An Intranasal GDNF Gene Therapy for Opioid Relapse Reduction

目前没有有效的非阿片类药物疗法来治疗阿片类药物的使用 无序(OUD)。目前的药物辅助治疗并没有解决神经适应性的变化 使强制药物使用永久化，使主要的病理生理学得不到治疗。这项提案将考验一项 新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和 使奖励赤字正常化，从而减少渴望和复发的风险。我们假设 鼻腔内胶质细胞源性神经营养因子(GDNF)基因疗法将纠正这些缺陷并 促进长期复苏。我们将在一只大鼠身上测试编码GDNF的鼻腔内质粒DNA纳米粒(NPs) OUD模型评估增加大脑GDNF是否可以减少渴求和防止复发。 在项目的UG3阶段，目标1将确定鼻腔内注射pGDNF NPs 抑制阿片类药物的渴求和在OUD大鼠自我给药模型中的恢复。目标2将决定是否 鼻腔注射pGDNF纳米粒可降低小鼠中脑边缘多巴胺奖赏系统中的多巴胺缺乏状态 这个型号。如果两者同时发生，后者可能对前者负有机械责任。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NPs是否能产生2-3- 在非人类灵长类动物(NHP)中，GDNF增加了一倍，并选择了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的结果，或者如果Aim1和Aim3产生 如果是积极的结果，但不是目标2，该项目将继续进入UH3阶段。(后一种结果将表明 该方法具有治疗OUD的潜力，但不是通过所提出的机制。)这个项目将会结束 在UG3之后，如果目标2产生积极的结果，但不是目标1，这将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和目标2都产生阴性结果，则更高剂量的NPs将 接受测试，看看这是否可以纠正多巴胺缺乏和奖赏不足。最后，项目将在以下情况下结束 AIM 3不会导致大脑GDNF增加2倍，因为这种方法不太可能在人类身上成功。 在该项目的UH3阶段，将实现以下目标，以实现IND申请的成功： 目标4.与FDA举行IND前会议，以确定哪些支持IND的研究(特别是GLP (毒理学方案)将是在UH3供资结束前核准IND申请所必需的。 目的5.为FDA起草临床方案，以确定GLP毒理学研究设计是否充分。 目的6.设计GLP毒理学研究并提交FDA批准。为这项研究准备GMP级的NPs。 目的7.进行GLP毒理学研究和DNA生物分布研究。 目的8.在GLP/GMP指南下扩大生产pGDNF纳米粒的方法。 目的9.将神经营养因子纳米粒装入鼻腔喷雾剂，并进行长期稳定性研究。 目的10.提交IND申请，用于OUD患者的先导性临床研究。

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.