Gene therapy for CLN5 Batten disease

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.

CLN5 Batten disease is a lethal paediatric inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN5 gene. Children with CLN5 Batten disease suffer progressive and devastating dementia, motor decline, epilepsy, visual failure and ultimately premature death. There is no treatment for CLN5 disease and there is a desperate need for a novel effective therapy. We propose a preclinical assessment of AAV-mediated gene therapy to restore expression of CLN5 in both the brain and eye to prevent lethal neurodegeneration and maintain quality of life through prevention of blindness, respectively. This will be assessed using a CLN5 deficient mouse model that presents both the brain and eye symptoms observed in patients. We will also examine safety associated to over-expression of the CLN5 gene and biodistribution. Two vector iterations will be tested side-by-side administered either via intravenous or intracerebroventricular injection to verify which has the greatest therapeutic efficacy in the brain and by subretinal administration to the eye in pre-symptomatic neonatal mice as proof-of-concept. When optimisation of the individual treatments has progressed, combination therapy of both brain and eye will be performed in older early symptomatic mice to mimic the clinical scenario of treatment following diagnosis. A number of key factors support this proposal: (A) CLN5 protein is a soluble enzyme that can be secreted from a cell and taken up by another, amplifying the therapeutic effects of gene delivery, (B) The applicants and collaborators have significant experience in rescuing mouse models of neurodegenerative diseases using gene therapy, and (C) encouragingly, there is evidence supporting the therapeutic efficacy of AAV9-mediated gene therapy in the brain of a sheep model of CLN5 disease. This project is an essential first step towards treatment for CLN5 disease.

Impact for the patients and socioeconomics: Our hope is that the primary impact of this proposal will be on children with CLN5 disease. There is no established successful 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 burden. Within the UK alone, the Batten Disease Family Association is aware of 5 current patients and expects 1-2 new diagnoses per year. The financial impact of CLN5 disease has been estimated at ~£300K per family and £1.5M per child to NHS or Public Services. We believe that this study will provide life-saving therapy to the brain and maintenance of quality of life through treating the eye and preventing blindness. The socioeconomic impact of increased independence of patients from carers, families and the healthcare system would be significant.

Impact for similar conditions: A successful outcome for this proposal will support research into conditions similar to CLN5 disease that also affect both the brain and the eye, benefitting patients suffering from these conditions and academics and clinicians who work on them. Within the group of Batten diseases, patients with mutations in 8 distinct genes in addition to CLN5 all suffer from lethal neurodegeneration and retinal degeneration and cumulatively account for the majority of paediatric neurodegenerative diseases. Data from this proposal would feed into developing a similar approach for these conditions and beyond the Batten disease field of research.

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 brain and eye gene therapy (both of which individually have been invested in by a number of companies) introduces a new potential application for a new subset of target diseases. The isolation of a clinically relevant single vector that is efficient in both the eye and brain, information on the optimal routes of administration and a safety profile in mice would be attractive to them.

Impact of training new researchers: We will transfer technical and managerial skills to a new generation of research scientists, through the employment of postdoctoral Research Associates 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.