Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Although recent advancements in targeted treatments have made it possible to increase cystic fibrosis transmembrane conductance regulator (CFTR) function, the prognosis of patients with CF differs widely. Although CF is a multiorgan disorder, severe damage to lung tissue is still the leading cause of morbidity and mortality.1
Even though CF currently has no cure, various treatments are under development that may halt progression of the disease, help patients cope with symptoms, enhance their quality of life, and perhaps even eventually deliver a cure.2 The following is a summary of some of the experimental treatments for CF that are currently being developed.
For patients who have CF with nonsense mutations in the CFTR gene, which make existing CF treatments less efficacious, exon skipping may be a promising alternative treatment.3 Splice-switching antisense oligonucleotides (ASOs) have shown therapeutic potential in preclinical and clinical studies in a variety of disorders; their mechanism of action is to induce exon skipping in an attempt to re-establish the messenger RNA (mRNA) open reading frame. In primary human bronchial epithelial cells isolated from a patient homozygous for the W1282X-CFTR mutation, ASO-induced skipping of exon 23 corrected CFTR expression and the chloride current. These findings suggest that ASOs may be effective in the treatment of patients with CF who have CFTR class I mutations in exon 23, which cause unstable CFTR mRNA and truncations of CFTR protein.4
Adrulipase Alfa (MS1819)
MS1819, also known as adrulipase alfa, is a recombinant lipase enzyme designed to treat exocrine pancreatic insufficiency (EPI) in CF and chronic pancreatitis. It is derived from Yarrowia lipolytica yeast lipase and is administered as an oral, nonsystemic, biologic capsule. In patients with EPI, it breaks up fat molecules in the digestive tract so that they can be absorbed as nutrients.5
Monocyte Immune Cells
Monocytes from patients with CF are deficient in integrin activation and adhesion, according to recent research. Defective monocyte function may contribute to the progression of CF because monocytes play an important role in infection control. A study showed abnormal adhesion underflow in the monocytes of CFTRΔF508 mice (CF mice). After sublethal irradiation, CF mice received a transplant of wild-type (WT) bone marrow, in which 60% to 80% of their CF monocytes were replaced with WT monocytes. Following the transplant, survival increased and inflammation decreased. Delivering WT monocytes via bone marrow transplant reduced mortality in CF mice, which suggests that similar strategies could mitigate CF in humans.6
CRISPR/Cas9 is an experimental treatment in which a protein-RNA complex is introduced that targets the genetic alterations causing CF.7 The CRISPR/Cas9 genome editing system is used to rectify the CFTR locus via homologous recombination in cultured intestinal stem cells from patients with CF. The corrected allele shows full expression and complete function in clonally expanded organoids.8
Eloxx Pharmaceuticals is developing ELX-02 as an experimental therapy for CF due to nonsense mutations.9 ELX-02 is a translational read-through molecule made from a synthetic eukaryotic ribosome-selective glycoside. Read-through of nonsense mutations results in appropriately localized full-length functional proteins. To assess the safety and pharmacokinetics of ELX-02, 2 randomised, double-blind, placebo-controlled, single-ascending-dose phase 1a studies were performed in healthy humans. Single subcutaneously administered doses ranging from 0.3 to 7.5 mg/kg demonstrated a satisfactory safety profile; no severe or serious drug-related side effects, including renal toxicity and ototoxicity, occurred. After ELX-02 was injected, the time to peak concentration and elimination phase was quick; total elimination from the vascular compartment occurred within 10 hours. The maximum concentration demonstrated dose proportionality, and the area under the concentration-time curve to infinity demonstrated dose exposure linearity. The mean apparent volume of distribution was dose-dependent, indicating that higher doses enhanced ELX-02 distribution and tissue uptake. These findings should lead to future research into the safety, pharmacokinetics, and efficacy of repeated dosing.10
MRT5005 is an mRNA molecule that delivers instructions for protein synthesis. It is intended to increase the generation of CFTR protein, which is defective or lacking in people with CF. As a result, MRT5005 treats the underlying cause of CF and could be a therapy for all patients with CF, regardless of mutation type. The US Food and Drug Administration (FDA) designated MRT5005 as an orphan drug in 2015.11
In May 2018, a phase 1/2 clinical trial (NCT03375047) was started to assess the safety and tolerability of MRT5005. Patients with CF were given mRNA that encoded a fully functional CFTR protein. The drug was administered via nebulization. MRT5005 was well tolerated at low- and mid-dose levels (8-16 mg), with no significant side effects observed at any dose level. Lung function improved significantly following a single mid-dose of MRT5005. The FDA granted MRT5005 fast track and rare pediatric disease designations for the treatment of CF in early 2020.12
Eluforsen (Previously Known as QR-010)
Eluforsen is an inhalational single-stranded RNA ASO that targets CFTR and is administered to individuals with F508del CF. In a phase 1 clinical trial (NCT02564354) that began in 2015, CFTR activity was re-established after the intranasal delivery of Eluforsen. In 2017, the phase Ib clinical trial (NCT02532764) concluded that inhaled Eluforsen is safe and well tolerated, and that it reduces respiratory symptoms in patients with F508del CF. However, no plans have been made to pursue this drug candidate further in clinical trials.12
- Allan KM, Farrow N, Donnelley M, Jaffe A, Waters SA. Treatment of cystic fibrosis: from gene- to cell-based therapies. Front Pharmacol. 2021;12:639475. doi:10.3389/fphar.2021.639475.
- Experimental treatments for cystic fibrosis. Cystic Fibrosis News Today. Accessed February 15, 2022.
- Inacio P. Exon skipping may open nonsense CF mutations to current therapies. Published February 10, 2022, Accessed February 15, 2022.
- Michaels 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;119(3):e2114886119. doi:10.1073/pnas.2114886119
- AzurRx BioPharma announces WHO publication of “adrulipase alfa” as international nonproprietary name for MS1819. News release. GlobeNewswire; August 17, 2021.
- Fan Z, Pitmon E, Wen L, et al. Bone marrow transplantation rescues monocyte recruitment defect and improves cystic fibrosis in mice. J Immunol. 2022;208(3):745-752. doi:10.4049/jimmunol.1901171
- CRISPR/Cas9 approach for cystic fibrosis treatment. Cystic Fibrosis News Today. Accessed February 15, 2022.
- Schwank G, Koo BK, Sasselli V, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13(6):653-658. doi:10.1016/j.stem.2013.11.002
- ELX-02. Cystic Fibrosis News Today. Updated February 23, 2021, Accessed February 15, 2022.
- Leubitz A, Frydman-Marom A, Sharpe N, van Duzer J, Campbell KCM, Vanhoutte F. Safety, tolerability, and pharmacokinetics of single ascending doses of ELX-02, a potential treatment for genetic disorders caused by nonsense mutations, in healthy volunteers. Clin Pharmacol Drug Dev. 2019;8(8):984-994. doi:10.1002/cpdd.647
- MRT5005. Cystic Fibrosis News Today. Accessed February 15, 2022.
Chow MYT, Qiu Y, Lam JKW. Inhaled RNA therapy: from promise to reality.Trends Pharmacol Sci. 2020;41(10):715-729. doi:10.1016/j.tips.2020.08.002
Reviewed by Hasan Avcu, MD, on 2/15/2022.