Redmond D E, Roth R H, Spencer D D, Naftolin F, Leranth C, Robbins R J, Marek K L, Elsworth J D, Taylor J R, Sass K J
Neural Transplant Program, Yale University School of Medicine, New Haven, Connecticut 06510.
Ann N Y Acad Sci. 1993 Sep 24;695:258-66. doi: 10.1111/j.1749-6632.1993.tb23064.x.
After almost 100 years of sporadic, and marginally successful, studies of neural transplantation in animals, we are now on the threshold of a clinical treatment of the damaged brain. The initial studies of neural transplantation have focused on Parkinson's disease, primarily as a model for a more general strategy of "repair by cellular replacement." Parkinson's is known to result from the loss of a small population of cells that produce the essential neuromodulator, dopamine, for much of the brain. Further, the disease is improved significantly, during the early part of its course, by chemical augmentation of dopamine activity through drug therapies, such as L-dopa. Finally, the disease is often fatal in spite of the best medical treatments, therefore justifying more radical therapeutic experiments. If transplantation of brain cells can be accomplished successfully in humans, as it has been in animals, then replacement of a small population of dopamine-producing cells in Parkinson's disease should have important functional effects and possibly reverse the course and symptoms of the disease. Other useful applications will surely follow for conditions affecting millions of people for whom medicine now has only palliative and ineffective treatments. Just as Parkinson's disease is a model clinical condition for testing cellular replacements, fetal neural tissue transplants are also a first step for a broader strategy of molecular and cellular therapies. Fetal cells are, in many respects, the best replacements one could imagine, since precursor cells have the capacity to develop into every cell found in the adult. So, the best replacement for a dopamine neuron would likely be a precursor dopamine neuron or "neuroblast." Animal research through 1985 had demonstrated the unique properties of such fetal cells, but survivability after transplantation had not been attained with primate or human neural tissue. Our programs developed techniques to transplant monkey fetal neural tissue, to cryopreserve it, and to reverse functional effects of the neurotoxin, MPTP, in monkeys. This technique was applied to the collection and preservation of human tissue, and preliminary successful results have been obtained in patients with idiopathic Parkinson's disease. Others have reported success with different techniques in two MPTP-Parkinsonian patients and a small number of patients with idiopathic disease. If the most dramatic improvements can be replicated consistently and the benefits last for a reasonable period without complications, a clinical treatment might develop using "random-source" fetal cadaver cells.
在对动物进行了近100年零星且成效有限的神经移植研究之后，我们如今正处在对受损大脑进行临床治疗的开端。神经移植的初步研究聚焦于帕金森病，主要将其作为“细胞替代修复”这一更为通用策略的模型。众所周知，帕金森病是由于一小部分产生关键神经调质多巴胺的细胞缺失所致，多巴胺对大脑的许多区域都至关重要。此外，在疾病进程的早期，通过药物疗法（如左旋多巴）增强多巴胺活性，病情会有显著改善。最后，尽管采用了最佳的医疗手段，这种疾病往往仍是致命的，因此有理由进行更为激进的治疗实验。如果能像在动物身上那样成功地在人类身上完成脑细胞移植，那么在帕金森病中替换一小部分产生多巴胺的细胞应该会产生重要的功能效应，并有可能逆转疾病的进程和症状。对于数百万目前医学仅有姑息性和无效治疗方法的疾病患者，肯定会有其他有用的应用随之而来。正如帕金森病是测试细胞替代疗法的典型临床病症一样，胎儿神经组织移植也是更广泛的分子和细胞治疗策略的第一步。在许多方面，胎儿细胞是人们所能想象的最佳替代物，因为前体细胞有能力发育成成体中发现的每一种细胞。所以，多巴胺神经元的最佳替代物可能是前体多巴胺神经元或“成神经细胞”。到1985年为止的动物研究已经证明了此类胎儿细胞的独特特性，但灵长类或人类神经组织移植后的存活能力尚未实现。我们的项目开发了移植猴胎儿神经组织、将其冷冻保存以及逆转猴子体内神经毒素MPTP功能效应的技术。这项技术被应用于人体组织的采集和保存，并且在特发性帕金森病患者身上已经取得了初步的成功结果。其他人也报告了在两名MPTP诱导的帕金森病患者和少数特发性疾病患者身上使用不同技术取得的成功。如果能持续复制出最显著的改善效果，且益处能在合理的时间段内持续存在而无并发症，那么可能会开发出一种使用“随机来源”胎儿尸体细胞的临床治疗方法。
