Journal Article

GDNF gene therapy for alcohol use disorder in male non-human primates

Vanderhooft, Lauren E., Bringas, John, Dawes, Monica H., Forsayeth, John R., Bankiewicz, Krystof S., George, Brianna E., Peck, Emily G., Holleran, Katherine M., Jones, Sara R., Van Laar, Victor S., Naidoo, Jerusha, Ohno, Kousaku, Grant, Kathleen A., Samaranch, Lluis, Ford, Matthew M., McBride, Jodi L., Hadaczek, Piotr

2023

Overview

Alcohol use disorder (AUD) exacts enormous personal, social and economic costs globally. Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies. Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior. We tested this hypothesis by infusing adeno-associated virus serotype 2 vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF), a growth factor that enhances dopaminergic neuron function, into the VTA of four male rhesus monkeys, with another four receiving vehicle, following induction of chronic alcohol drinking. GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence–alcohol reintroduction challenges. This behavioral change was accompanied by neurophysiological modulations to dopamine signaling in the nucleus accumbens that countered the hypodopaminergic signaling state associated with chronic alcohol use, indicative of a therapeutic modulation of limbic circuits countering the effects of alcohol. These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD. In a preclinical study, the delivery of an AAV-based gene therapy encoding GDNF in the brain prevented the return to alcohol use behaviors in a non-human primate model.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/1689 / 692/617/375 / Ablation / Abstinence / Alcohol Drinking - genetics / Alcohol Drinking - metabolism / Alcohol use / Alcoholism - drug therapy / Alcoholism - therapy / Alcohols / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Circuits / Dopamine / Dopamine - metabolism / Dopamine receptors / Dopaminergic Neurons - metabolism / Drinking / Drinking behavior / Economic impact / Ethanol / Ethanol - metabolism / Ethanol - pharmacology / Ethanol - therapeutic use / Gene therapy / Genetic Therapy / Glial cell line-derived neurotrophic factor / Glial Cell Line-Derived Neurotrophic Factor - genetics / Growth factors / Infectious Diseases / Male / Males / Mesolimbic system / Metabolic Diseases / Molecular Medicine / Neuronal-glial interactions / Neurosciences / Neurotrophic factors / Nucleus accumbens / Nucleus Accumbens - metabolism / Primates / Primates - genetics / Reintroduction / Ventral Tegmental Area - metabolism / Ventral tegmentum