MICA: Towards clinical trial readiness of gene therapy for Niemann-Pick disease type c

Niemann-Pick Type C Disease (NP-C) is a devastating fatal disorder caused in 95% of cases by mutations in the NPC1 gene and is usually diagnosed in childhood. NPC1 deficiency causes fats to accumulate in cells of the body and premature death is associated with degeneration of the brain. As a result, patients experience progressive decline in their ability to walk and balance, learning and intellect, speech and eye movement and they experience tremor, seizures and problems with swallowing. This subsequently leads to premature death and there is no effective treatment available. Therefore, there is an overwhelming need to develop an effective treatment. Gene therapy is a relatively new treatment technology that holds immense potential for treating patients with NP-C. This technology involves using 'safe vectors' to deliver a normal and fully functional copy of the NPC1 gene into the cells of patients to compensate for the defective version they have. Although it is a new type of medicine, it has had a life-saving or life-changing effect in patients that have been involved in clinical trials for immunological, neurological, haematological and ophthalmic conditions. Gene therapy is unlike other conventional medicines in that it treats the genetic cause of the disease rather than the symptoms and may only have to be administered once in the lifetime of the patient. The aim of this proposal is to develop gene therapy that can provide life-saving treatment for the brain for NP-C. To use gene therapy in patients, it must first be tested in animals that have the disease to demonstrate that it will work and that it is safe to be used in humans. We have a mouse model that also has a defect in the NPC1 gene and develops the same symptoms resulting in premature death. This is a good model and we have conducted a proof-of-concept study showing that gene therapy given to newborn NP-C mice is safe and has a significant therapeutic effect on the lifespan, mobility and degeneration of the brain. While encouraging, there is scope to further improve on the therapeutic efficacy. We will be making new viral vectors and administering them to older early symptomatic NP-C mice to more closely mimic what happens in the clinic i.e. initiation of therapy upon diagnosis. By measuring and comparing increases in lifespan and improvements in mobility and pathology we will be able to identify the optimal parameters for maximum therapeutic benefit. We will then bridge the differences in size and anatomy between a mouse and human brain by examining how the optimal identified gene therapy vector spreads through the brain of larger animals. This is an important consideration in evaluating how the gene therapy will perform in humans. Using this information we will then perform very sensitive tests to makes sure that the gene therapy is safe. Finally, we will look at data which exists in a patient database to assess how NP-C progresses in order to help us decide the best way to design a potential gene therapy clinical trial. A successful outcome of this proposal will not only be of benefit to NP-C patients but also provide invaluable information for the development of gene therapy for a number of genetic diseases that affect the brain.