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

• 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
• 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

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.

目前尚无有效的基于非阿片类药物的药物治疗阿片类药物的治疗 障碍（OUD）。当前的药物辅助治疗无法解决神经适应性的变化 长期使用强迫药物，使原发性病理生理学未经治疗。该建议将测试 新型的非阿片类药物治疗OUD的方法，旨在纠正潜在的多巴胺缺乏症和 将奖励缺陷归一化，导致渴望减少和复发风险降低。我们假设这一点 鼻内神经胶质细胞系衍生的神经营养因子（GDNF）基因疗法将纠正这些缺陷和 促进长期恢复。我们将测试编码大鼠GDNF的鼻内质粒DNA纳米颗粒（NP） OUD的模型评估增加脑GDNF是否可以减少渴望并防止复发。 在项目的UG3阶段，AIM 1将确定鼻内施用PGDNF NPS是否是否 在大鼠的OUD自我管理模型中抑制阿片类药物的渴望和恢复原状。 AIM 2将确定是否 鼻内PGDNF NPS降低了中唇胺多巴胺奖励系统中多巴胺缺乏状态 这个模型。如果两者同时发生，则后者可能是对前者的机械责任。目标3 将是大型动物剂量反应和时间过程，以确定鼻内NP是否可以产生2-3-- 非人类灵长类动物（NHP）中脑GDNF的折叠增加，并为GLP毒理学研究选择剂量。 UG3阶段的里程碑如下：如果所有目标都会产生积极的结果，或者AIM1和3产生 积极的结果，但不是目标2，该项目将继续延续到UH3阶段。 （后来的结果将表明 该方法具有OUD的治疗潜力，但没有提出的机制。）该项目将结束 在UG3之后，如果AIM 2产生积极的结果，而不是AIM 1，这意味着纠正多巴胺不足 不会降低复发潜力。如果两个目标1和2产生负面结果，则NP的剂量更高 进行测试以查看是否可以纠正多巴胺缺乏症和奖励缺陷。最后，如果项目将结束 AIM 3不会导致大脑GDNF增加2倍，因为该方法不太可能在人类中取得成功。 在该项目的UH3阶段，将追求以下目标以成功进行IND： 目标4。与FDA举行预先开会，以确定哪些辅助研究（尤其是GLP 毒理学方案）对于在UH3资金结束时批准IND申请是必要的。 AIM 5。FDA的临床方案草案，以确定GLP毒理学研究设计是否足够。 目标6。设计GLP毒理学研究并提交FDA批准。为这项研究准备GMP级NP。 AIM 7。进行GLP毒理学研究和DNA生物分布研究。 AIM 8。根据GLP/GMP指南来规模制造PGDNF NP的生产方法。 AIM 9。将GDNF NP载入鼻喷雾器并进行长期稳定研究。 AIM10。在OUD患者中提交IND申请进行试点临床研究。