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，可能具有减缓和逆转神经退行性过程的潜力。迄今为止，通过基因疗法外源性给药神经营养因子是最有希望改善运动症状和延缓疾病进展的方法。初步研究表明，在6-羟多巴胺（6-OHDA）啮齿动物PD模型中，病毒载体介导的神经营养因子多营养因子（PTN）在黑质纹状体系统中的过表达可提供神经保护和功能恢复。PTN在发育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起生长促进因子。PTN蛋白和受体由中脑多巴胺（DA）神经元表达，并在纹状体失神经支配和其他神经系统损伤的反应中上调。PTN及其受体在PD患者存活的黑质DA神经元中高度上调。尽管在损伤前给予PTN可以保护SN DA神经元，但在DA神经元严重损失后的形态恢复和功能恢复对于临床应用是必要的。目的1将研究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，在6-OHDA导致显著的DA神经元和终端丢失后。目的2将测试PTN过表达在显著DA神经元和突触核蛋白（¿- synnuclein, syn）过表达后的治疗潜力。-syn啮齿动物模型显示含有-syn的神经元体和营养不良的神经突，神经毒素模型无法概括。神经营养因子在模拟PD病理特征、神经细胞死亡和路易体形成的动物模型中产生积极作用，对PD患者具有更大的临床益处。本研究的长期目标是确定PTN基因转移是否可以作为一种治疗策略，用于治疗已经发生显著黑质纹状体损伤的PD。本提案的目的是确定PTN基因治疗的潜力，以阻止正在进行的黑质纹状体变性，并提供PD大鼠模型的形态和功能恢复。核心假设是PTN在受损大鼠黑质纹状体系统中的过表达可以促进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基因转移是否可以作为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.