Development of new injectable, PolyGeneCaP composites for gene therapy

The aim of gene therapy is to treat patients who are born with inherited diseases by providing a normal gene to repair or replace the damaged or missing gene. Potential applications of gene therapy include well-known diseases such as haemophilia, cystic fibrosis, muscular dystrophy, some types of cancer and many other disorders where the defective genes are now being identified. Current procedures for the introduction of healthy genes into the cells of affected patients have relied primarily on the use of virus-derived 'carriers', but there is growing concern that these agents are not yet well enough understood and have the potential to be dangerous, even fatal. Unfortunately, alternative synthetic gene-delivery systems have thus far been inefficient and have had only very limited success. In this project we are proposing to develop a non-viral delivery system that has a specific healthy gene entrapped within a safe chemical particle. We plan to use a new method to convert these into very small 'nanoparticles' (called GeneCaP) that fully surround the gene and therefore protect it from breakdown and also enable it to get more readily into the patient's cells. To increase further the efficiency of gene entry, which has been one of the major problems in gene therapy, we will place the GeneCaP into a novel liquid (PolyGeneCaP) which can be injected. This will be designed so that it will rapidly solidify very close to the diseased organ and then degrade slowly, releasing the encased GeneCaP adjacent to the cell where the gene is needed to function. The 'model' disease which will be used in this proposal is called Sly Disease (Mucopolysaccharidosis Type VII), one of a large group of lysosomal gene defects which result in progressive mental and physical disability and are usually fatal at an early age. Illness occurs because the defective gene is unable to produce a particular lysosomal protein, which when restored in the presence of the healthy gene alleviates the disease. In this study we will, for the first time, measure and carefully correlate the properties of the DNA-containing particles and the ability of these new 'gene-drugs' to help correct the MPS VII disease, in order to be able to develop the optimal treatment strategies for a range of genetic diseases.