Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor:: Results of a phase I study
Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor:: Results of a phase I study
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DOI：
10.1089/hum.2004.15.968
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发表时间：
2004-10-01
影响因子：
4.2
通讯作者：
Peschanski, M
中科院分区：
文献类型：
--
作者：
Bloch, J;Bachoud-Lévi, AC;Peschanski, M
亨廷顿病（HD）是一种影响纹状体传出神经元的单基因神经退行性疾病。在成年期临床发作后，病理学在15至20年内的长期演变强调了旨在保护纹状体神经元的治疗工具的潜力。在成人脑中具有神经保护作用的蛋白质已经被鉴定，其中包括睫状神经营养因子（CNTF），其在HD动物模型中保护纹状体神经元。因此，我们已经进行了一项I期研究，评估了这种蛋白质在HD受试者脑内给药的安全性，使用的装置由半渗透膜封装的BHK细胞系工程合成CNTF。6例1期或2期HD受试者将1个胶囊植入右侧脑室;每6个月取出1个胶囊并更换为1个新胶囊，共持续2年。没有观察到CNTF诱导的毒性迹象;然而，在移除最后一粒胶囊后，3名受试者发生抑郁，这可能与缺乏任何未来治疗选择相关。所有回收的囊是完整的，但含有不同数量的存活细胞，CNTF释放低13 24例。观察到电生理结果的改善，并且与释放最大量的CNTF的胶囊相关。这项I期研究显示了这种基因治疗程序的安全性，可行性和耐受性。然而，异质细胞存活强调了改进该技术的必要性。
Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor ( CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.