Gene therapy device-based delivery of progranulin, prosaposin, and GDNF as a combined precision and neurorestorative therapy in the rat 6-OHDA model of parkinsonism

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2025-09-22 DOI:10.1016/j.expneurol.2025.115474

Chiara Bertasini , Marco Rossini , Jacopo Grisotto , Dwaine Emerich , Matteo Brunelli , Serena Pedron , Cristina Parrado , Lars U. Wahlberg , Johan Lundkvist , Giovanna Paolone

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引用次数: 0

Abstract

Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disorder, characterized by a progressive degeneration of dopaminergic neurons, leading to significant motor impairments frequently associated with cognitive dysfunction and comorbidities in the elderly. Current treatments of PD are primarily symptomatic, highlighting the urgent need for disease-modifying therapies. An increasing body of evidence supports the pivotal role of lysosomal dysfunction in PD pathogenesis, providing new targets for therapeutic approaches. Particularly, recent studies suggest that among the genes implicated in PD are GRN and PSAP, encoding for progranulin (PGRN) and prosaposin (PSAP), respectively.

We proved that conditioned media from a Gene Therapy Device-based delivery system (GTD)-PGRN, -PSAP, and -PGRN+PSAP were internalized by primary cortical neurons, leading to enhanced glucocerebrosidase (GCase) activity.

Furthermore, we developed a GTD-delivered therapy to target lysosomal dysfunction and support the dopaminergic system, combining the lysosomal factors PGRN and PSAP with the neurorestorative glial cell line-derived neurotrophic factor (GDNF). Interestingly, each factor provided neuroprotection to dopaminergic neurons and preserved motor function in a 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model. Furthermore, eight-month treatments with GTD-PSAP and PSAP+GDNF resulted in significant neurorecovery effects on dopaminergic neurons and motor deficits following 6-OHDA injection.

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基于基因治疗装置的前颗粒蛋白、丙皂苷和GDNF作为帕金森大鼠6-OHDA模型的精确和神经修复联合治疗。

帕金森病（PD）是一种复杂的多因素神经退行性疾病，以多巴胺能神经元的进行性变性为特征，导致显著的运动损伤，通常与老年人的认知功能障碍和合并症相关。目前对帕金森病的治疗主要是对症治疗，因此迫切需要改善疾病的治疗。越来越多的证据支持溶酶体功能障碍在帕金森病发病机制中的关键作用，为治疗方法提供了新的靶点。特别是，最近的研究表明，在PD相关的基因中有GRN和PSAP，分别编码前颗粒蛋白（PGRN）和prosapin （PSAP）。我们证明了来自基于基因治疗装置的递送系统（GTD）的条件介质-PGRN， -PSAP和-PGRN+PSAP被初级皮质神经元内化，导致葡萄糖脑苷酶（GCase）活性增强。此外，我们开发了一种gtd靶向溶酶体功能障碍和支持多巴胺能系统的治疗方法，将溶酶体因子PGRN和PSAP与神经恢复性胶质细胞系来源的神经营养因子（GDNF）结合起来。有趣的是，在6-羟基多巴胺（6-OHDA）诱导的神经毒性模型中，每个因子都对多巴胺能神经元提供神经保护，并保持运动功能。此外，GTD-PSAP和PSAP+GDNF治疗8个月后，6-OHDA注射后多巴胺能神经元和运动缺陷的神经恢复效果显著。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.