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.

目前没有有效的非阿片类药物治疗阿片类药物使用 疾病（OUD）。目前的药物辅助治疗不能解决神经适应性变化， 使强迫性药物使用永久化，使主要的病理生理学得不到治疗。该提案将测试A 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症， 使奖励赤字正常化，从而减少渴望并降低复发的风险。我们假设 鼻内神经胶质细胞系衍生的神经营养因子（GDNF）基因治疗将纠正这些缺陷， 促进长期复苏。我们将在大鼠中测试编码GDNF的鼻内质粒DNA纳米颗粒（NPs） OUD模型，以评估增加脑GDNF是否可以减少渴望并防止复发。 在该项目的UG 3阶段，目标1将确定鼻内施用pGDNF NPs 在OUD的大鼠自我给药模型中抑制阿片样物质渴求和恢复。目标2将确定是否 鼻内pGDNF NPs减少中脑边缘多巴胺奖赏系统中的多巴胺缺乏状态， 该模型如果两者同时发生，后者可能是前者的机械责任。目标3 将是大型动物剂量-反应和时程研究，以确定鼻内NP是否可以产生2-3- 在非人灵长类动物（NHP）中脑GDNF的倍数增加，并选择用于GLP毒理学研究的剂量。 UG 3阶段的里程碑如下：如果所有目标都产生了积极的结果，或者如果目标1和3产生了积极的结果， 如果项目取得了积极成果，但目标2没有实现，则项目将继续进行到UH 3阶段。(The后来的结果表明， 该方法具有治疗OUD的潜力，但不是通过提出的机制。该项目将结束 在UG 3之后，如果目标2产生阳性结果，但目标1没有，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均产生阴性结果，则较高剂量的NP将 我们将进行测试，看看这是否可以纠正多巴胺缺乏和奖励不足。最后，项目将结束，如果 Aim 3不会导致脑GDNF增加2倍，因为该方法不太可能在人类中成功。 在项目的UH 3阶段，IND申请的成功将遵循以下目标： 目标4。与FDA举行IND前会议，以确定哪些IND使能研究（尤其是GLP） 毒理学方案）将是在UH 3资助结束时批准IND申请所必需的。 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。为本研究制备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指导原则放大生产pGDNF NP的生产方法。 瞄准9将GDNF NPs加载到鼻喷雾器中并进行长期稳定性研究。 目标10提交IND申请，在OUD患者中开展初步临床研究。