The development of gene therapy for infantile neuroaxonal dystrophy

Infantile neuroaxonal dystrophy is a devastating and prematurely lethal disorder that affects children. It is caused by a defect in a gene called PLA2G6 and heavily effects the brain and the nervous system. The progressive symptoms can begin between 6 months and 3 years of age and include a decline in skills such as walking and talking, seizures, spasticity leading to paralysis and the inability to perform reflex actions like swallowing. Subsequent death usually occurs within the first decade of life. The patients are completely dependent on their families, carers and the healthcare system which carries a huge emotional and financial burden. There is no treatment available and there is an overwhelming need to develop a treatment for this debilitating and lethal disease.

Gene therapy is a relatively new treatment technology that holds immense potential for treating patients with INAD. This technology involves using 'safe vectors' to deliver a normal and fully functional copy of the PLA2G6 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 and nervous system for INAD.

Any gene therapy approach will have to 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 has the same defect in the PLA2G6 gene found in many INAD patients 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 INAD mice is safe and has a significant therapeutic effect on the lifespan, mobility and degeneration of the brain and spinal cord. While encouraging, there is scope to further improve on the therapeutic efficacy. We will be making viral vectors and administering them to the INAD mice via different routes of administration. 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. Finally, we will conduct experiments using the optimal gene therapy vector to bridge the differences in size and anatomy between a mouse and human brain. This is an important consideration in evaluating how the gene therapy will perform in humans.

A successful outcome of this proposal will not only be of benefit to INAD patients, but also provide invaluable information for the development of gene therapy for a number of genetic diseases that affect the brain and nervous system.

We aim to develop AAV-mediated gene therapy to treat infantile neuroaxonal dystrophy (INAD). INAD is a devastating and fatal inherited neurodegenerative disease of children caused by mutations in the PLA2G6 gene. Patients suffer neurodegeneration, severe spasticity and progressive cognitive decline leading to death within the first decade of life. No treatment is available, and patients receive only palliative care. There is an overwhelming need to develop an effective therapy for INAD. AAV-mediated gene therapy holds great potential as a treatment for INAD. This is based on our preliminary data using AAV9 to deliver a functional copy of the PLA2G6 gene to neurons of a mouse model of INAD. This neonatal intervention provided significant improvements in lifespan, locomotor function and quality of life and extensive amelioration of neurodegeneration in the brain and spinal cord. While promising, there is considerable room for optimization of the gene therapy vector itself before potential translation to the clinic. Following a meeting with the UK Medicines and Healthcare products Regulatory Agency (MHRA) and based on their feedback, we propose a pre-clinical study in older early symptomatic INAD mice to model the clinical scenario of providing therapy after diagnosis. This will include further optimization of INAD gene therapy by (A) comparing the use of a clinically used ubiquitous promoter in the AAV9 vector to our original neuron specific promoter, (B) comparing different routes, or combination of routes, of administration of the optimal vector to assess therapeutic response, (C) conduct biodistribution studies using the optimal vector and route(s) of administration in a larger brain. This proposal is supported by (i) our preliminary proof-of-concept data (ii) our experience in pre-clinical gene therapy studies in mouse models of neurodegeneration (iii) feedback and guidance from the MHRA.

Impact for the patients and socioeconomics: Our hope is that the primary impact of this proposal will be on the children with INAD. There is no established 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, applicant Kurian sees 5-10 patients per year at Great Ormond Street Hospital. 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, orthopaedic and respiratory complications, 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 novel dual intracerebroventricular and intravenous administration route to be assessed in this proposal will also be informative for those conditions which effect the nervous system together with pathology in other visceral organs. This will benefit the patients with these diseases and the academics and clinicians who research them. More specifically, INAD is one of 10 conditions referred to as Brain Iron Accumulation Disorders. 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 combination of dual intracerebroventricular and intravenous administration routes introduces a new potential application for those conditions affecting broad regions of the brain but also systemic symptoms . The isolation of a clinically relevant single vector that is effective from both optimal route(s) of administration and data from canine studies would be of interest to industry.

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 and a Research Assistant requested in this proposal. 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.