The development of gene therapy for infantile neuroaxonal dystrophy

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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.