The development of gene therapy for infantile neuroaxonal dystrophy

婴儿神经轴索营养不良基因治疗的进展

• 批准号: MR/S036784/1
• 负责人: Ahad Rahim
• 金额: $ 83.45万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS036784%2F1
• 关键词: development; gene; therapy; infantile; neuroaxonal

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.

婴儿神经轴突营养不良是一种影响儿童的破坏性和过早致死的疾病。它是由一种名为PLA2G6的基因缺陷引起的，严重影响大脑和神经系统。进行性症状可能在6个月到3岁之间开始，包括走路和说话等技能的下降，癫痫发作，痉挛导致瘫痪，以及无法进行吞咽等反射动作。随后的死亡通常发生在生命的头十年。患者完全依赖于他们的家庭、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。目前尚无治疗方法，迫切需要开发一种治疗这种使人衰弱和致命的疾病的方法。基因治疗是一种相对较新的治疗技术，在治疗INAD患者方面具有巨大的潜力。这项技术包括使用“安全载体”将PLA2G6基因的正常和完全功能的拷贝传递到患者的细胞中，以弥补他们有缺陷的版本。虽然它是一种新型药物，但它已经对参与免疫学、神经学、血液学和眼科疾病临床试验的患者产生了挽救生命或改变生活的作用。基因治疗不同于其他常规药物，因为它治疗的是疾病的遗传原因，而不是症状，而且在患者的一生中可能只需要进行一次治疗。这项提议的目的是开发基因疗法，为INAD的大脑和神经系统提供挽救生命的治疗。任何基因治疗方法都必须在患有这种疾病的动物身上进行试验，以证明它是有效的，并且可以安全地用于人类。我们有一个小鼠模型，在许多INAD患者身上发现了相同的PLA2G6基因缺陷，并出现了相同的症状，导致过早死亡。这是一个很好的模型，我们已经进行了一项概念验证研究，表明对新生INAD小鼠进行基因治疗是安全的，并且对大脑和脊髓的寿命、活动性和变性有显著的治疗效果。虽然令人鼓舞，但仍有进一步提高治疗效果的余地。我们将制作病毒载体并通过不同的给药途径给INAD小鼠注射。通过测量和比较寿命的增加以及活动能力和病理的改善，我们将能够确定获得最大治疗效益的最佳参数。最后，我们将使用最佳的基因治疗载体进行实验，以弥合小鼠和人类大脑在大小和解剖结构上的差异。这是评估基因治疗在人类中的表现的一个重要考虑因素。这一建议的成功结果不仅将有利于INAD患者，而且还将为一些影响大脑和神经系统的遗传疾病的基因治疗的发展提供宝贵的信息。

项目成果

Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors.

使用腺相关病毒载体产生产光体细胞转基因小鼠。

• DOI: 10.1038/s41598-020-59075-3
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Karda R

Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

• DOI: 10.1038/s41418-019-0442-2
• 发表时间: 2020-05-01
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Plotegher, Nicoletta;Perocheau, Dany;Duchen, Michael R.
• 通讯作者: Duchen, Michael R.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.

• DOI: 10.1126/scitranslmed.aaw1564
• 发表时间: 2021-05-19
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Ng J;Barral S;De La Fuente Barrigon C;Lignani G;Erdem FA;Wallings R;Privolizzi R;Rossignoli G;Alrashidi H;Heasman S;Meyer E;Ngoh A;Pope S;Karda R;Perocheau D;Baruteau J;Suff N;Antinao Diaz J;Schorge S;Vowles J;Marshall LR;Cowley SA;Sucic S;Freissmuth M;Counsell JR;Wade-Martins R;Heales SJR;Rahim AA;Bencze M;Waddington SN;Kurian MA
• 通讯作者: Kurian MA

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development.

• DOI: 10.3390/biom11040611
• 发表时间: 2021-04-20
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Massaro G;Geard AF;Liu W;Coombe-Tennant O;Waddington SN;Baruteau J;Gissen P;Rahim AA
• 通讯作者: Rahim AA