Pleiotrophin for Neurorestoration in Parkinson's Disease

描述（由申请人提供）：帕金森病 (PD) 的治疗历来侧重于症状缓解，而不是改变疾病自然进展的治疗。神经营养因子促进黑质纹状体系统的存活、分化和维持，并可能具有减缓和逆转神经退行性过程的潜力。迄今为止，通过基因治疗外源性施用神经营养因子一直是改善运动症状和阻止疾病进展的最有希望的方法。初步研究表明，病毒载体介导的黑质纹状体系统中神经营养因子多效营养因子 (PTN) 的过度表达可在 6-羟基多巴胺 (6-OHDA) 啮齿动物模型中提供神经保护和功能恢复。 PTN 在发育中和受损的黑质纹状体系统中都是一种有效的细胞存活和神经突生长促进因子。 PTN 蛋白和受体由中脑多巴胺 (DA) 神经元表达，并因纹状体去神经支配和其他神经系统损伤而上调。 PTN 及其受体在 PD 患者幸存的黑质 DA 神经元中高度上调。尽管在损伤前施用 PTN 可以保护 SN DA 神经元，但临床应用需要在 DA 神经元显着损失后进行形态恢复和功能恢复。目标 1 将检查 PTN 过表达的治疗潜力，PTN 过表达是通过黑质纹状体注射编码 PTN 的腺相关病毒载体产生的，随后出现显着的 DA 神经元和 6-OHDA 的末端损失。目标 2 将测试 PTN 过表达在 DA 神经元显着丢失和 ¿-突触核蛋白 (¿-syn) 过表达导致的末端丢失后的治疗潜力。 ¿-syn 啮齿动物模型表现出含有 ¿-syn 的神经元体和营养不良的神经突，而神经毒素模型无法重现这些神经元体和营养不良的神经突。在模拟帕金森病病理特征、黑质细胞死亡和路易体形成的动物模型中引发积极作用的神经营养因子更有可能在临床上对帕金森病患者有益。该提案的长期目标是确定 PTN 基因转移是否可以作为治疗策略来治疗已经发生显着黑质纹状体损伤后的 PD。该提案的目的是确定 PTN 基因治疗在阻止持续的黑质纹状体变性并在 PD 大鼠模型中提供形态和功能恢复的潜力。核心假设是，受损大鼠黑质纹状体系统中 PTN 的过度表达可以促进 6-OHDA 和 ¿-syn 帕金森模型的长期形态和功能恢复。这些结果可能最终决定 PTN 基因转移是否可以用作 PD 和其他神经系统疾病的治疗选择。

DESCRIPTION (provided by applicant): Treatments for Parkinson's disease (PD) have historically focused on symptomatic relief, rather than therapies that alter the natural progression of the disease. Neurotrophic factors promote survival, differentiation, and maintenance of the nigrostriatal system and may have the potential to slow and reverse neurodegenerative processes. To date, exogenous administration of neurotrophic factors by gene therapy has been the most promising approach to ameliorate motor symptoms and stall disease progression. Preliminary studies have shown that viral vector-mediated overexpression in the nigrostriatal system of the neurotrophic factor pleiotrophin (PTN) provides neuroprotection and functional restoration in a 6-hydroxydopamine (6-OHDA) rodent model of PD. PTN is a potent cell survival and neurite outgrowth-promoting factor both in the developing and lesioned nigrostriatal system. PTN protein and receptors are expressed by mesencephalic dopamine (DA) neurons and are upregulated in response to striatal denervation and other nervous system injuries. PTN and its receptors are highly upregulated in the surviving nigral DA neurons of PD patients. Although PTN can protect SN DA neurons when administered prior to insult, morphological restoration and functional recovery after significant DA neuron loss are necessary for clinical application. Aim 1 will examine the therapeutic potential of PTN overexpression, generated by nigrostriatal injections of adeno-associated viral vectors encoding for PTN, following significant DA neuron and terminal loss by 6-OHDA. Aim 2 will test the therapeutic potential of PTN overexpression following significant DA neuron and terminal loss by ¿-synuclein (¿-syn) overexpression. ¿ -syn rodent models exhibit ¿-syn containing neuron bodies and dystrophic neurites that neurotoxin models fail to recapitulate. Neurotrophic factors that elicit positive effects in animal models mimicking both pathological hallmarks of PD, nigral cell death and Lewy body formation, have greater potential to be clinically beneficial to PD patients. The long-term goal of this proposal is to determine if PTN gene transfer can be used as a therapeutic strategy to treat PD after significant nigrostriatal damage has already occurred. The objective of this proposal is to determine the potential of PTN gene therapy to halt ongoing nigrostriatal degeneration and provide both morphological and functional restoration in rat models of PD. The central hypothesis is that overexpression of PTN in the damaged rat nigrostriatal system can facilitate long- term morphological and functional recovery in both the 6-OHDA and ¿-syn parkinsonian models. These results may ultimately determine if PTN gene transfer can be used as a therapeutic option for PD and other nervous system disorders.