Multiplexed in vivo optimisation of non-toxic gene transfer agents.

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Putting material into cells is very challenging as cells have natural barriers that prevent the entry of most foreign materials. However being able to put specific genetic material (DNA) into human cells would have immense medical applications. For example the genetic material could be used to correct a defective gene (such as in cystic fibrosis), fight viral infection or prevent the growth of cancers.This project aims to develop tools that allow the rapid discovery of delivery devices that enable the efficient delivery of DNA into cells. One such tool is so-called multiplexed analysis where we will prepare 100 different combinations of DNA and carrier materials and then analyze these in such a way in which a hundred different compounds will be evaluated at one time. The winner will be compound that enters the cell most efficiently. Multiplexing is of course a well known term in relations to movie theatres with multiple screens. The analogy here is that we have 100 movies running (the analogy is that these are the 100 formulations we are examining), we admit 10,000 people (these by analogy are the cells) and analyze the distribution of people (cells) i.e. what was the most favourite film. A second element of this project is the development of delivery devices that are non-toxic and degrade naturally. Extending our movie analogy further we are looking for the one that will leave a positive lasting impression on the viewer (which may not of course be the movie that had the greatest audience!). Cystic fibrosis (CF) is a genetic disease affecting over 7000 individuals in the UK. Patients suffer frequent bacterial infections which lead to more and more lung damage. While there have been great improvements in CF treatment, lung disease leads to early death with a life expectancy at birth of about 30 years. Gene therapy, involving replacement of the defective CF gene with a working copy, has the potential to greatly improve the health of CF patients. Gene therapy offers the possibility of improving the patient?s prospects dramatically as well as reducing the disease s economic impact. This project is focused on producing better gene therapy formulations for the treatment of cystic fibrosis. However, indirectly, the formulation and characterization of novel gene transfer reagents would feed into the gene therapy field in general, and such reagents may find application in the treatment of other genetic disorders.