genetic condition that affects a protein in the body. People with CF have a faulty protein that affects the body’s cells, tissues, and the glands that make mucous and sweat.1 CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which causes the CFTR protein to become dysfunctional. When the protein malfunctions, it fails to move chloride (a component of salt) to the cell surface. Without the chloride to attract water to the cell surface, mucus in various organs becomes thick and sticky. In the lungs, the viscous mucus clogs the airways and traps bacteria leading to infections, inflammation, and potentially to respiratory failure. Over 30,000 children and adults in the U.S. have CF (70,000 globally).2
CFTR MODULATOR TREATMENTS
Since the discovery of the CFTR gene in 1989, a cooperative effort has been underway to correct the basic cellular defect. A major contribution to this effort has been the introduction of CFTR modulators, small molecules that either correct protein misfolding and misprocessing or improve channel gating to enhance apical anion transport (e.g., chloride and bicarbonate)3. By partially restoring channel function, CFTR modulators enhance an array of clinical outcomes in CF from improved lung function, to increased Body Mass Index (BMI), to better quality of life outcomes as assessed on the Cystic Fibrosis Questionnaire-Revised-Respiratory Domain (CFQ-R-RD).4
There are currently four FDA-approved CFTR modulators available for treatment of CF in people with specific mutations of the CFTR gene: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), tezacaftor/ivacaftor (Symdeko®), and elexacaftor/tezacaftor/ivacaftor (Trikafta®). The most recently approved CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) is a triple combination therapy. It combines the gene corrector elexacaftor with tezacaftor/ivacaftor, another corrector and a potentiator. The most common CF mutation worldwide is the F508del allele and occurs in at least 85% of people with CF. Elexacaftor helps the F508del-CFTR protein form the right shape so that it can traffic to the cell surface. Including elexacaftor with tezacaftor/ivacaftor helps the CFTR protein perform better than other modulators for an even greater number of people with CF because elexacaftor corrects an additional flaw in the formation of the F508del-CFTR protein. ETI has been approved for people with CF ages 6 and older who have at least one copy of the F508del mutation or at least one copy of 177 specified mutations.5
The PROMISE study, a real-world prospective observational study of 487 people with CF starting ETI treatment, examined clinical outcomes including change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, BMI, and self-reported respiratory symptoms. Visits occurred at 1, 3, and 6 months with additional follow up planned for 18 and 30 months. At 6 months into ETI twice-daily oral therapy, ppFEV1 improved 9.76 percentage points, CFQ-R-RD score improved 20.4 points, and sweat chloride decreased 241.7 mmol/L. BMI also significantly increased. This indicates substantial improvement in clinical outcomes and may set a new clinical benchmark for CFTR modulator treatment. The results also indicate strong health benefits of ETI in real-world practice.6
NEW GENETIC TREATMENTS FOR CYSTIC FIBROSIS WITH RARE AND NONSENSE MUTATIONS
While CFTR modulators like ETI and others can have an enormous beneficial impact on people with CF with at least one copy of the F508del mutation, (or one of hundreds of other mutations approved for treatment with modulators) there are still a minority of people with CF who have nonsense and rare mutations who will not benefit from these treatments. Nonsense mutations (also known as “x” or “stop” mutations) cause cells to stop the production of the CFTR protein midway through the process, resulting in shortened, non-functional protein that the cell recognizes as defective and destroys.7 Current modulator treatments for CF target residual protein function and are less effective in patients with x or stop mutations due in part to low CFTR protein levels.8 Fortunately, preclinical and clinical research into potential treatments for nonsense mutations in CF are ongoing, including read-through treatments, gene editing, and gene therapy. Antisense oligonucleotide (ASO) therapy is also being explored to correct the effects of rare mutations that disrupt the production of mRNA.
One potential new approach for CF patients with nonsense mutations is read-through treatment. As mentioned above, nonsense mutations stop the production of the CFTR protein, and the goal of read-through therapies is to “read through” or bypass the stop signals. One new drug entering Phase II trials is ELX-02, which is being developed by Eloxx Pharmaceuticals. ELX-02 is an aminoglycoside analogue that induces read-through of nonsense mutations through interaction with the ribosome, resulting in the production of full-length functional proteins. Phase I studies in healthy participants indicated an acceptable PK and safety profile9 to support a Phase II study examining ELX-2 with and without Ivacaftor in CF patients with nonsense mutations.
Gene Therapy and Gene Editing Treatments
There are several gene therapy and gene editing treatments being explored for CF patients with nonsense mutations. For example, the new startup Carbon Biosciences is doing preclinical work on a potential gene therapy to deliver a functional CFTR gene directly to the lungs using a novel parvovirus delivery mechanism. While adeno-associated viruses (AAVs) are more commonly used in gene therapy, the hope is that the parvovirus will be able to deliver a larger gene to less accessible tissue like the lungs.10
Early, preclinical research is also being conducted in gene editing treatments for nonsense mutations. Such treatments would use an enzyme to cut DNA at a specific site or sequence, then use the cell’s DNA repair system to correct the CFTR mutation. The low cost and anticipated low risk of off-target breaks has made CRISPR-Cas9 the preferred choice of gene editing tool in cystic fibrosis.11 While early research has often focused on editing the F508del mutation, there is preclinical work being conducted on the W1282X-CFTR variant, the second most common nonsense CF-causing mutation in the CFTR gene.12
Antisense Oligonucleotide Treatment
ASO treatments are another possible avenue of treatment for nonsense mutations in CF. Splice-switching ASOs, designed to induce skipping of exons in order to restore the mRNA open reading frame, have shown therapeutic promise preclinically and clinically for a number of diseases and may show promise for CF as well. For example, one preclinical study demonstrated that elimination of the relatively common nonsense mutation, CFTR-W1282X, by ASO-induced skipping of CFTR exon 23, which encodes the mutation, recovers CFTR expression. The activity of this CFTR isoform, lacking 52 amino acids, would require CFTR modulator drugs that are currently used to treat CF patients. A combination approach such as this could provide a therapeutic option for CF patients who are currently unable to benefit from modulators.13
Globally, over 70,000 people are living with the often-debilitating effects of CF. For the approximately 85% with more common mutations like the F508del mutation, CFTR modulator treatments offer significant health benefits. For the remainder of CF patients with rare and nonsense mutations, preclinical research into treatments such as read-through, gene editing, gene therapy, and ASOs offer continuing hope.
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1NHLBI web site, accessed 11Jul2022. https://www.nhlbi.nih.gov/health/cystic-fibrosis
2Cystic Fibrosis Foundation web site, accessed 11Jul2022. https://www.cff.org/intro-cf/about-cystic-fibrosis
3Nichols DP, Paynter AC, Heltshe SL, Donaldson SH, Frederick CA, Freedman SD, Gelfond D, Hoffman LR, Kelly A, Narkewicz MR, Pittman JE, Ratjen F, Rosenfeld M, Sagel SD, Schwarzenberg SJ, Singh PK, Solomon GM, Stalvey MS, Clancy JP, Kirby S, Van Dalfsen JM, Kloster MH, Rowe SM; PROMISE Study group. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial. Am J Respir Crit Care Med. 2022 Mar 1;205(5):529-539. doi: 10.1164/rccm.202108-1986OC. PMID: 34784492; PMCID: PMC8906485.
4Ibid, p. 531.
5Cystic Fibrosis Foundation web site, accessed 11Jul2022. https://www.cff.org/managing-cf/cftr-modulator-therapies
6Nichols, Paynter, Heltshe, et al., p. 530.
8Michaels WE, Pena-Rasgado C, Kotaria R, Bridges RJ, Hastings ML. Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis. Proc Natl Acad Sci U S A. 2022 Jan 18;119(3):e2114886119. doi: 10.1073/pnas.2114886119. PMID: 35017302; PMCID: PMC8784102.
9Leubitz A, Vanhoutte F, Hu MY, Porter K, Gordon E, Tencer K, Campbell K, Banks K, Haverty T. A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of ELX-02 in Healthy Subjects. Clin Pharmacol Drug Dev. 2021 Aug;10(8):859-869. doi: 10.1002/cpdd.914. Epub 2021 Jan 19. PMID: 33465285; PMCID: PMC8451797.
10Alvaredo, D. A biotech startup launches with $38M to develop a cystic fibrosus gene therapy. 21Jun2022. Accessed 13Jul2022. https://www.biopharmadive.com/news/carbon-biosciences-launch-series-a-cystic-fibrosis/625804/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202022-06-22%20BioPharma%20Dive%20%5Bissue:42585%5D&utm_term=BioPharma%20Dive
11Wilson, C. Future Therapies for cystic fibrosis. The Lancet Respiratory Medicine. 29Jun2022. Accessed 13Jul2022. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00253-3/fulltext
12Santos L, Mention K, Cavusoglu-Doran K, Sanz DJ, Bacalhau M, Lopes-Pacheco M, Harrison PT, Farinha CM. Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation. J Cyst Fibros. 2022 Jan;21(1):181-187. doi: 10.1016/j.jcf.2021.05.014. Epub 2021 Jun 5. PMID: 34103250.
13Michaels, Pena-Rasgado, Kotaria, et al., p. 5.