Editing Cystic fibrosis (section)

==Research==
People with CF may be listed in a [[disease registry]] that allows researchers and doctors to track health results and identify candidates for clinical trials.<ref name="Freudenheim-2009">{{cite news| vauthors = Freudenheim M |url=https://www.nytimes.com/2009/12/22/health/22cyst.html|title=Tool in Cystic Fibrosis Fight: A Registry|date=22 December 2009|newspaper=[[The New York Times]]|access-date=21 December 2009|url-status=live|archive-url=https://web.archive.org/web/20130524095423/http://www.nytimes.com/2009/12/22/health/22cyst.html|archive-date=24 May 2013|pages=D1}}</ref>

===Gene therapy===
[[Gene therapy]] has been explored as a potential cure for CF. Results from clinical trials have shown limited success {{as of|2016|lc=y}}, and using gene therapy as routine therapy is not suggested.<ref name="pmid27314455">{{cite journal | vauthors = Lee TW, Southern KW, Perry LA, Penny-Dimri JC, Aslam AA | title = Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 6 | pages = CD005599 | date = June 2016 | pmid = 27314455 | pmc = 8682957 | doi = 10.1002/14651858.CD005599.pub5 | veditors = Southern KW }}</ref> A small study published in 2015 found a small benefit.<ref name="pmid26149841">{{cite journal | vauthors = Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DD, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JS, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P | title = Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial | journal = The Lancet. Respiratory Medicine | volume = 3 | issue = 9 | pages = 684–691 | date = September 2015 | pmid = 26149841 | pmc = 4673100 | doi = 10.1016/S2213-2600(15)00245-3 }}</ref>

The focus of much CF gene therapy research is aimed at trying to place a normal copy of the ''CFTR'' gene into affected cells. Transferring the normal ''CFTR'' gene into the affected epithelial cells would result in the production of functional CFTR protein in all target cells, without adverse reactions or an inflammation response; this is known as somatic cell therapy. To prevent the lung manifestations of CF, only 5–10% of the normal amount of CFTR gene expression is needed.<ref name="pmid12397022">{{cite journal | vauthors = Ramalho AS, Beck S, Meyer M, Penque D, Cutting GR, Amaral MD | title = Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 27 | issue = 5 | pages = 619–627 | date = November 2002 | pmid = 12397022 | doi = 10.1165/rcmb.2001-0004oc | s2cid = 8714332 }}</ref> Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options,<ref name="pmid16296753">{{cite journal | vauthors = Tate S, Elborn S | title = Progress towards gene therapy for cystic fibrosis | journal = Expert Opinion on Drug Delivery | volume = 2 | issue = 2 | pages = 269–280 | date = March 2005 | pmid = 16296753 | doi = 10.1517/17425247.2.2.269 | s2cid = 30948229 }}</ref> mainly because very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.<ref name="Online Mendelian Inheritance in Man">{{OMIM|219700|CYSTIC FIBROSIS; CF}}</ref> There has been a functional repair in culture of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.<ref name="pmid24315439">{{cite journal | vauthors = Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H | title = Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients | journal = Cell Stem Cell | volume = 13 | issue = 6 | pages = 653–658 | date = December 2013 | pmid = 24315439 | doi = 10.1016/j.stem.2013.11.002 | doi-access = free }}</ref>

===Bacteriophage therapy===
Bacteriophage therapy ([[phage therapy]]) is being studied for multidrug-resistant bacteria in people with CF.<ref name="pmid26213462">{{cite journal | vauthors = Hraiech S, Brégeon F, Rolain JM | title = Bacteriophage-based therapy in cystic fibrosis-associated Pseudomonas aeruginosa infections: rationale and current status | journal = Drug Design, Development and Therapy | volume = 9 | pages = 3653–3663 | date = 2015 | pmid = 26213462 | pmc = 4509528 | doi = 10.2147/DDDT.S53123 | doi-access = free }}</ref><ref name="pmid28720345">{{cite journal | vauthors = Trend S, Fonceca AM, Ditcham WG, Kicic A, Cf A | title = The potential of phage therapy in cystic fibrosis: Essential human-bacterial-phage interactions and delivery considerations for use in Pseudomonas aeruginosa-infected airways | journal = Journal of Cystic Fibrosis | volume = 16 | issue = 6 | pages = 663–670 | date = November 2017 | pmid = 28720345 | doi = 10.1016/j.jcf.2017.06.012 | doi-access = free }}</ref> Bacteriophage therapy is a treatment method that uses viruses, known as [[bacteriophage]]s, to target and destroy harmful bacteria in the body. Unlike antibiotics, which can kill a wide range of bacteria and potentially disrupt the body's normal flora, phage therapy is highly specific, targeting only the harmful bacteria while leaving the beneficial ones unharmed. As such, bacteriophage therapy is a promising alternative for treating infections caused by multidrug-resistant bacteria, such as Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa in CF patients, which are often protected by biofilms and thus resistant to conventional antibiotics.<ref name="a">{{cite journal | vauthors = Petrovic Fabijan A, Iredell J, Danis-Wlodarczyk K, Kebriaei R, Abedon ST | title = Translating phage therapy into the clinic: Recent accomplishments but continuing challenges | journal = PLOS Biology | volume = 21 | issue = 5 | pages = e3002119 | date = May 2023 | pmid = 37220114 | doi = 10.1371/journal.pbio.3002119 | doi-access = free | pmc = 10204993 }}</ref><ref name="b">{{cite journal | vauthors = Ashworth EA, Wright RC, Shears RK, Wong JK, Hassan A, Hall JP, Kadioglu A, Fothergill JL | title = Exploiting lung adaptation and phage steering to clear pan-resistant Pseudomonas aeruginosa infections in vivo | journal = Nature Communications | volume = 15 | issue = 1 | pages = 1547 | date = February 2024 | pmid = 38378698 | doi = 10.1038/s41467-024-45785-z | pmc = 10879199 | bibcode = 2024NatCo..15.1547A }}</ref><ref name="c">{{cite journal | vauthors = Liu K, Wang C, Zhou X, Guo X, Yang Y, Liu W, Zhao R, Song H | title = Bacteriophage therapy for drug-resistant <i>Staphylococcus aureus</i> infections | journal = Frontiers in Cellular and Infection Microbiology | volume = 14 | pages = 1336821 | date = 31 January 2024 | pmid = 38357445 | doi = 10.3389/fcimb.2024.1336821 | doi-access = free | pmc = 10864608 }}</ref>

Bacteriophage therapy uses viruses as antimicrobial agents to overcome the antibiotic resistance in bacteria with biofilms<ref name="pmid17566713">{{cite journal | vauthors = Hanlon GW | title = Bacteriophages: an appraisal of their role in the treatment of bacterial infections | journal = International Journal of Antimicrobial Agents | volume = 30 | issue = 2 | pages = 118–128 | date = August 2007 | pmid = 17566713 | doi = 10.1016/j.ijantimicag.2007.04.006 }}</ref> Phage therapy is used to treat the [[Pseudomonas aeruginosa]] infection in the lungs, which is frequently seen in cystic fibrosis patients, as these bacteria produce biofilms which give them multi-drug resistance.<ref name="pmid31130925">{{cite journal | vauthors = Ciofu O, Tolker-Nielsen T | title = Tolerance and Resistance of <i>Pseudomonas aeruginosa</i> Biofilms to Antimicrobial Agents-How <i>P. aeruginosa</i> Can Escape Antibiotics | journal = Frontiers in Microbiology | volume = 10 | pages = 913 | date = 2019 | pmid = 31130925 | pmc = 6509751 | doi = 10.3389/fmicb.2019.00913 | doi-access = free }}</ref>

===Gene modulators===
Several small molecules that aim at compensating various mutations of the ''CFTR'' gene are under development. CFTR [[Gene modulation|modulator therapies]] has been used instead of other types of genetic therapies. These therapies focus on the expression of a genetic mutation instead of the mutated gene itself. Modulators are split into two classes: potentiators and correctors. Potentiators act on the CFTR ion channels that are embedded in the cell membrane, and these drugs help open up the channel to allow transmembrane flow. Correctors are meant to assist in the transportation of nascent proteins, proteins that are formed by ribosomes before it is morphed into a specific shape, to the cell surface to be implemented into the cell membrane.<ref name=Ram2019>{{cite journal | vauthors = Ramsey BW, Downey GP, Goss CH | title = Update in Cystic Fibrosis 2018 | journal = American Journal of Respiratory and Critical Care Medicine | volume = 199 | issue = 10 | pages = 1188–1194 | date = May 2019 | pmid = 30917288 | pmc = 6519861 | doi = 10.1164/rccm.201902-0310UP | id = {{ProQuest|2230820891}} }}</ref>

Most target the transcription stage of genetic expression. One approach has been to try and develop medication that get the ribosome to overcome the [[stop codon]] and produce a full-length CFTR protein. About 10% of CF results from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target [[nonsense mutation]]s such as G542X, which consists of the amino acid [[glycine]] in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with protein synthesis and error correction. In some cases, they can cause the cell to overcome a premature stop codon by inserting a random amino acid, thereby allowing the expression of a full-length protein. Future research for these modulators is focused on the cellular targets that can be affected by a change in a gene's expression. Otherwise, genetic therapy will be used as a treatment when modulator therapies do not work given that 10% of people with cystic fibrosis are not affected by these drugs.<ref name="pmid20818846">{{cite journal | vauthors = Dietz HC | title = New therapeutic approaches to mendelian disorders | journal = The New England Journal of Medicine | volume = 363 | issue = 9 | pages = 852–863 | date = August 2010 | pmid = 20818846 | doi = 10.1056/NEJMra0907180 | s2cid = 5809127 | doi-access = free }} Free full text</ref>

[[Elexacaftor/ivacaftor/tezacaftor]] was approved in the United States in 2019 for cystic fibrosis.<ref name=FDA2019Tx>{{Cite web|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis|title=FDA approves new breakthrough therapy for cystic fibrosis | author = Office of the Commissioner |date=24 October 2019|website=FDA|language=en|access-date=13 November 2019}}</ref> This combination of previously developed medicines can treat up to 90% of people with cystic fibrosis.<ref name=Ram2019/><ref name=FDA2019Tx/> This medication restores some effectiveness of the CFTR protein so that it can work as an ion channel on the cell's surface.<ref name="Cystic Fibrosis Foundation-2">{{Cite web|url=https://www.cff.org/Life-With-CF/Treatments-and-Therapies/Medications/CFTR-Modulator-Therapies/|title=CFTR Modulator Therapies | location = Bethesda, Md. | publisher = Cystic Fibrosis Foundation |language=en|access-date=13 November 2019}}</ref>

===Ecological therapy===
It has previously been shown that inter-species interactions are an important contributor to the pathology of CF lung infections. Examples include the production of antibiotic degrading enzymes such as β-lactamases and the production of metabolic by-products such as short-chain fatty acids (SCFAs) by anaerobic species, which can enhance the pathogenicity of traditional pathogens such as ''Pseudomonas aeruginosa''.<ref name="pmid26774156">{{cite journal | vauthors = Sherrard LJ, McGrath SJ, McIlreavey L, Hatch J, Wolfgang MC, Muhlebach MS, Gilpin DF, Elborn JS, Tunney MM | title = Production of extended-spectrum β-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota | journal = International Journal of Antimicrobial Agents | volume = 47 | issue = 2 | pages = 140–145 | date = February 2016 | pmid = 26774156 | pmc = 4746055 | doi = 10.1016/j.ijantimicag.2015.12.004 }}</ref> Due to this, it has been suggested that the direct alteration of CF microbial community composition and metabolic function would provide an alternative to traditional antibiotic therapies.<ref name="Khanolkar"/>

===Antisense therapy===
[[Antisense therapy]] is being researched to treat a subset of mutations that have limited or no response to CFTR modulators.<ref name="pmid36697233">{{cite journal | vauthors = Kim YJ, Krainer AR | title = Antisense Oligonucleotide Therapeutics for Cystic Fibrosis: Recent Developments and Perspectives | journal = Molecules and Cells | volume = 46 | issue = 1 | pages = 10–20 | date = January 2023 | pmid = 36697233 | pmc = 9880599 | doi = 10.14348/molcells.2023.2172 }}</ref> Such mutations fall into two classes: splicing (e.g., c.3718-2477C>T) and nonsense (e.g., G542X, W1282X), both of which result in very low expression of CFTR protein, although the protein itself is usually unaffected. This is contrary to the more common mutations such as ΔF508 which have normal CFTR expression but in a non-functional form. Modulators serve only to correct these aberrant proteins and are of little to no benefit in the case of insufficient expression. Antisense oligonucleotides (ASOs) can solve this problem through the promotion of mRNA degradation or by changing pre-mRNA splicing, nonsense-mediated mRNA decay, or translation, thus increasing CFTR expression.