MICA: Towards clinical trial readiness of gene therapy for Niemann-Pick disease type c

尼曼-皮克C型疾病（NP-C）是一种毁灭性的致命疾病，95%的病例是由NPC 1基因突变引起的，通常在儿童时期被诊断出来。NPC 1缺乏导致脂肪在身体细胞中积累，过早死亡与大脑退化有关。因此，患者的行走和平衡能力、学习和智力、言语和眼球运动能力逐渐下降，他们会出现震颤、癫痫发作和吞咽问题。这随后导致过早死亡，并且没有有效的治疗方法。因此，迫切需要开发一种有效的治疗方法。基因治疗是一种相对较新的治疗技术，在治疗NP-C患者方面具有巨大的潜力。这项技术涉及使用“安全载体”将正常和功能齐全的NPC 1基因拷贝递送到患者细胞中，以补偿他们的缺陷版本。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，可以为NP-C的大脑提供挽救生命的治疗。要在患者中使用基因疗法，必须首先在患有该疾病的动物中进行测试，以证明它将起作用，并且用于人类是安全的。我们有一个小鼠模型，它也有NPC 1基因缺陷，并出现相同的症状，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NP-C小鼠进行基因治疗是安全的，并且对大脑的寿命，移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。我们将制造新的病毒载体，并将其给予老年早期有症状的NP-C小鼠，以更接近地模拟临床中发生的情况，即在诊断后开始治疗。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。然后，我们将通过研究最佳识别的基因治疗载体如何在较大动物的大脑中传播，来弥合小鼠和人类大脑之间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。利用这些信息，我们将进行非常敏感的测试，以确保基因治疗是安全的。最后，我们将研究存在于患者数据库中的数据，以评估NP-C的进展情况，以帮助我们决定设计潜在基因治疗临床试验的最佳方法。这一建议的成功结果不仅对NP-C患者有益，而且为许多影响大脑的遗传性疾病的基因治疗的发展提供了宝贵的信息。

Niemann-Pick Type C Disease (NP-C) is a devastating fatal disorder caused in 95% of cases by mutations in the NPC1 gene and is usually diagnosed in childhood. NPC1 deficiency causes fats to accumulate in cells of the body and premature death is associated with degeneration of the brain. As a result, patients experience progressive decline in their ability to walk and balance, learning and intellect, speech and eye movement and they experience tremor, seizures and problems with swallowing. This subsequently leads to premature death and there is no effective treatment available. Therefore, there is an overwhelming need to develop an effective treatment. Gene therapy is a relatively new treatment technology that holds immense potential for treating patients with NP-C. This technology involves using 'safe vectors' to deliver a normal and fully functional copy of the NPC1 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 for NP-C.To use gene therapy in patients, it must first 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 also has a defect in the NPC1 gene 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 NP-C mice is safe and has a significant therapeutic effect on the lifespan, mobility and degeneration of the brain. While encouraging, there is scope to further improve on the therapeutic efficacy. We will be making new viral vectors and administering them to older early symptomatic NP-C mice to more closely mimic what happens in the clinic i.e. initiation of therapy upon diagnosis. 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. We will then bridge the differences in size and anatomy between a mouse and human brain by examining how the optimal identified gene therapy vector spreads through the brain of larger animals. This is an important consideration in evaluating how the gene therapy will perform in humans. Using this information we will then perform very sensitive tests to makes sure that the gene therapy is safe. Finally, we will look at data which exists in a patient database to assess how NP-C progresses in order to help us decide the best way to design a potential gene therapy clinical trial.A successful outcome of this proposal will not only be of benefit to NP-C patients but also provide invaluable information for the development of gene therapy for a number of genetic diseases that affect the brain.