The development of gene therapy for Niemann-Pick type C disease

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Niemann-Pick type C disease (NPC) is a devastating and ultimately fatal genetic disorder that profoundly affects the brain and other organs of the body. A diagnosis is usually made in infancy/childhood where approximately half of the patients have liver abnormalities. Ten per cent of these patients will die from liver failure before six months of age. The symptoms of NPC patients that survive infancy are dominated by progressive degeneration of the brain with debilitating consequences and subsequent death, usually in the second decade of life. The genetic defect causing NPC in the vast majority of cases is caused by mutations in a gene called NPC1. This causes an accumulation of a number of complex substances such as cholesterol in cells of the body resulting in the symptoms seen the brain and visceral organs. Currently, there are no major specific disease modifying treatments for NPC patients and the need to develop effective life-saving therapies is overwhelming. Gene therapy involves the delivery of a functional copy of a gene into a cell in order to compensate for a defective version. In most cases, the genes are delivered into cells using viral vectors. These vectors are based on viruses that have been stripped of their harmful components, rendered safe and used as a vehicle to efficiently deliver therapeutic genes to cells of the body. Using this approach, gene therapy has demonstrated life-saving and life-changing results in clinical trials. The objective of this project is to develop gene therapy for treating NPC. We have made a viral vector that can efficiently deliver a therapeutic version of the NPC1 gene into cells. We propose using this vector in a pre-clinical proof-of-concept gene therapy study to rescue a mouse model of NPC that recapitulates the symptoms seen in human patients. The aims of this research project are: (1) To deliver the viral vector carrying the therapeutic NPC1 gene directly into the brain of new-born NPC mice to assess, using a range of analyses, whether this ameliorates of prevents the symptoms in the brain. Our preliminary data shows that this has significant therapeutic affect but requires further investigation; (2) To deliver the viral vector intravenously into the bloodstream of new-born NPC mice and assess the therapeutic affect. This viral vector is known to deliver genes to visceral organs and also cross into the brain following intravenous injection. This approach offers potential treatment for both the brain and visceral organs symptoms such as in the liver; (3) To simultaneously deliver the viral vector both directly to the brain and also intravenously to effectively increase the systemic dose and assess the therapeutic efficacy; (4) To deliver the viral vector using the most therapeutically efficacious route of administration (identified in aims 1, 2 and 3) to progressively older mice and assess the therapeutic effect. The purpose of this is to gauge how the gene therapy may perform in more symptomatic mice. This would mimic the potential clinical situation where diagnosis of NPC may be delayed and patients have developed symptoms. It is our hope that this study will provide proof-of-concept data supporting the clinical application of gene therapy as an effective treatment for NPC patients.