Kordower J H, Isacson O, Emerich D F
Research Center for Brain Repair and Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, Illinois, 60612, USA.
Exp Neurol. 1999 Sep;159(1):4-20. doi: 10.1006/exnr.1999.7156.
The elucidation of the genetic defect in patients with Huntington's disease (HD) has allowed for the detection of individuals at risk for HD prior to the onset of symptoms. Thus "neuroprotection strategies" aimed at preventing the neuropathological and behavioral sequelae of this disease might be powerful therapeutically since they could be introduced to healthy patients before the initiation of a massive degenerative cascade principally localized to the striatum. A variety of trophic factors potently protect vulnerable striatal neurons in animal models of HD. A number of experimental variables are critical in determining the success of trophic factors in animal models. In this regard, the method of trophic factor delivery may be crucial, as delivery via genetically modified cells often produces greater and more widespread effects on striatal neurons than infusions of that same factor. The mechanisms by which cellularly delivered trophic factors forestall degeneration and prevent behavioral deficits are complex and often appear to be unrelated to the trophic factor binding to its cognate receptor. In this regard, cells genetically modified to secrete nerve growth factor (NGF) or ciliary neurotrophic factor (CNTF) protect degenerating striatal neurons which do not express either NGF or CNTF receptors. This review will discuss some of the non-receptor-based events that might underlie these effects and present the hypothesis that cellular delivery of certain trophic factors using genetically modified cells may be ready for clinical testing in HD patients.
亨廷顿舞蹈病（HD）患者遗传缺陷的阐明，使得在症状出现之前就能检测出有患HD风险的个体。因此，旨在预防该疾病神经病理学和行为后遗症的“神经保护策略”在治疗上可能会很有效，因为它们可以在主要局限于纹状体的大规模退行性级联反应开始之前应用于健康患者。多种营养因子能有效保护HD动物模型中易损的纹状体神经元。在确定营养因子在动物模型中的成功与否时，有许多实验变量至关重要。在这方面，营养因子的递送方法可能至关重要，因为通过基因改造细胞进行递送通常比注入相同因子对纹状体神经元产生更大、更广泛的影响。细胞递送的营养因子阻止退化和预防行为缺陷的机制很复杂，而且往往似乎与营养因子与其同源受体的结合无关。在这方面，经基因改造以分泌神经生长因子（NGF）或睫状神经营养因子（CNTF）的细胞能保护不表达NGF或CNTF受体的退化纹状体神经元。本综述将讨论可能是这些效应基础的一些非受体介导的事件，并提出使用基因改造细胞进行某些营养因子的细胞递送可能已准备好在HD患者中进行临床试验的假说。
