Cystic fibrosis (CF) is an incurable genetic disorder that mainly affects the lungs and digestive system, and is the UK’s most common life threatening inherited disease. It affects about 1 in 2,000 children in the UK; five affected children are born and three patients die each week
CF is caused by a defect in the CFTR gene (identified in 1989), which makes a protein that transports salt and water in and out of the cells that line the lungs and gut. More than 1,200 disease-causing mutations are known to occur, some of which are more common than others. Depending on the exact type of mutation a CF child has inherited from their parents, the disease can be relatively mild or cause death in infancy.
Repeated lung infections and inflammation means that the average life expectancy for a cystic fibrosis sufferer is only 31 years – but improved treatments and the continued efforts of researchers mean that today’s CF babies may live well beyond this. Patients suffer repeated lung infections from various strains of the bacteria Pseudomonas aeruginosa and Burkholderia cepacia complex, which rarely cause problems in healthy people.
P. aeruginosa mutates in CF patients, changing its outer membrane and reducing the body’s defences. It may be possible to develop, using animals, a drug that blocks this mutation . This susceptibility to infection is linked to low levels of lipoxin, tiny lipids that switch off infection-fighting white cells that accidentally damage the lung when fighting bacteria. Mice with damaged lungs infected with P. aeruginosa were able to fight off infection better when given lipoxin—which is related to aspirin and ibuprofen and explains why these drugs are beneficial to CF patients .
In 1992 four medical research teams in Britain and the USA bred mice with defects in their cystic fibrosis gene
The underlying lung damage in CF is caused by high concentrations of salt, and the mechanism has been identified in CF mice as a defect in fluid transport. Several ways of correcting this have been developed in mice .
Research using CF mouse models has shown that it is possible to deliver a 'good' copy of the CFTR gene using liposomes to the lungs, which corrects the biochemical defect and restores normal lung function
Now working together as a consortium backed by the Cystic Fibrosis Trust, three UK groups in London, Oxford and Edinburgh, have made substantial improvements to the gene therapy protocol. This has been tested in mice and sheep in preparation for further clinical trials. Fifteen CF volunteers are to join a single dose gene therapy trial in 2007, while a further 200 people are to be monitored. In 2008 up to 100 of these people will be recruited into a multi-dose gene therapy trial .
Natural defences against allergens and irritants have made inhaled gene therapy hard to get into the lungs. Using a natural detergent-like substance called LPC, scientists have removed this resistance in mice. The introduced gene and the benefit from it persisted for at least three months, which is as long as lung lining cells survive. This suggests that the gene had entered stem cells and been passed on with the stem cells' DNA when the cells divided. This may be a step towards overcoming the problems of human gene therapy.
Research with adenovirus vectors using mice, rats and primates has also shown that gene therapy in the womb may be more effective, while avoiding side effects.
In 2004 scientists found that treatment with oral curcumin, the yellow pigment of the spice turmeric, corrected the principal physiological defects associated with cystic fibrosis and prevented the gastrointestinal manifestations of the disease in mice.
- Cystic Fibrosis Trust (accessed 15 June 2007) What is Cystic Fibrosis? http://www.cftrust.org.uk/aboutcf/whatiscf/
- Hajjar AM, Ernst RK, Tsai JH et al (2002) Human Toll-like receptor 4 recognizes host-specific LPS modifications Nature Immunol. 3, 354
- Pier GB (2007) Pseudomonas aeruginosa lipopolysaccharide: A major virulence factor, initiator of inflammation and target for effective immunity Int. J. Med. Microbiol. 297(5), 277-95. [Epub 2007 Apr 27]
- Takai D, Nagase T, Shimizu T (2004) New therapeutic key for cystic fibrosis: a role for lipoxins Nature Immunol, 5, 357
- Snouwaert JN, Brigman KK, Latour AM et al (1992) An animal model for cystic fibrosis made by gene targeting Science 257, 1083
- Clarke LL, Grubb BR, Gabriel SE et al (1992) Defective epithelial chloride transport in a gene targeted mouse model of cystic fibrosis Science 257, 1125
- Dorin JR, Dickinson P, Alton EW et al (1992) Cystic fibrosis in the mouse by targeted insertional mutagenesis Nature 359, 211
- Colledge WH, Ratcliff R, Foster D et al (1992) Cystic fibrosis mouse with intestinal obstruction The Lancet 340, 680
- Mall M, Grubb BR, Harkema JR (2004) Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice Science 10, 487
- Tarran R, Grubb BR, Parsons D et al (2001) The CF salt controversy: In vivo observations and therapeutic approaches Mol. Cell 8, 149
- Alton EW, Middleton PG, Caplen NJ et al (1993) Non-invasive-liposome mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice Nat. Genet. 5, 135
- Hyde SC, Gill DR, Higgins CF (1993) Correction of the ion transport defect in cystic fibrosis by gene therapy Nature 362, 250
- Caplen NJ, Alton EW, Middleton PG et al (1995) Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis Nat. Med. 1, 39
- Gill DR, Southern KW, Mofford KA et al (1997) A placebo-controlled study of liposome-mediate gene transfer to the nasal epithelium of patients with cystic fibrosis Gene Therapy 4, 199
- Porteous DJ, Dorin JR, McLachlan G et al (1997) Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis Gene Ther. 4 210
- Alton EWFW, Stern M, Farley R et al (1999) Cationic lipid-mediated CFTR gene transfer to the lungs and noses of patients with cystic fibrosis: a double-blind placebo-controlled trial The Lancet 353, 947
- Hyde SC, Southern KW, Gileadi U et al (2000) Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis Gene Ther. 7 1156
- Ostedgaard LS, Zabner J, Vermeer DW, et al (2002) CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo Proc Nat Acad Sci 99, 3093
- Stern M, Ulrich K, Geddes DM, Alton EW (2003) Poly (D, L-lactide-co-glycolide)/DNA microspheres to facilitate prolonged transgene expression in airway epithelium in vitro, ex vivo and in vivo Gene Ther. 10(16), 1282
- Medical advances and animal research. The contribution of animal science to the medical revolution: some case histories (2007) RDS and Coalition for Medical Progress
- Cystic Fibrosis Trust (accessed 15 June 2007) Gene therapy in Cystic Fibrosis http://www.cftrust.org.uk/research/researchincf/genetherapy/
- Limberis M, Anson DS, Fuller M, Parsons DW (2002) Recovery of airway cystic fibrosis transmembrance conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer Hum. Gene Ther. 13, 1961
- Larson JE, Morrow SL, Happel L, Sharp JF, Cohen JC (1997) Reversal of cystic fibrosis phenotype in mice by gene therapy in utero The Lancet 349, 619
- Cohen JC, Larson JE (2006) Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis Dev Dyn 235(10), 2736
- Garrett DJ, Larson JE, Dunn D et al (2003) In utero recombinant adeno-associated virus gene transfer in mice, rats, and primates BMC Biotechnol 3, 16
- Egan ME, Pearson M, Scott A et al (2004) Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects Science 304, 600