Gene therapy for cystic fibrosis.
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Biomedical subjects
Publications and source records attributed to E Alton.
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Gene therapy provides the best prospect of a fundamental new treatment for cystic fibrosis. The lungs are the most important target, because this organ is the most severely affected by the disease and is also accessible for topical treatment. Advances in this field have been very rapid, and the prospects remain good although a number of problems need to be overcome. The two main approaches to gene transfer, namely adenoviruses and liposomes, are efficient in vitro, but early clinical trials have shown that they work less well in vivo. A number of proof of concept studies have shown that gene transfer is possible, but full functional correction of the cystic fibrosis defect has not yet been achieved. Adenoviruses have provoked an inflammatory response, and new viral vectors are being developed to overcome this. Existing lipids are relatively inefficient, but new liposomes are being developed to enhance gene transfer. Much work needs to be done to improve safety and efficacy of gene transfer before materials are ready for large scale clinical trials. However, progress is very rapid, and there is a real prospect of developing an effective gene therapy for cystic fibrosis within the next decade.
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The cornerstones of CF medical treatment remain optimised nutrition, antibiotics and chest physiotherapy. There are however a number of promising new approaches which may add considerably to these traditional treatments. The most fundamental prospective new treatment is gene therapy which is still a long way off but could, in theory, provide a virtual cure for the disease. Less visionary but potentially as important is drug therapy aimed at the basic defect in airway ion transport. Both of these approaches are best suited to patients with early or even pre-symptomatic disease. In contrast, a third group of new treatments may prove useful in patients with established lung damage; these include a variety of anti-inflammatory drugs and DNase. This chapter will discuss each of these new treatments as well as exploring the difficult issue of assessing new treatments in pre-symptomatic disease.
Measurements of nasal transepithelial potential differences (TEPD) were performed in 77 patients in order to assess a routine simplified method of recording. TEPD assays were performed in 34 patients with cystic fibrosis aged 1 month to 25 years, in 22 children with another chronic respiratory illness and in 21 subjects without any bronchopulmonary impairment. In the cystic fibrosis group TEPD values (mean +/- SD) were significantly higher (-49.077 +/- 9.38 mV) than in patients with chronic respiratory illnesses (-20.590 +/- 5.011 mV) or in subjects without bronchopulmonary impairment (-19.857 +/- 5.033 mV) (p less than 0.0001). Measurements could not be performed in 10 patients due to major nasal inflammation. The excellent specificity (100%) and sensitivity (93%) of the method confirm its diagnostic value. It may be used from the neonatal period and may represent an alternative to the sweat test, especially in dubious cases.
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Twenty-six normal volunteers were exposed to rhinovirus or influenza B virus. Measurement of nasal mucociliary clearance, ciliary beat frequency, percent of epithelium ciliated, ciliary ultrastructure and nasal transmucosal potential difference were made before exposure, during viral incubation and at the time of expected overt infection. Ten volunteers failed to become infected, six were subclinically infected and nine were infected with symptoms. There were no significant differences between the results in volunteer groups during the incubation period or between uninfected and subclinical groups at the time of expected symptoms. Six of nine symptomatic infected volunteers had prolonged nasal clearance, and six of the seven biopsied had less than 50% of their epithelium ciliated. However, there was no significant reduction in ciliary beat frequency nor increase in ultrastructural ciliary abnormalities within this group of symptomatic volunteers. Of the two symptomatic infected (influenza B) volunteers tested, both showed significantly reduced transmucosal potential difference.
Three consecutive doses of approximately 10 mg/kg of a once daily slow-release theophylline preparation (Uniphyllin) were given at 22.00 hours to 15 patients with nocturnal asthma who were recovering from an acute exacerbation of their asthma. Twenty-four hour plasma theophylline profiles were obtained after the first and third doses. Following the first dose, the mean peak level was 12.5 mg/litre, mean time to peak was 8.1 hours and mean apparent elimination half-life was 6.6 hours. Pharmacokinetic data were similar following the third dose. In nocturnal asthma, Uniphyllin should be given at about 20.00 hours to coincide peak levels with the time of maximum airflow obstruction.
A glaucoma-screening examination was performed on 119 full-blooded Zuni Indians and 286 control subjects who were aged 40 years or older. The mean intraocular pressure (IOP) of the Zuni Indians was significantly lower than that of the control group, adjusted for age and sex differences, in both diabetic and nondiabetic subjects. The control group demonstrated an increasing IOP with age, while the Zunis did not. The prevalence of ocular hypertension was significantly greater in the control group than in the Zunis. The majority of the Zuni subjects with ocular hypertension had diabetes mellitus. None of the Zuni Indians who were screened had primary open-angle glaucoma and none had a family history of glaucoma.
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