Gene therapy targeting striatal dysfunction for Parkinson’s disease

针对帕金森病纹状体功能障碍的基因疗法

基本信息

批准号：
10557885
负责人：
Stella M Papa
金额：
$ 56.15万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557885
关键词：
Affect Animal Model Area Attention Behavior Behavioral Bilateral Binding Sites Brain Brain region Cell membrane Cells Chronic Clinical Clinical Trials Cognitive Cognitive deficits Corpus striatum structure Data Development Disease Disease Progression Disease model Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dose Dyskinetic syndrome Electrophysiology (science)Evaluation Evolution Functional disorder Gene Expression Gene Silencing Genes Genetic Glutamates Grant Health Hyperactivity Impaired cognition Injections Learning Levodopa MPTP Poisoning MPTP model MPTP non-human primate Measures Memory Midbrain structure Modeling Morphology Motor Movement Neurobehavioral Manifestations Neurons Outcome Measure Parkinson Disease Parkinsonian Disorders Pathologic Patients Performance Periodicals Pharmacotherapy Phenotype Physiological Play Primates Rattus Recombinant adeno-associated virus (rAAV)Regulation Research Resolution Rodent Role Safety Signal Transduction Standard Model Structure Synapses Testing Therapeutic Effect Up-Regulation Viral Vector Virus cognitive change cognitive testing disability drug action efficacy evaluation functional restoration gene therapy glutamatergic signaling improved improved mobility in vivo inhibitor knock-down motor deficit motor disorder motor impairment motor symptom nigrostriatal degeneration nonhuman primate novel novel therapeutic intervention optogenetics parkinsonian non-human primate preclinical study promoter response safety assessment small hairpin RNA synaptic function targeted treatment therapeutic target tool translational study vector

项目摘要

Project Summary Parkinson’s disease (PD) is characterized by motor abnormalities primarily caused by loss of midbrain dopamine (DA) cells, which significantly modulate striatal neurons. DA depletion is thus associated with altered function of striatal projection neurons (SPNs). SPN dysregulation is evidenced by significant morphological and physiological changes, as shown in numerous ex-vivo and in-vivo studies. Furthermore, our studies in primate models and patients have revealed pathological hyperactivity of SPNs. A key contributor to this hyperactivity is the excitatory glutamate signaling. This has been recently demonstrated with selective striatal blockade of NMDARs. The block reduces hyperactivity and controls the altered neuronal responses to DA replacement. Furthermore, it has significant effects on parkinsonian motor symptoms. Therefore, data support that reducing NMDAR signaling on SPNs may have therapeutic effects in PD. Given the largely conserved structure of NMDARs across brain regions, pharmacotherapies are generally limited by widespread drug actions. We recently tested gene therapies targeting NMDAR subunit expression in the striatum. Our preliminary data generated with exploratory tests in rodents showed that, indeed, gene knockdown (KD) of GluN2 subunits may offer a novel therapeutic strategy to improve motor symptoms of PD. Thus, data support advanced preclinical studies of GluN2 gene KD in non-human primates (NHP) for extensive evaluation of this gene therapy in the gold-standard model of PD. In this project we plan to demonstrate “efficacy” of GluN2 gene KD for various motor and cognitive symptoms of PD. The studies will use primate MPTP models and shRNA viral vector injections in the striatum to suppress gene expression of GluN2 in SPNs. A battery of motor and cognitive tests will be used over a prolonged term post-virus administration to determine stable, chronic effects. Taking advantage of PD modeling in NHPs, different disease stages will also be evaluated. We also include additional outcome measures to evaluate “safety” of targeting the proper assembly of NMDAR in the striatum. Finally, we will validate this gene therapy with electrophysiology data demonstrating specific effects on altered SPN activity, and applying optogenetics. for cell resolution in NHP recordings. Overall, the research strategy in this proposal is based on optimal animal models, viral vectors of proven efficiency, extensive testing of motor, cognitive, and other behaviors, and precision tools for electrophysiology. We expect that results of these studies demonstrate efficacy and safety with translational data to support further development of striatal GluN2 gene therapy for PD.

项目概要帕金森病 (PD) 的特点是主要由中脑缺失引起的运动异常多巴胺 (DA) 细胞显着调节纹状体神经元，因此与 DA 消耗有关。纹状体投射神经元 (SPN) 的功能失调可通过显着的形态学和生理变化，如许多离体和体内研究所示此外，我们对灵长类动物的研究。模型和患者已经揭示了 SPN 的病理性过度活跃，这是造成这种过度活跃的一个关键因素。最近通过选择性纹状体阻断证实了这一点。 NMDAR。该阻断可减少多动症并控制对 DA 替代的神经反应的改变。此外，它对帕金森运动症状有显着影响，因此，数据支持减少。鉴于 SPN 的结构很大程度上保守，NMDAR 信号传导可能对 PD 具有治疗作用。 NMDAR 跨脑区，药物治疗通常受到广泛的药物作用的限制。我们最近测试了针对纹状体 NMDAR 亚基表达的基因疗法。在啮齿类动物中进行的探索性测试表明，GluN2 亚基的基因敲低（KD）确实可能提供了一种改善帕金森病运动症状的新治疗策略，因此，数据支持先进的临床前研究。在非人类灵长类动物 (NHP) 中进行 GluN2 基因 KD 的研究，以广泛评估该基因疗法在 PD 的金标准模型。在这个项目中，我们计划展示 GluN2 基因 KD 对各种运动和认知症状的“功效” 该研究将使用灵长类 MPTP 模型和在纹状体中注射 shRNA 病毒载体来抑制 PD。 SPN 中 GluN2 的基因表达将长期使用一系列运动和认知测试。病毒后给药以确定稳定的慢性效应，利用 NHP 的 PD 模型，我们还将评估不同的疾病阶段。靶向 NMDAR 在纹状体中正确组装的“安全性” 最后，我们将验证这种基因疗法。电生理学数据证明了对 SPN 活性改变的特定影响，并应用光遗传学。总体而言，本提案中的研究策略基于最佳动物。模型、经过验证的效率的病毒载体、对运动、认知和其他行为的广泛测试，以及我们期望这些研究的结果能够证明其有效性和安全性。转化数据支持进一步开发针对 PD 的纹状体 GluN2 基因疗法。