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RESEARCH |
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We have previously carried out 5 clinical trials using cationic lipids to carry genes into the nose and lungs of Cystic Fibrosis (CF) patients. These as well as studies by other groups using a variety of gene transfer agents (GTA), have proved the principle that CFTR (cystic fibrosis transmembrane regulator) gene transfer is possible without major safety issues and that partial correction of the basic defect in the airways of CF patients can be achieved. Despite these encouraging human studies, gene transfer to the CF lung is still sub-optimal and needs further improvement. The aim of the UK Cystic Fibrosis Gene Therapy Consortium is to develop a clinically effective gene therapy for CF. Focus on Non-viral Approaches We are currently focusing on non-viral gene transfer systems as they offer several potential advantages over viral approaches. They are non-infectious, relatively non-immunogenic, have low toxicity, can accommodate a large DNA plasmid and may be produced simply on a large scale. Improving Non-Viral Gene Transfer Agents Finding or developing new, better non-viral gene transfer agents is one way that gene transfer could be improved and to this aim we have adopted a combined approach that involves both procurement and in-house development of new GTAs. We have established high throughput core facilities in which the in vivo efficiency of gene transfer agents can be assessed. In-house development includes adding peptides and sugars in various ways to existing GTA in order to target them to the correct cells, increase their uptake and guide their path through the cell to the nucleus. |
Plasmid Modification We are also looking at ways to improve the plasmids that we are using in order to increase the efficiency and length of expression and reduce any toxicity and immune response. Physical Methods We are investigating physical methods for improving gene transfer to the cells of the lung including ultrasound and magnetofection. Through addition of energy, all of these methods induce very transient holes in the cell membrane, which may allow gene transfer agents to enter. Contact Time Studies have shown that gene transfer efficiency can be improved by increasing the length of time that a GTA is in contact with the cells and we are exploring how this may be achieved in the lung. Assays It is possible that only low levels of CFTR expression (in sufficient numbers of appropriate cells) may be required to correct the basic CF defect and that existing assays may not be sensitive enough to reliably detect a level of CFTR gene transfer that may be clinically effective. Hence we are putting substantial effort into both validating and improving existing assays and developing more sensitive novel assays. Clinical Programme We started our clinical programme in July 2006. Tracking Study - July 06 The aim was to track the cycle of a respiratory exacerbation, following admission to hospital for IV antibiotics. |
Measurements were taken within 24hrs of admission and again 2 weeks and 5 weeks later. By taking a series of measurements we have assessed the quality of a number of assays that we wish to use in future clinical studies of gene therapy. Run-in - Early 2008 The Run-in study is now underway. We intend to recruit 200 patients in order to gather longitudinal data on a series of clinical measures. The information we gather from this study will help to inform us of the optimal disease severity to take through to our clinical trials, as well as which are the best assays with which to measure any improvement. Pilot - Mid 2008 This study will help us to determine the optimum dose of gene therapy and also the duration of gene therapy. Initially, we will assess 3 doses of gene therapy in a group of patients and the optimum dose will be judged by efficacy and safety. The optimal dose will then be administered to a further group of patients and the duration of gene expression will be assessed by taking assays at 2 different time points after administration. The results will show us how often gene therapy needs to be repeated in our multi-dose trial. Multi-dose - Early 2010 We aim to recruit around 100 of the patients who took part in the Run-in for the Multi-dose trial. 50 of these patients will be given gene therapy and 50 will be given a placebo. Gene therapy will be delivered to the lungs once a month for 6 to 12 months and during this time the assays which were taken during the Run-in will be used to assess the benefit of gene therapy. For further information on our studies and our clinical team, please visit our Clinical Programme page. | ||||||||||
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