Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model.
Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model.
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DOI：
10.1021/acs.nanolett.7b00616
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发表时间：
2017-06-14
期刊：
影响因子：
10.8
通讯作者：
Price RJ
中科院分区：
文献类型：
--
作者：
Mead BP;Kim N;Miller GW;Hodges D;Mastorakos P;Klibanov AL;Mandell JW;Hirsh J;Suk JS;Hanes J;Price RJ
能够减缓甚至阻止帕金森病（PD）神经变性的治疗方法仍然难以捉摸。测试神经营养因子（如胶质细胞系衍生的神经营养因子（GDNF））的递送的PD基因疗法的临床试验由于在脑中整个患病区域中的不良载体分布而在很大程度上无效。此外，目前的递送策略涉及侵入性程序，这使得最有可能从基于GDNF的基因治疗中受益的早期患者被排除在外。在这里，我们介绍了一种双管齐下的治疗策略，由磁共振图像引导的聚焦超声（FUS）和脑穿透纳米颗粒（BPN），提供广泛的，但有针对性的GDNF转基因表达在大脑系统管理。MR图像引导的FUS允许循环基因载体通过在应用FUS的区域内的血脑屏障（BBB）的非侵入性和瞬时开放而分配到脑组织中。一旦超过BBB，BPN在整个靶向脑组织中提供广泛和均匀的GDNF表达。仅在单次治疗后，我们的策略导致6-OHDA诱导的PD大鼠模型纹状体中的FUS靶向区域中的GDNF蛋白含量达到治疗相关水平，持续至少长达10周。重要的是，我们的策略恢复了多巴胺水平和多巴胺能神经元密度，并逆转了PD相关运动功能障碍的行为指标，并且没有局部或全身毒性的证据。我们的组合方法克服了当前递送策略的局限性，从而潜在地提供了治疗PD的新手段。
Therapies capable of decelerating, or perhaps even halting, neurodegeneration in Parkinson’s disease (PD) remain elusive. Clinical trials of PD gene therapy testing the delivery of neurotrophic factors, such as the glial cell-line derived neurotrophic factor (GDNF), have been largely ineffective due to poor vector distribution throughout the diseased regions in the brain. In addition, current delivery strategies involve invasive procedures that obviate the inclusion of early stage patients who are most likely to benefit from GDNF-based gene therapy. Here, we introduce a two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF transgene expression in the brain following systemic administration. MR image-guided FUS allows circulating gene vectors to partition into the brain tissue by noninvasive and transient opening of the blood–brain barrier (BBB) within the areas where FUS is applied. Once beyond the BBB, BPN provide widespread and uniform GDNF expression throughout the targeted brain tissue. After only a single treatment, our strategy led to therapeutically relevant levels of GDNF protein content in the FUS-targeted regions in the striatum of the 6-OHDA-induced rat model of PD, which lasted at least up to 10 weeks. Importantly, our strategy restored both dopamine levels and dopaminergic neuron density and reversed behavioral indicators of PD-associated motor dysfunction with no evidence of local or systemic toxicity. Our combinatorial approach overcomes limitations of current delivery strategies, thereby potentially providing a novel means to treat PD.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
3.7
作者：
Bergen, Jamie M.;Park, In-Kyu;Horner, Philip J.;Pun, Suzie H.
通讯作者：
Pun, Suzie H.
影响因子：
6.1
作者：
Hegarty SV;O'Keeffe GW;Sullivan AM
通讯作者：
Sullivan AM
影响因子：
6.1
作者：
Gasmi, Mehdi;Brandon, Eugene P.;Bartus, Raymond T.
通讯作者：
Bartus, Raymond T.
影响因子：
2.9
作者：
Björklund, A;Kirik, D;Mandel, RJ
通讯作者：
Mandel, RJ