Peschanski M, Cesaro P, Hantraye P
INSERM U 421, IM3, Neuroplasticité et Thérapeutique, Faculté de Médecine, Créteil, France.
Neuroscience. 1995 Sep;68(2):273-85. doi: 10.1016/0306-4522(95)00162-c.
Huntington's disease is a genetic disease, autosomal and dominant, that induces motor disorders, an inexorable deterioration of higher brain functions and psychiatric disturbances. At present, there are no known therapeutics against Huntington's disease. The Network of European CNS Transplantation and Restoration (NECTAR) has begun a program aimed at defining the conditions under which intrastriatal transplantation of fetal striatal cells could be attempted as an experimental treatment for Huntington's disease. This review presents the reasons why our group is considering participating in these trials. The validity of this therapeutic approach is supported by three main series of data: (i) neuropathological, clinical and imaging data indicate that Huntington's disease is, above all, a localized affection of a specific neuronal population ("medium-spiny" neurons) in the striatum; (ii) a large body of experimental results, obtained in rats and non-human primates, demonstrates that transplanted fetal striatal cells are able to integrate the host brain and to substitute for previously lesioned host striatal neurons; (iii) expertise in clinical neural transplantation has now been acquired from the treatment of patients with Parkinson's disease. These different sets of data are presented and discussed in this review. There are a number of problems which do not yet appear to be entirely resolved, nor are they likely to be using the experimental models currently available. These problems are identified and explicitly presented as working hypotheses. (1) Anatomo-functional results obtained in rodents and non-human primates with excitotoxic striatal lesions can serve as a basis for the extrapolation of what can be obtained from patients with Huntington's disease. (2). Huntington's disease can be efficiently fought by substituting degenerated striatal neurons alone. (3) Huntington's disease is due to a genetic defect which either hits the neurons that carry it directly or hits them indirectly only after several decades. Transplanted neurons, because they do not carry the gene or because they are of fetal origin, will not be rapidly affected by the ongoing disease process. Given the current state of knowledge, intracerebral transplantation appears to be the most serious opportunity (if not the only one that has been experimentally validated) for clinical improvement to be obtained in patients with Huntington's disease. The purpose of this review is to open a scientific discussion on its experimental bases before actual clinical trials start.
亨廷顿舞蹈症是一种常染色体显性遗传病，会引发运动障碍、大脑高级功能的不可逆转的衰退以及精神紊乱。目前，尚无针对亨廷顿舞蹈症的已知疗法。欧洲中枢神经系统移植与修复网络（NECTAR）已启动一项计划，旨在确定在何种条件下可尝试将胎儿纹状体细胞进行纹状体内移植，作为治疗亨廷顿舞蹈症的一种实验性疗法。本综述阐述了我们团队考虑参与这些试验的原因。这种治疗方法的有效性得到了三大系列数据的支持：（i）神经病理学、临床和影像学数据表明，亨廷顿舞蹈症首先是纹状体中特定神经元群体（“中等棘状”神经元）的局部病变；（ii）在大鼠和非人灵长类动物身上获得的大量实验结果表明，移植的胎儿纹状体细胞能够整合到宿主大脑中，并替代先前受损的宿主纹状体神经元；（iii）目前已从帕金森病患者的治疗中积累了临床神经移植方面的专业知识。本综述将呈现并讨论这些不同的数据组。有一些问题似乎尚未完全解决，而且利用目前可用的实验模型也不太可能解决。这些问题被识别出来并明确作为工作假设提出。（1）在患有兴奋性毒性纹状体损伤的啮齿动物和非人灵长类动物身上获得的解剖学功能结果，可作为推断亨廷顿舞蹈症患者可能获得的结果的基础。（2）仅通过替代退化的纹状体神经元就能有效对抗亨廷顿舞蹈症。（3）亨廷顿舞蹈症是由一种基因缺陷导致的，这种缺陷要么直接影响携带该基因的神经元，要么在几十年后才间接影响它们。移植的神经元由于不携带该基因或因其源自胎儿，不会很快受到正在进行的疾病进程的影响。鉴于目前的知识水平，脑内移植似乎是在亨廷顿舞蹈症患者身上实现临床改善的最有希望的机会（如果不是唯一经过实验验证的机会的话）。本综述的目的是在实际临床试验开始之前，就其实验基础展开科学讨论。
