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

MICA：为尼曼-匹克病 c 型基因治疗的临床试验做好准备

• 批准号: MR/T044853/1
• 负责人: Ahad Rahim
• 金额: $ 240.95万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT044853%2F1
• 关键词: MICA; Towards; clinical; trial; readiness

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.

尼曼-皮克C型病（NP-C）是一种毁灭性的致命疾病，95%的病例由NPC1基因突变引起，通常在儿童时期被诊断出来。缺乏NPC1会导致脂肪在身体细胞中积聚，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、语言和眼球运动能力逐渐下降，并出现震颤、癫痫发作和吞咽问题。这随后导致过早死亡，而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。这项技术包括使用“安全载体”将正常的、功能完整的NPC1基因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，为大脑的NP-C提供挽救生命的治疗。要在病人身上使用基因疗法，首先必须在患有这种疾病的动物身上进行试验，以证明它会起作用，而且用于人类是安全的。我们有一只老鼠模型，它也有NPC1基因缺陷，并出现同样的症状，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，表明给予新生NP-C小鼠的基因治疗是安全的，并且对大脑的寿命、活动性和退化有显著的治疗效果。虽然令人鼓舞，但仍有进一步提高治疗效果的余地。我们将制造新的病毒载体，并将其施用于老年早期症状NP-C小鼠，以更接近地模拟临床上发生的情况，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。然后，我们将通过检查最佳确定的基因治疗载体如何在大型动物的大脑中传播，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。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，我们将查看患者数据库中存在的数据，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将有利于NP-C患者，而且还将为一些影响大脑的遗传疾病的基因治疗的发展提供宝贵的信息。

项目成果

Gene therapy effective in model of infantile parkinsonism

基因疗法对婴儿帕金森病模型有效

• DOI: 10.1038/s41582-021-00522-8
• 发表时间: 2021
• 期刊: Nature Reviews Neurology
• 影响因子: 38.1
• 作者: Lemprière S

A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.

• DOI: 10.1038/s41598-022-17338-1
• 发表时间: 2022-08-15
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Poupon-Bejuit, L.;Hughes, M. P.;Liu, W.;Geard, A.;Faour-Slika, N.;Whaler, S.;Massaro, G.;Rahim, A. A.
• 通讯作者: Rahim, A. A.

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