Steece-Collier Kathy, Caulfield Margaret E, Vander Werp Molly J, Muller Scott J, Stancati Jennifer A, Chu Yaping, Sandoval Ivette M, Collier Timothy J, Kordower Jeffrey H, Manfredsson Fredric P
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Mol Ther. 2025 May 27. doi: 10.1016/j.ymthe.2025.05.027.
There remain several unmet clinical needs in Parkinson's disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. Ca1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against Ca1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-Ca1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-Ca1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-Ca1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD.
帕金森病（PD）仍存在若干未满足的临床需求，包括症状性疗法的疗效逐渐减弱且不完全、药物副作用（即左旋多巴诱导的运动障碍[LID]）的出现以及疾病的持续进展。Ca1.3钙通道是PD中备受关注的治疗靶点。我们开发了一种基于RNA干扰（RNAi）的载体方法，利用表达针对Ca1.3通道的短发夹（sh）RNA的腺相关病毒（AAV），对在帕金森病纹状体中功能失调的这些通道进行有效、靶向特异性的沉默。我们在此报告了前所未有的证据，即在患有长期（8个月）严重帕金森运动功能障碍的老年（25 - 29岁）雄性和雌性非人灵长类动物中，磁共振成像引导下向壳核内注射AAV - Ca1.3 - shRNA，在无药物治疗的情况下导致功能缺陷显著逐渐逆转，一些方面包括姿势不稳和基于动机的精细运动表现恢复到正常/帕金森病前基线。这与接受对照/乱序载体（AAV - SCR - shRNA）的动物维持稳定的中重度残疾形成对比。接受AAV - Ca1.3 - shRNA的动物还表现出在接受AAV - SCR - shRNA载体的这些老年帕金森病受试者中丧失的左旋多巴运动益处得以维持，类似于晚期PD。最后，尽管长期（5.5个月）每日两次进行剂量递增的左旋多巴治疗，接受AAV - Ca1.3 - shRNA的动物仍表现出前所未有的、近乎完全预防LID诱导的效果。在临床上实现这些一流的多模式基因治疗特性将代表PD治疗的重大进展。
