Pleiotrophin for Neurorestoration in Parkinson's Disease

描述(申请人提供)：帕金森氏病(PD)的治疗历来侧重于症状缓解，而不是改变疾病自然发展的治疗方法。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变过程的潜力。到目前为止，外源性神经营养因子基因治疗是改善运动症状和延缓疾病进展的最有前途的方法。初步研究表明，病毒载体介导的神经营养因子多营养素(PTN)在黑质纹状体系统的过表达可为6-羟基多巴胺(6-OHDA)啮齿动物帕金森病模型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轴突生长促进因子。PTN蛋白和受体由中脑多巴胺(DA)神经元表达，并在纹状体失神经和其他神经系统损伤时上调。在PD患者存活的黑质DA神经元中，PTN及其受体高度上调。虽然PTN在损伤前给药可以保护黑质DA神经元，但在DA神经元显著丢失后，形态和功能的恢复是临床应用的必要条件。目的1通过黑质纹状体注射编码PTN的腺相关病毒载体，在6-OHDA导致大量DA神经元和终末缺失后，检测PTN过度表达的治疗潜力。目的2将测试PTN过度表达对显著DA神经元和突触核蛋白(SYN)过度表达所致终末缺失的治疗潜力。同步性啮齿动物模型表现出神经毒素模型未能概括的神经元体和营养不良的神经突起。神经营养因子在模拟帕金森病病理特征、黑质细胞死亡和路易小体形成的动物模型中产生积极作用，具有更大的临床应用潜力。这项建议的长期目标是确定PTN基因转移是否可以作为一种治疗策略，用于治疗已经发生重大黑质纹状体损伤的帕金森病。该建议的目的是确定PTN基因治疗在阻止黑质纹状体变性和提供帕金森病大鼠模型的形态和功能恢复方面的潜力。中心假设是PTN在受损的大鼠黑质纹状体系统中的过度表达可以促进6-OHDA和？-SYN帕金森病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帕金森病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.