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.

We aim to move AAV-mediated gene therapy for treating Niemann-Pick Disease Type C (NP-C) towards clinical translation. NP-C is a fatal lysosomal storage disorder caused in 95% of cases by mutations in the NPC1 gene. NPC1 deficiency causes intracellular lipid accumulation leading to systemic pathology. NP-C is usually diagnosed in childhood and premature death is associated with neurodegeneration, where patients experience progressive ataxia, dystonia and cognitive decline. No major disease modifying treatments currently exist and there is an overwhelming need to develop an effective treatment. AAV-mediated gene therapy holds great potential for treating NP-C by preventing or decelerating neurodegeneration and subsequent fatal neurological disease. Direct brain delivery of an AAV9 vector expressing the human NPC1 gene in neurons of a murine NP-C model demonstrated long-term prevention of neurological symptoms accompanied with extension in lifespan. We will optimise our approach to enhance therapeutic efficacy, by expanding NPC1 expression to also include brain glial cells. The therapeutic efficacy of a neuronal and ubiquitous promoter within our vector will be compared in the early symptomatic NP-C mouse to model the clinical scenario of providing therapy at diagnosis. We will assess biodistribution of the optimal vector in larger models, evaluating both route and rate of administration and conduct a GLP toxicology study in rodents. We will progress to clinical trial readiness by establishing vector potency assays and applying for clinical trial authorisation. We are facilitated by a unique partnership with the Fundacion Columbus that will fund and manufacture GMP AAV vector for both this proposal and a future clinical trial. This proposal is supported by (i) preliminary proof-of-concept data, (ii) our experience in pre-clinical and translational gene therapy studies, (iii) guidance from the MHRA and (iv) collaboration with the Fundacion Columbus.

Impact for the patients and socioeconomics: Our hope is that the primary impact of this proposal will be patients with Niemann-Pick type C Disease (NP-C). There is no major disease modifying treatment for this condition, which has a devastating effect on patients' longevity and quality of life. The emotional burden this places on families and carers is overwhelming. Development of a new therapeutic approach would alleviate some or all of their burden. In addition, a new therapy could reduce the significant socioeconomic impact. Within the UK alone, there are approximately 100 NP-C patients. An effective therapy would significantly reduce the socioeconomic impact of the disease through reduced dependency on family and carers. Furthermore, a reduction in the frequency of hospital admissions, seizure burden and mortality would reduce the healthcare burden of this disease.

Impact for similar conditions: A successful outcome for this proposal will support research into a very broad range of genetic neurometabolic conditions. The information provided through the proposed investigation into routes and rates of gene therapy vector administration, biodistribution and toxicity studies will facilitate the development of treatments for these other conditions. This will benefit the patients with these diseases and the academics and clinicians who research them. More specifically, NP-C is one of more than 50 conditions referred to as lysosomal storage diseases. Data from this proposal would feed into developing a similar approach for some of these conditions and beyond.

Impact for industry: The recent ascendency of gene therapy has resulted in significant interest and investment from the biotechnology and pharmaceutical industry. This proposal contains a number of elements that industry could benefit from. The aforementioned optimization of routes and rates of gene therapy vector delivery will be of significant value to industry who are currently developing gene therapy pipelines for neurodegenerative diseases.

Impact of training new researchers: We will transfer technical and managerial skills to a new generation of research scientists, through the employment of a Postdoctoral Research Associate. The gene therapy field is growing and the knowledge and technical skills they will acquire would be highly valued. This will also help to develop an international skill base through the subsequent mobility of these new scientists. Former Ph.D. students and postdoctoral scientists have had positive career trajectories by training in our labs and are now in posts at many other universities or industry/healthcare.