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.

PROJECT NARRATIVE GDNF is a beneficial protein normally present in low levels in the adult brain, and there is strong evidence that it has clinical potential as a therapy for opioid use disorder and relapse reduction. The Waszczak lab at Northeastern University has developed a non-invasive approach that bypasses the BBB to increase brain GDNF, i.e., intranasal administration of gene nanoparticles that make GDNF protein within the brain. Our proposal will test whether this intranasal GDNF gene therapy can suppress drug craving and reduce the tendency to reinstate drug-taking after a period of abstinence, thus providing a long-term therapeutic strategy for reducing opioid craving and preventing relapse.