Gene Therapy for Tay-Sachs and Sandhoff diseases

Tay-Sachs和Sandhoff病的基因治疗我们的目标是治疗导致年轻人无情和致命的神经退行性疾病（Tay-Sachs和Sandhoff病-称为GM 2神经节苷脂沉积症）的遗传问题。需要一种激进的方法，因为溶酶体疾病，其中GM 2神经节苷脂沉积症是一个经典的原型，占近一半的负担，逐步智力和神经功能退化诊断在英国儿童。没有有效的治疗方法是已知的，在英国的1164名儿童中发现的进行性智力和神经系统恶化的病例负担具有巨大的人力和社会成本。已知的溶酶体疾病约有70种，其中三分之二损害大脑。溶酶体疾病的重要性最近已经通过发现缺陷的溶酶体功能易患帕金森综合征而显示，从而使这种小细胞颗粒在许多社区普遍存在的脑和神经退行性疾病中具有核心重要性。经过15年的深入科学研究，我们已经完善了将基因转移到活的哺乳动物大脑中的方法：我们使用其他人证明对人类安全的试剂（灭活的不会引起疾病的乘客病毒），努力推进对此类疾病的治疗。缺陷的溶酶体成分具有特殊的优势，即基因转移可用于治疗小的组织病灶，但校正因子从该靶标分泌，以被远处的细胞摄取。以这种方式，将用于基因治疗的载体一次性接种到脑中可以挽救大面积脑组织的功能，从而大大提高了年幼动物的存活率，否则这些动物将在几个月内濒临死亡。我们证明我们在这些研究中的计划是合理的，因为我们发现脑溶酶体中的一种必需酶的功能可以在整个中枢神经系统（脑和脊髓）中维持。此外，对缺陷的明确纠正解决了疾病的特征，并防止了脑细胞的严重损失，而脑细胞是无法替代的。早期进行基因治疗的结果是最佳的。我们将开发用于首次人体基因转移研究的试验用药品，作为临床试验的一部分;将由熟练的神经外科医生进行单一程序，对大脑结构进行安全的治疗。这将涉及产生有效的治疗方法，可以在已知患有GM 2神经节苷脂沉积症的活人患者中首次进行测试。我们的试验将基于我们多年来在Tay-Sachs和Sandhoff疾病中进行的概念验证研究，这些疾病在活体动物中真实建模;它将探索安全性和有效性的早期迹象（I/II期临床试验）。一个成功的结果将推进对患有这种疾病的儿童和年轻人以及受其他更熟悉和流行的神经退行性疾病影响的患者的治疗。

Gene Therapy for Tay-Sachs and Sandhoff diseasesOur aim is to treat the genetic problem that causes relentless and lethal neurodegenerative diseases (Tay-Sachs and Sandhoff diseases - termed GM2 gangliosidosis) in young people. A radical approach is needed because lysosomal diseases, of which GM2 gangliosidosis is a classical prototype, account for nearly half the burden of progressive intellectual and neurological deterioration diagnosed in UK children. No effective treatment is known and the caseload burden of progressive intellectual and neurological deterioration identified in 1164 children in the United Kingdom has immense human and societal costs. About 70 lysosomal diseases are known - two-thirds of which damage the brain. The importance of lysosomal disorders has recently been shown by the discovery that defective lysosomal function predisposes to Parkinsonism, thus investing this small cellular particle with central importance in the brain and neurodegenerative diseases which are prevalent in many communities. Over 15 years of intensive scientific research we have perfected gene transfer to the living mammalian brain: we use agents (inactivated passenger viruses that do not cause disease), shown by others to be safe in humans, in efforts to advance treatment for such conditions. Deficient lysosomal components have the special advantage that gene transfer can be used to treat a small focus of tissue but the corrective factor is secreted from this target to be taken up by cells far away. In this way, inoculation of the vector for gene therapy into the brain on a single occasion can rescue the function of a large field of brain tissue and so greatly improve survival in young animals that would otherwise be moribund within a few months. We justify our plans in these studies to translate our previous research findings into patients because we have found that function of an essential enzyme in brain lysosomes can be maintained throughout the entire central nervous system (brain and spinal cord). Moreover, definitive correction of the defect resolves the disease hallmarks and prevents critical loss of brain cells, which cannot otherwise be replaced. Outcomes are optimal when gene therapy is given early.We will develop Investigational Medicinal Products for first-into-human gene transfer studies as part of a clinical trial; there will be a single procedure by a neurosurgeon skilled in the safe administration of treatments to brain structures. This will involve generating effective treatments that can be tested for the first time in living human patients known to afflicted by GM2 gangliosidosis. Our trial will be based on our proof-of-concept studies with correction over years of the disease in Tay-Sachs and Sandhoff diseases authentically modelled in living animals; it will explore safety and early signs of effectiveness (phase I/II clinical trial). A successful outcome would advance treatment for stricken children and young persons with this disease as well as patients affected by other, more familiar and prevalent neurodegenerative diseases.