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Abstract
Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.
Highlights
Animal models with protein depletion represent a powerful strategy to investigate the functional consequence of the loss of a target gene[1]
We investigated the importance of FKBP12 in the maintenance of cardiac functions using FKBP12 knockdown generated by Proteolysis-targeting chimeras (PROTACs) in mice and rhesus monkeys
Because FKBP12 is a highly conserved protein, this chemical knockdown strategy is promising for creating large animal models with targeted protein knockdown
Summary
Animal models with protein depletion represent a powerful strategy to investigate the functional consequence of the loss of a target gene[1]. PROTACs are mainly applied in the discovery of new anti-cancer agents due to their unique advantages over classic inhibitors[15,16,17]. To our knowledge, this novel strategy has not been used to achieve global protein knockdown in large animal models in vivo. A model species that is closely related to humans, the rhesus monkey, is a unique model for studying various diseases due to its human-like genome, the controllability of environmental factors, and the feasibility of monitoring the metabolic phenotypes in real time It is unknown whether PROTACs work in non-human primates
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