Gene therapy for CLN5 Batten disease

CLN5 Batten 病的基因治疗

• 批准号: MR/R025134/1
• 负责人: Ahad Rahim
• 金额: $ 117.17万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR025134%2F1
• 关键词: Gene; therapy; 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.

CLN 5 Batten病是一种在儿童时期开始的破坏性和过早致命的神经退行性疾病。它是由一种名为CLN 5的基因缺陷引起的。症状开始于4-7岁的患者，包括发育进行性放缓，视力丧失，痴呆，癫痫发作和无法协调，移动四肢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，护理人员和医疗保健系统，这给他们带来了巨大的情感和经济负担。目前还没有针对CLN 5疾病的任何方面的治疗方法，并且迫切需要开发这种致命疾病的治疗方法。基因治疗是一种相对较新的治疗技术，具有治疗CLN 5疾病患者的巨大潜力。这项技术涉及使用安全的“病毒载体”将CLN 5基因的正常和全功能拷贝递送到患者的细胞中，以补偿他们所拥有的缺陷版本。虽然它是一种新型药物，但它对参与免疫学、神经学、血液学和眼科疾病临床试验的患者具有挽救生命或改变生命的作用。基因治疗与其他传统药物不同，它治疗疾病的遗传原因而不是症状，并且可能在患者的一生中只需施用一次。在CLN 5患者中有两个主要靶点需要基因治疗的优先治疗：（A）大脑--是大脑中细胞的损失最终导致死亡和（B）眼盲对CLN 5疾病患者的生活质量和他们的独立性水平有巨大影响.这项提案的目的是开发基因疗法，这种疗法可以第一次为大脑提供拯救生命的治疗，并通过治疗眼睛和预防失明来提高生活质量。任何基因疗法都必须在患有这种疾病的动物身上进行测试，以证明它会起作用，而且用于人类是安全的。我们有一种小鼠，它在CLN 5基因中有突变，并出现了患者和过早死亡的症状。这是一个很好的模型来测试我们的基因治疗方法，我们将制作病毒载体来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。这将涉及监测它们的行为和随着时间的推移通过一系列测试的能力，并将其与未接受治疗的小鼠进行比较。我们还将评估治疗小鼠的寿命是否增加。将检查接受治疗的小鼠的大脑和眼睛，以观察基因治疗是否能防止细胞丢失并减少随后的炎症。最后，我们将在小鼠中进行研究，以确认对大脑和眼睛施用的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CLN 5基因表达。这项提案的成功结果不仅对CLN 5疾病患者有益，而且还为开发一些影响大脑和眼睛的遗传疾病的基因治疗提供了宝贵的信息。

项目成果

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.

• DOI: 10.1038/s41467-018-05972-1
• 发表时间: 2018-08-29
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baruteau J;Perocheau DP;Hanley J;Lorvellec M;Rocha-Ferreira E;Karda R;Ng J;Suff N;Diaz JA;Rahim AA;Hughes MP;Banushi B;Prunty H;Hristova M;Ridout DA;Virasami A;Heales S;Howe SJ;Buckley SMK;Mills PB;Gissen P;Waddington SN
• 通讯作者: Waddington SN

Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

新生儿大脑定向基因治疗拯救神经退行性 CLN6 Batten 病小鼠模型

• DOI: 10.1101/673848
• 发表时间: 2019
• 作者: Holthaus S

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses.

• DOI: 10.1016/j.isci.2020.102020
• 发表时间: 2021-02-19
• 期刊: iScience
• 影响因子: 5.8
• 作者: Iwan K;Clayton R;Mills P;Csanyi B;Gissen P;Mole SE;Palmer DN;Mills K;Heywood WE
• 通讯作者: Heywood WE

AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease.

• DOI: 10.1093/hmg/ddy212
• 发表时间: 2018-09-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Hughes MP;Smith DA;Morris L;Fletcher C;Colaco A;Huebecker M;Tordo J;Palomar N;Massaro G;Henckaerts E;Waddington SN;Platt FM;Rahim AA
• 通讯作者: Rahim AA

Retinal Degenerative Diseases

视网膜退行性疾病

• DOI: 10.1007/978-3-319-75402-4_12
• 发表时间: 2018
• 作者: Kleine Holthaus S