老年帕金森雄性和雌性猕猴壳膜CaV1.3-shRNA基因治疗的疾病改善和多维疗效

IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Kathy Steece-Collier, Margaret E Caulfield, Molly J Vander Werp, Scott J Muller, Jennifer A Stancati, Yaping Chu, Ivette M Sandoval, Timothy J Collier, Jeffrey H Kordower, Fredric P Manfredsson
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引用次数: 0

摘要

帕金森病(PD)仍存在一些未满足的临床需求,包括对症治疗的疗效减弱和不完全,药物副作用的发展(即左旋多巴诱导的运动障碍(LID))和无拘无束的疾病进展。CaV1.3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,利用腺相关病毒(AAV)表达短发卡(sh)RNA来对抗CaV1.3通道,以提供有效的靶向特异性沉默这些在帕金森纹状体中功能失调的通道。我们在此报告了前所未有的证据,mri引导的年龄(25-29岁)患有长期(8mos)晚期帕金森运动缺陷的雄性和雌性非人灵长类动物体内的AAV-CaV1.3-shRNA在没有药物治疗的情况下导致功能缺陷的显著进行性逆转,包括姿势不稳定和基于动机的精细运动表现恢复到正常/帕金森病前的基线。这与接受控制/打乱载体(AAV-SCR-shRNA)的患者维持稳定的中度至重度残疾形成对比。在接受AAV-SCR-shRNA载体的老年帕金森患者中,AAV-CaV1.3-shRNA受体也表现出维持左旋多巴运动益处的丧失,类似于终末期PD。最后,AAV-CaV1.3-shRNA受体尽管长期(5.5个月)、每日两次、剂量递增的左旋多巴,仍显示出前所未有的、近乎完全的预防LID诱导。在临床中实现这些一流的多模态基因治疗属性将代表PD治疗的重大进步。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disease-modifying, multidimensional efficacy of putaminal CaV1.3-shRNA gene therapy in aged parkinsonism male and female macaques.

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. CaV1.3 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 CaV1.3 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-CaV1.3-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-CaV1.3-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-CaV1.3-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.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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