An Intranasal GDNF Gene Therapy for Opioid Relapse Reduction

鼻内 GDNF 基因疗法可减少阿片类药物复发

基本信息

批准号：
10154341
负责人：
ELIZABETH M BYRNES
金额：
$ 669.35万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154341
关键词：
Abstinence Adult Animals Biodistribution Blood - brain barrier anatomy Brain Buprenorphine Bypass Cell Line Cells Chronic Clinical Clinical Protocols Clinical Research DNA Disadvantaged Dopamine Dose Drug usage Exocytosis Fibrinogen Functional disorder Funding Genes Guidelines Human Intervention Intranasal Administration Logistics Measures Methadone Methods Midbrain structure Modeling Nerve Growth Factors Neurons Nose Opiate Addiction Opioid Opioid replacement therapy Outcome Parkinson Disease Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Population Production Proteins Protocols documentation Rattus Reaction Time Recovery Relapse Research Design Rewards Route Self Administration System Testing Therapeutic Time Toxicology Universities addiction base brain cell craving design disorder later incidence prevention disorder prevention dopaminergic neuron drug craving gene therapy glial cell-line derived neurotrophic factor medication-assisted treatment meetings nanoparticle neurotrophic factor non-opioid analgesic nonhuman primate novel novel therapeutic intervention opioid therapy opioid use disorder plasmid DNA prevent psychologic relapse risk scale up therapeutic opioid

项目摘要

There are currently no effective non-opioid-based pharmacotherapies for treatment of opioid use disorder (OUD). Current medication assisted treatments do not address the neuroadaptive changes that perpetuate compulsive drug use, leaving the primary pathophysiology untreated. This proposal will test a novel, non-opioid approach for treatment of OUD designed to correct the underlying dopamine deficiency and normalize the reward deficit, resulting in reduced craving and a decreased risk of relapse. We hypothesize that an intranasal glial cell line-derived neurotrophic factor (GDNF) gene therapy will correct these deficits and promote long-term recovery. We will test intranasal plasmid DNA nanoparticles (NPs) encoding GDNF in a rat model of OUD to assess whether increasing brain GDNF can reduce craving and prevent relapse. In the UG3 phase of the project, Aim 1 will determine if intranasal administration of pGDNF NPs suppresses opioid craving and reinstatement in a rat self-administration model of OUD. Aim 2 will determine if intranasal pGDNF NPs reduce the dopamine deficiency state in the mesolimbic dopamine reward system in this model. If both occur simultaneously, the latter may be mechanistically responsible for the former. Aim 3 will be large animal dose-response and time course studies to determine if intranasal NPs can generate 2-3- fold increases in brain GDNF in non-human primates (NHPs), and to select a dose for a GLP toxicology study. The milestones for the UG3 phase are as follows: If all Aims yield positive results, or if Aim1 and 3 produce positive results, but not Aim 2, the project will continue to the UH3 phase. (The later outcome would indicate that the approach has therapeutic potential for OUD but not by the mechanism proposed.) The project will end after the UG3 if Aim 2 yields positive results but not Aim 1, which would mean correcting the dopamine deficit does not reduce relapse potential. If both Aims 1 and 2 yield negative results, a higher dose of the NPs would be tested to see if this could correct the dopamine deficiency and reward deficit. Finally, the project will end if Aim 3 does not result in 2-fold increases in brain GDNF since the approach is unlikely to succeed in humans. In the UH3 phase of the project, the following Aims will be pursued for a successful IND application: Aim 4. Hold a pre-IND meeting with the FDA to determine which IND-enabling studies (especially the GLP toxicology protocol) would be necessary for approval of an IND application by the end of UH3 funding. Aim 5. Draft clinical protocol for FDA to determine if GLP toxicology study design is adequate. Aim 6. Design GLP toxicology study and submit for FDA approval. Prepare GMP-grade NPs for this study. Aim 7. Perform GLP toxicology study and DNA biodistribution study. Aim 8. Scale up production methods for manufacturing of pGDNF NPs under GLP/GMP guidelines. Aim 9. Load GDNF NPs into nasal sprayer and conduct long-term stability studies. Aim 10. Submit IND application for a pilot clinical study in patients with OUD.

目前没有有效的非阿片类药物治疗方法来治疗阿片类药物的使用紊乱（OUD）。目前的药物辅助治疗无法解决神经适应性变化使强迫性药物使用长期存在，而使主要的病理生理学得不到治疗。该提案将测试用于治疗 OUD 的新型非阿片类药物方法，旨在纠正潜在的多巴胺缺乏和使奖赏赤字正常化，从而减少渴望并降低复发风险。我们假设鼻内神经胶质细胞源性神经营养因子（GDNF）基因疗法将纠正这些缺陷促进长期恢复。我们将在大鼠体内测试编码 GDNF 的鼻内质粒 DNA 纳米颗粒 (NP) OUD 模型来评估增加大脑 GDNF 是否可以减少渴望并防止复发。在该项目的 UG3 阶段，目标 1 将确定 pGDNF NP 是否鼻内给药在 OUD 的大鼠自我给药模型中抑制阿片类药物的渴望和恢复。目标 2 将确定是否鼻内 pGDNF NP 可减少中脑边缘多巴胺奖赏系统中的多巴胺缺乏状态这个模型。如果两者同时发生，则后者可能是前者的机制原因。目标 3 将进行大型动物剂量反应和时间过程研究，以确定鼻内 NP 是否可以产生 2-3- 非人灵长类动物 (NHP) 脑部 GDNF 增加倍数，并选择 GLP 毒理学研究的剂量。 UG3 阶段的里程碑如下：如果所有目标都产生积极结果，或者如果目标 1 和 3 产生取得积极成果，但不是目标 2，该项目将继续进行到 UH3 阶段。（后来的结果表明该方法对 OUD 具有治疗潜力，但不是通过所提出的机制实现的。）该项目将结束在 UG3 之后，如果目标 2 产生积极结果但目标 1 没有产生积极结果，这意味着纠正多巴胺缺乏不会降低复发的可能性。如果目标 1 和 2 都产生负面结果，则更高剂量的 NP 将进行测试，看看这是否可以纠正多巴胺缺乏和奖励不足。最后，如果目标 3 不会导致大脑 GDNF 增加 2 倍，因为该方法不太可能在人类身上取得成功。在该项目的 UH3 阶段，为了成功 IND 申请，将追求以下目标：目标 4. 与 FDA 举行 IND 前会议，以确定哪些 IND 支持研究（尤其是 GLP）在 UH3 资助结束前，需要批准 IND 申请。目标 5. 为 FDA 起草临床方案以确定 GLP 毒理学研究设计是否充分。目标 6. 设计 GLP 毒理学研究并提交 FDA 批准。为此研究准备 GMP 级 NP。目标 7. 进行 GLP 毒理学研究和 DNA 生物分布研究。目标 8. 根据 GLP/GMP 指南扩大 pGDNF 纳米颗粒的生产方法。目标 9. 将 GDNF NP 装入鼻喷雾器并进行长期稳定性研究。目标 10. 提交针对 OUD 患者的试点临床研究的 IND 申请。