GDNF 基因治疗雄性非人灵长类酒精使用障碍
GDNF gene therapy for alcohol use disorder in male non-human primates
酒精使用障碍（AUD）复发率高，现有药物疗效有限。慢性酒精暴露会损害中脑腹侧被盖区（VTA）多巴胺能神经元功能。本研究将携带人 GDNF 基因的 AAV2 载体注射到 4 只雄性恒河猴的 VTA，另 4 只注射载体对照。在随后 12 个月的反复戒酒-复饮挑战中，GDNF 治疗组完全消除了复饮行为，并伴随伏隔核多巴胺信号恢复。这些临床前结果表明，靶向复饮预防的基因治疗可能成为 AUD 的潜在治疗策略。
为什么推荐给您：在非人灵长类中首次证明 GDNF 基因治疗可长期消除酒精复饮，转化前景明确但尚属动物实验。
不需要生物学背景，多打比方
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摘要Abstract
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.