The development of gene therapy for infantile neuroaxonal dystrophy

婴儿神经轴索营养不良是一种影响儿童的破坏性和过早致命的疾病。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。进行性症状可在6个月至3岁之间开始，包括行走和说话等技能下降、癫痫发作、导致瘫痪的痉挛状态以及无法执行吞咽等反射动作。随后的死亡通常发生在生命的第一个十年。患者完全依赖于他们的家人，护理人员和医疗保健系统，这带来了巨大的情感和经济负担。没有可用的治疗方法，并且迫切需要开发针对这种使人衰弱和致命的疾病的治疗方法。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。这项技术涉及使用“安全载体”将PLA2G6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。该提案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测试，以证明它会起作用，并且用于人类是安全的。我们有一个小鼠模型，在许多INAD患者中发现了相同的PLA2G6基因缺陷，并出现了导致过早死亡的相同症状。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，活动性和退化具有显着的治疗效果。虽然令人鼓舞，但仍有进一步改善疗效的余地。我们将制作病毒载体，并通过不同的给药途径将其给予INAD小鼠。通过测量和比较寿命的增加以及活动性和病理学的改善，我们将能够确定最佳参数以获得最大的治疗益处。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如何发挥作用的重要考虑因素。该提案的成功结果不仅将使INAD患者受益，而且还为影响大脑和神经系统的许多遗传疾病的基因治疗的发展提供了宝贵的信息。

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.