The Dorsal Column of this issue of Brain features a perspective by Bart Lutters and Peter Koehler that looks back at the history of cisterna magna puncture, a procedure that was first described in detail by James Bourne Ayer in 1920. They point out that adoption of the technique was driven, to a great extent, by the goal of delivering therapeutic agents directly to the CNS, and that its popularity waned as antibiotics that could be administered intramuscularly or intravenously replaced intrathecal anti-meningococcal serum, arsphenamine and ‘salvarsanized’ serum (a cocktail of arsphenamine and the patient’s own serum). Advances in radiology and an appreciation of the risks of the procedure no doubt also contributed to the decline of cisternal puncture. Kehrer (1949) reported four deaths in 8335 personally undertaken procedures, implying a substantially higher rate of complications among practitioners who may have been less keen to publicize their experience. Remarkably, 100 years after its introduction, cisterna magna puncture is back in the news, again because of the need to deliver therapeutic agents to the brain and spinal cord. Studies in rodents, cats, dogs, pigs and non-human primates have shown that adeno-associated viral vectors delivered via the cisternal route, as opposed to via a lumbar puncture, can reach the brain as well as the spinal cord. At least four clinical trials of gene therapy delivered by cisterna magna puncture are currently recruiting, targeting mucopolysaccharidosis type II, Tay Sachs disease, Parkinson’s disease in GBA1 mutation carriers, and Alzheimer’s disease associated with APOE4 homozygosity. The cisterna magna approach is arguably less invasive than intracerebroventricular or intraparenchymal delivery, which are also being used in clinical trials of gene therapy for monogenic or degenerative disorders. Other routes of delivery may yet eclipse the cisternal approach, and Brain recently published a promising preclinical study of gene therapy for alpha-mannosidosis in a feline model, which showed that intra-arterial delivery was more effective than intravenous administration (Yoon et al., 2020), raising the possibility of selective delivery to brain regions as defined by their arterial supply.

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社论。

本期《大脑背》专栏以Bart Lutters和Peter Koehler的观点为基础，回顾了大水箱穿刺的历史，这一过程由James Bourne Ayer于1920年首次详细描述。他们指出，在很大程度上推动了该技术的采用。 ，其目的是将治疗剂直接递送至中枢神经系统，并且其流行性逐渐减弱，因为可以通过肌肉内或静脉内注射的抗生素代替鞘内注射抗脑膜炎球菌血清，阿斯非明和“萨尔伐沙定”血清（阿斯非明与患者自身血清的混合物） ）。放射学的进步和对手术风险的认识无疑也导致了胸腔穿刺的减少。Kehrer（1949）报告在8335个人进行的程序中有4人死亡，这意味着可能不太愿意公开其经验的从业者中并发症的发生率大大提高。引人注目的是，在引入水槽大穿刺一百年之后，又再次成为新闻，这也是因为需要将治疗剂输送到大脑和脊髓。对啮齿动物，猫，狗，猪和非人类灵长类动物的研究表明，与通过腰椎穿刺相反，通过脑脊液途径递送的腺相关病毒载体可以到达大脑和脊髓。目前正在招募至少四项通过大水罐穿刺进行基因治疗的临床试验，这些试验针对II型粘多糖贮积病，Tay Sachs病，GBA1突变携带者中的帕金森氏病和与APOE4纯合性相关的阿尔茨海默氏病。大水罐疗法的侵害性可能比脑室内或实质内递送的侵袭性小，后者也被用于单基因或变性疾病的基因治疗的临床试验中。其他分娩途径可能仍使胸骨方法黯然失色，并且Brain最近发表了一项在猫科动物模型中进行α-甘露糖苷病基因治疗的有希望的临床前研究，该研究表明动脉内给药比静脉内给药更为有效（Yoon等人，2020年），从而增加了选择性向脑区给药的可能性由他们的动脉供应量定义。