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Biomedical subjects

E Alton

Publications and source records attributed to E Alton.

At least 19 recordsLinked to original sources
PubMed2003

Immunological hurdles to lung gene therapy.

Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.

Antibodies, Blocking↗
PubMed2000

Differential binding of mannose-binding lectin to respiratory pathogens in cystic fibrosis.

We have found that mannose-binding lectin binds to Burkholderia cepacia, an important pathogen in patients with cystic fibrosis, and leads to complement activation, but that this is not the case for Pseudomonas aeruginosa, the more common colonising organism in this disease. We suggest that patients with cystic fibrosis with mannose-binding-lectin deficiency will be at particular risk of B cepacia colonisation.

Burkholderia cepacia↗
PubMed2000

Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema.

Resolution of pulmonary oedema is mediated by active absorption of liquid across the alveolar epithelium. A key component of this process is the sodium-potassium ATPase (Na+K+-ATPase) enzyme located on the basolateral surface of epithelial cells and up-regulated during oedema resolution. We hypothesised that lung liquid clearance could be further up-regulated by lipid-mediated transfer and expression of exogenous Na+K+-ATPase cDNA. We demonstrate proof of this principle in a model of high permeability pulmonary oedema induced by intraperitoneal injection of thiourea (2.5 mg/kg) in C57/BL6 mice. Pretreatment of mice (24 h before thiourea) by nasal sniffing of cationic liposome (lipid #67)-DNA complexes encoding the alpha and beta subunits of Na+K+-ATPase (160 microg per mouse), significantly (P<0.01) decreased the wet:dry weight ratios measured 2 h after thiourea injection compared with control animals, pretreated with an equivalent dose of an irrelevant gene. Whole lung Na+K+-ATPase activity was significantly (P<0.05) increased in mice pretreated with Na+K+-ATPase cDNA compared both with untreated control animals as well as animals pretreated with the irrelevant gene. Nested RT-PCR on whole lung homogenates confirmed gene transfer by detection of vector-specific mRNA in three of four mice studied 24 h after gene transfer. This demonstration of a significant reduction in pulmonary oedema following in vivo gene transfer raises the possibility of gene therapy as a novel, localised approach for pulmonary oedema in clinical settings such as ARDS and lung transplantation.

Animals↗
PubMed2000

Gene therapy for cystic fibrosis.

The gene for cystic fibrosis was identified in 1989 and this together with the emerging technology of gene therapy heralded a new dawn for the treatment of genetic disease. The initial optimism however gave way to the realisation that gene therapy for cystic fibrosis was unlikely to be straightforward. The lung was considered an ideal organ to target due to ease of access, but subsequent research has shown that the airway surface provides an efficient barrier to topically applied gene transfer agents. A number of Phase I clinical safety trials were carried out through the 1990s and provided proof of concept evidence that delivery of DNA by either viral or non-viral means was safe though not clinically efficacious. Current research is now focusing more on the barriers faced by delivery agents, with the aim that more efficient gene delivery will lead to a gene therapeutic for cystic fibrosis.

Cystic Fibrosis↗
PubMed1999

Effects of altering dosing on cationic liposome-mediated gene transfer to the respiratory epithelium.

Liposome-mediated gene transfer is currently sub-optimal with respect to both the extent and duration of transgene expression. We investigated whether simple changes in DNA dosing could enhance either of these outcomes. Increasing DNA doses produced highest transgene expression at an intermediate dose with toxicity observed at higher doses, thereby likely limiting expression. Adminis- tering an equivalent DNA dose in aliquots over a 1-3 day period resulted in significantly lower gene expression and did not increase the duration of expression. Administration at different times of the day (and hence wake/sleep cycles of the animals) did not alter gene expression. We conclude that such simple changes in dosing regimes are unlikely to contribute to improvements in gene transfer efficiency.

Animals↗
PubMed1998

Cystic fibrosis clinical trials.

The ion transport abnormalities in cystic fibrosis are becoming increasingly well defined, although how these lead to lung pathology is still speculation. Correction of these defects could theoretically be achieved either through pharmacological means or via gene therapy. Pharmacological approaches include increasing the amount of CFTR protein that reaches its correct localisation in epithelial cells. Secondly, approaches have been suggested which could increase the function of the protein already present at this correct localisation. Finally, it may be possible to identify alternative channels which could subserve the function of CFTR. Gene therapy is theoretically an attractive proposition as it should circumvent each of the identified abnormalities in cystic fibrosis. The principal difficulty at present relates to delivering sufficient copies of the normal CFTR gene into the appropriate cell population in vivo. A number of clinical trials have now been undertaken and steady and encouraging progress has been made in moving this approach from theory to practice.

Journal Article↗
PubMed1996

Gene therapy.

Explore the source record for details and available documents.

Cystic Fibrosis↗
PubMed1995

The prospects for gene therapy in cystic fibrosis.

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.

Cystic Fibrosis↗
PubMed1992

New treatments for cystic fibrosis.

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.

Amiloride↗
PubMed1991

[Determination of nasal transepithelial potential difference (DDPTE) in cystic fibrosis. Analysis of a simplified measurement technique].

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.

Child↗
PubMed1987

Upper respiratory tract viral infection and mucociliary clearance.

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.

Adult↗
PubMed1986

The pharmacokinetics of uniphyllin in nocturnal asthma.

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.

Acute Disease↗
PubMed1978

Intraocular pressure and glaucoma in the Zuni indians.

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.

Adult↗