Gene therapy for CLN5 Batten disease

CLN5巴顿病是一种毁灭性的、过早致命的神经退行性疾病，始于儿童时期。它是由一种名为CLN5的基因缺陷引起的。这些症状始于4-7岁的患者，包括发育逐渐放缓、失明、痴呆症、癫痫发作以及无法协调、移动肢体或进行吞咽等反射动作。死亡通常发生在14-36岁之间。患者完全依赖于他们的家人、照顾者和医疗体系，这给他们带来了巨大的情感和经济负担。目前还没有针对CLN5疾病的任何方面的治疗方法，迫切需要开发这种致命疾病的治疗方法。基因疗法是一种相对较新的治疗技术，在治疗CLN5疾病患者方面具有巨大的潜力。这项技术包括使用安全的“病毒载体”将CLN5基因的正常和全功能拷贝输送到患者的细胞中，以弥补他们的缺陷版本。虽然它是一种新型药物，但它已经在参与免疫学、神经学、血液学和眼科疾病临床试验的患者中产生了挽救生命或改变生命的效果。基因疗法不同于其他传统药物，因为它治疗疾病的遗传原因，而不是症状，而且可能在患者一生中只需给药一次。CLN5患者有两个主要目标需要从基因疗法中优先治疗：(A)大脑--正是大脑中细胞的丧失最终导致死亡和(B)失明对CLN5患者的生活质量和他们的独立性水平有巨大影响。这项提议的目的是开发基因疗法，首次能够通过治疗眼睛和预防失明来为大脑提供挽救生命的治疗，并提高生活质量。任何基因疗法方法都必须在患有这种疾病的动物身上进行测试，以证明它是有效的，并且在人类身上使用是安全的。我们有一种带有CLN5基因突变的小鼠，会出现患者的症状和过早死亡。这是测试我们的基因治疗方法的一个很好的模型，我们将制作病毒载体，将基因治疗传递到这些小鼠的大脑和眼睛，并评估它们是否有治疗反应。这将包括随着时间的推移监测它们的行为和通过一系列测试的能力，并将其与没有接受治疗的小鼠进行比较。我们还将评估接受治疗的小鼠的寿命是否延长。将对接受治疗的小鼠的大脑和眼睛进行检查，看看基因疗法是否在防止细胞丢失和减少随后的炎症方面有效。最后，我们将在小鼠身上进行研究，以确认对大脑和眼睛进行基因治疗的安全性，以及由此产生的来自病毒载体的高水平治疗性CLN5基因表达。这一提议的成功结果不仅将有利于CLN5疾病患者，还将为开发多种同时影响大脑和眼睛的遗传病的基因疗法提供宝贵的信息。

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.