Chemogenetics is a gene therapy approach in development where designer receptors activated exclusively by designer drugs (DREADD) are introduced via genetic manipulation to modulate specific pathways and, in the case of the nervous system, specific neurons or brain areas. Despite their potential interest in human therapeutics, the lack of proper preclinical validation impedes their advancement. A study in Scientific Reports examined the use of chemogenetics to treat rats, showing a proof-of-concept for future translational studies. The viral vector containing the DREADD hM4D(Gi) was injected in the lateral hypothalamus (LH), a target area for anti-obesity treatments in rats. Rats were subcutaneously injected with clozapine-N-oxide or deschloroclozapine to activate LH-hM4D(Gi). Here, injecting deschloroclozapine was more effective at decreasing food intake than injecting clozapine-N-oxide. Administering deschloroclozapine orally decreased the effect of the drug on food intake compared to injecting. When observing the brain histologically, the designer drugs successfully targeted the LH. These results show evidence of the feasibility of using a chemogenetic approach for drug discovery and represent a proof-of-concept that chemogenetics can be used for the treatment of obesity.

Original reference: Kovács, P. et al Sci. Rep. 14, 11402 (2024)

化学遗传学是一种正在开发的基因治疗方法，其中通过基因操作引入专门由设计药物 （DREADD） 激活的设计受体，以调节特定通路，在神经系统的情况下，调节特定神经元或大脑区域。尽管他们对人类疗法有潜在的兴趣，但缺乏适当的临床前验证阻碍了他们的进步。Scientific Reports 上的一项研究检查了化学遗传学治疗大鼠的使用，为未来的转化研究提供了概念验证。将含有 DREADD hM4D （Gi） 的病毒载体注射到大鼠抗肥胖治疗的目标区域下丘脑外侧 （LH） 中。大鼠皮下注射氯氮平-N-氧化物或去氯氯氮平以激活 LH-hM4D（Gi）。在这里，注射去氯氯氮平比注射氯氮平-N-氧化物更有效地减少食物摄入量。与注射相比，口服去氯氮平可降低药物对食物摄入的影响。在组织学上观察大脑时，设计药物成功地靶向了 LH。这些结果显示了使用化学遗传学方法进行药物发现的可行性的证据，并代表了化学遗传学可用于治疗肥胖的概念验证。

原始参考资料：Kovács， P. et al Sci. Rep.14， 11402 （2024年）