Answers are grounded in this paper and cite their sources.
Aims Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo assay in rats, which could support chemogenetic drug discovery. We also aimed to establish the proof-of-concept for the chemogenetic approach in obesity indication. Methods Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Results Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts for 1–3 hours post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-n-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. Conclusion This study demonstrates that the chemogenetic silencing of the LH is a potential strategy in obesity treatment. The study also supports the development of chemogenetics by providing a “first in vivo” tool for the validation of new chemogenetic constructs.
No takes yet. Share an insight, caveat, or question.
Kovács et al. (2023) studied this question.