Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF
Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF
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DOI：
10.1089/10430340050111377
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发表时间：
2000-08-10
影响因子：
4.2
通讯作者：
Aebischer, P
中科院分区：
文献类型：
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作者：
Bachoud-Lévi, AC;Déglon, N;Aebischer, P
亨廷顿氏病（HD）是一种常染色体显性遗传疾病，对认知、心理和运动功能具有破坏性的临床影响。这些临床症状主要与纹状体的中型棘状GABA能神经元的进行性丧失有关，迄今为止还没有已知的治疗方法。然而，几种神经营养因子已经证明了在各种IID实验模型中保护纹状体神经元的能力，这包括睫状神经营养因子（CNTF），本方案中检查的物质。将使用基于包封的遗传修饰BHK细胞的离体基因治疗方法进行CNTF的连续和长期脑内递送。将在6名患者的右侧脑室中植入含有最多10（6）个由半透膜包围的人CNTF产生BHK细胞的装置。将使用每天释放0.15-0.5 μ g CNTF的胶囊。在这项I期研究中，主要目标是评价手术的安全性和耐受性。作为次要目标，将使用大量神经心理学、运动、神经学和神经生理学测试分析HD症状，并使用MRI和PET扫描成像监测纹状体病理学。预期本方案中描述的基因治疗方法将减轻与外周给予重组hCNTF相关的副作用，并允许神经保护因子的耐受性良好的连续脑室内递送。
Huntington's disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum, There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of IID, This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF, A device, containing up to 10(6) human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 mu g CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.