Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys
Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys
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DOI：
10.1016/j.biomaterials.2016.09.015
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发表时间：
2016-12-01
期刊：
影响因子：
14
通讯作者：
Jose Blanco-Prieto, Maria
中科院分区：
文献类型：
--
作者：
Garbayo, Elisa;Ansorena, Eduardo;Jose Blanco-Prieto, Maria
胶质细胞源性神经营养因子（GDNF）仍然是多巴胺神经元最有效的神经营养因子。尽管GDNF具有治疗帕金森病（PD）的潜力，但其临床应用受到与GDNF体内半衰期短相关的安全性和有效性问题以及显著的脑递送障碍的阻碍。药物制剂系统如微粒（MP）可以克服这些问题，提供蛋白质免于降解的保护和随时间的持续药物释放。因此，我们试图在临床相关的PD模型中评估通过可注射的可生物降解的MP递送的GDNF的有效性和安全性，并研究有助于其有益作用的机制。将MP单侧注射到患有严重黑质纹状体变性的帕金森病猴的壳核中。值得注意的是，单次施用微囊化神经营养因子在脑中实现了持续的GDNF水平，提供了运动改善和多巴胺能功能恢复。这反映在治疗后9个月纹状体多巴胺能神经元密度的双侧增加。此外，GDNF逆行运输到黑质增加双边的多巴胺能神经元和总神经元的数量，无论严重的变性。壳核内注射GDNF-MP未引起免疫原性、小脑变性或体重减轻等不良反应。因此，MP是一种安全、有效的载体，用于持续向大脑递送蛋白质，支持GDNF在封装在MP中用于大脑修复时的治疗益处。总的来说，这些发现构成了GDNF-MP临床开发的重要基础。(C)2016爱思唯尔有限公司版权所有
Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development. (C) 2016 Elsevier Ltd. All rights reserved.