Development of a novel, potent, safe, long-lasting lentivirus-based gene therapy for cystic fibrosis

点击翻译按钮获取中文摘要

Cystic Fibrosis (CF) is a common genetic disease that affects over 8000 people in the UK. It is the result of a mutation in a single gene called CFTR that causes the build up of thick sticky mucus in the lungs. Eventually the lungs become repeatedly infected and inflamed, leading to lung failure and premature death. All current therapies are aimed at coping with the symptoms; there is no cure. In 2001, three research groups in the UK formed the CF Gene Therapy Consortium to develop a new kind of treatment based on introducing new (healthy) copies of the CFTR gene into the lungs of people with CF. Many advances have been made, and we have learned a great deal about the obstacles to this approach, but we are not yet in a position to offer an effective gene therapy for CF lung disease. The aim of this research application is to use a new kind of gene therapy based on a virus called lentivirus, which we think has the potential to be more efficient at delivering the gene into the lungs and to provide an effective treatment for CF lung disease. In order to make the lentivirus carrying the CF gene as effective as possible, it is wrapped up in two new coat proteins called F and HN, a process known as 'pseudotyping'. We have shown that when the lentivirus is pseudotyped with F and HN it is efficient at entering lung cells and the gene it carries can be expressed for many months, even years in some situations. Another key feature that this pseudotyped virus displays is that it can be repeatedly administered, a property we have not seen previously with other viruses. This has an important advantage for treating chronic diseases, such as CF where the effects last for the life-time of the individual. The objectives of this application are i) to engineer the virus so it is suitable for use in patients; ii) to improve virus production methods so that it can be made in sufficient quantities to use as a therapy; and iii) to understand the potential for side-effects associated with administering the virus. The research project is 18 months long and at the end of it we hope to have selected a final version of the virus that we can take forward to test in patients. If we are successful in manufacturing the virus and selecting a suitable version to give to patients, we envisage that it could be delivered to the lungs of CF individuals using a device called a nebuliser, which generates a fine mist that can be breathed in. The increased efficiency of this virus along with the ability to have an effect that is long-lived effect means that this could form the basis of a new, more effective treatment for CF.