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给予神经营养因子已成为改善运动症状和阻止疾病进展的最有前途的方法。初步研究表明，病毒载体介导的黑质纹状体系统中神经营养因子多效生长因子（PTN）的过表达在6-羟基多巴胺（6-OHDA）啮齿动物PD模型中提供了神经保护和功能恢复。PTN是一种有效的细胞存活和轴突生长促进因子，在发育和受损的黑质纹状体系统。PTN蛋白和受体由中脑多巴胺（DA）神经元表达，并且响应于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患者存活的黑质DA神经元中高度上调。尽管PTN在损伤前给药可以保护SN DA神经元，但在DA神经元显著丧失后的形态学恢复和功能恢复对于临床应用是必要的。目的1将检查PTN过表达的治疗潜力，通过黑质纹状体注射编码PTN的腺相关病毒载体，在6-OHDA引起的显著DA神经元和终末损失后产生。目的2将测试PTN过表达在<$-突触核蛋白（<$-syn）过表达引起的显著DA神经元和终末丢失后的治疗潜力。啮齿类动物模型表现出神经毒素模型不能重现的含有神经元体和营养不良的神经突的<$-syn。在模拟PD的病理学标志、黑质细胞死亡和路易体形成的动物模型中引起积极作用的神经营养因子对PD患者具有更大的临床有益潜力。这项建议的长期目标是确定PTN基因转移是否可以作为一种治疗策略来治疗PD后，显着的黑质纹状体损伤已经发生。本提案的目的是确定PTN基因治疗阻止正在进行的黑质纹状体变性的潜力，并在PD大鼠模型中提供形态和功能恢复。中心假设是PTN在受损大鼠黑质纹状体系统中的过表达可以促进6-OHDA和<$-syn帕金森病模型中的长期形态和功能恢复。这些结果可能最终决定PTN基因转移是否可用作PD和其他神经系统疾病的治疗选择。 公共卫生相关性：帕金森病是一种进行性神经退行性疾病，无法治愈，预计随着人口老龄化的增加，疾病患病率将增加。帕金森病通常以运动症状的发作来诊断，并且症状的改善是当前治疗的主要焦点。应用外源性神经营养因子（参与神经元生长和存活的蛋白质）的基因治疗策略具有恢复正常运动功能和阻止疾病进展的潜力。在这项提案中，我们的目标是测试的神经营养因子多效生长因子，通过病毒载体提供的治疗潜力，在形态学上保护退化途径和恢复功能的两个啮齿动物模型的帕金森综合征。

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. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a progressive neurodegenerative disorder without a cure, and disease prevalence is predicted to increase with the growing aging population. Parkinson's disease is commonly diagnosed with the onset of motor symptoms, and amelioration of symptoms is the primary focus of current therapies. Gene therapy strategies that apply exogenous application of neurotrophic factors, proteins involved in neuron growth and survival, have the potential to both restore normal motor function and stop disease progression. In this proposal we aim to test the therapeutic potential of the neurotrophic factor pleiotrophin, delivered by viral vectors, to morphologically protect degenerating pathways and restore function in two rodent models of parkinsonism.