Gene therapy for CLN5 Batten disease

点击翻译按钮获取中文摘要

CLN5 Batten disease is a devastating and prematurely lethal neurodegenerative disorder that begins in childhood. It is caused by a defect in a gene called CLN5. The symptoms start in patients at 4-7 years of age and include progressive slowing in development, loss of sight, dementia, epileptic seizures and an inability to co-ordinate, move their limbs or conduct reflex actions like swallowing. Death usually occurs between 14-36 years of age. The patients are completely dependent on their families, carers and the healthcare system which has a huge emotional and financial burden. There is currently no treatment available for any aspect of CLN5 disease and there is an overwhelming need to develop a treatment of this lethal condition.Gene therapy is a relatively new treatment technology that holds immense potential for treating patients with CLN5 disease. This technology involves using safe 'viral vectors' to deliver a normal and fully functional copy of the CLN5 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. There are two main targets in CLN5 patients that need priority treatment from gene therapy: (A) The brain - it is the loss of cells in the brain that ultimately leads to death and (B) The eye - blindness has a huge impact on the quality of life of CLN5 disease patients and their level of independence. The aim of this proposal is to develop gene therapy that can, for the first time, provide both life-saving treatment for the brain and quality of life enhancement by treating the eye and preventing blindness.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 strain of mice that have the mutation in the CLN5 gene and develop the symptoms seen in the patients and premature death. This is a good model to test our gene therapy approach and we will make viral vectors to deliver gene therapy to both the brain and eyes of these mice and assess them to see if there is a therapeutic response. This will involve monitoring their behaviour and ability to see through a series of tests over time and comparing this to mice that have not received the treatment. We will also assess whether there is an increase in lifespan of the treated mice. The brains and eyes of treated mice will be examined to see if the gene therapy works in preventing the cells from being lost and reducing the subsequent inflammation. Finally, we will conduct studies in mice to confirm the safety of the gene therapy administered to both the brain and eye and the resultant high levels of therapeutic CLN5 gene expression from the viral vector. A successful outcome of this proposal will not only be of benefit to CLN5 disease patients, but also provide invaluable information for the development of gene therapy for a number of genetic diseases that also affect both the brain and eye.