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毁灭性和过早致命性疾病。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内。患者完全依赖于他们的家人、照顾者和医疗体系，这带来了巨大的情感和经济负担。目前还没有可用的治疗方法，迫切需要为这种虚弱和致命的疾病开发一种治疗方法。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。这项技术包括使用“安全载体”将正常且功能完整的PLA2G6基因拷贝送入患者的细胞中，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。这项提议的目的是开发能够为INAD的大脑和神经系统提供挽救生命的治疗方法的基因疗法。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，以证明它是有效的，并且用于人类是安全的。我们有一个小鼠模型，它在许多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、活动能力和退化有显著的治疗效果。虽然令人鼓舞，但治疗效果仍有进一步提高的余地。我们将制造病毒载体，并通过不同的给药途径将它们注射给INAD小鼠。通过测量和比较寿命的延长、机动性和病理学的改善，我们将能够确定最佳参数，以获得最大的治疗效益。最后，我们将使用最优的基因治疗载体进行实验，以弥合老鼠和人脑在大小和解剖上的差异。这是评估基因治疗将如何在人类身上发挥作用的一个重要考虑因素。这一提议的成功结果不仅将有利于INAD患者，还将为开发针对影响大脑和神经系统的多种遗传性疾病的基因疗法提供宝贵信息。

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.