New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

Abstract

The macrolide rapamycin and its analogues (rapalogs) constitute the first generation of mammalian target of rapamycin (mTOR) inhibitors. Since the introduction of rapamycin as an immunosuppressant, there has been extensive progress in understanding its complex mechanisms of action. New insights into the function of mTOR in different immune cell types, vascular endothelial cells and neoplastic cells have opened new opportunities and challenges regarding mTOR as a pharmacological target. Currently, the two known mTOR complexes, mTOR complex (mTORC) 1 and mTORC2, are the subject of intense investigation, and the introduction of second‐generation dual mTORC kinase inhibitors (TORKinibs) and gene knockout mice is helping to uncover the distinct roles of these complexes in different cell types. While the pharmacological profiling of rapalogs is advanced, much less is known about the properties of TORKinibs. A potential benefit of mTOR inhibition in transplantation is improved protection against transplant‐associated viral infections compared with standard calcineurin inhibitor‐based immunosuppression. Preclinical and clinical data also underscore the potentially favourable antitumour effects of mTOR inhibitors in regard to transplant‐associated malignancies and as a novel treatment option for various other cancers. Many aspects of the mechanisms of action of mTOR inhibitors and their clinical implications remain unknown. In this brief review we discuss new findings and perspectives of mTOR inhibitors in transplantation.

Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors

“…To translate our findings to a clinically more relevant model, we assessed the effect of pharmacological autophagy induction in NHPs ( Macaca fascicularis ). We chose rapamycin, which induces autophagy in the liver, because this drug is already in clinical use . One NHP was infused with vehicle solution, and two NHPs were infused with 3 mg/kg of rapamycin.…”

“…On the other hand, our results also call for the development of strategies to use the dependence on autophagy to improve efficacy of rAAV. In our proof‐of‐concept experiments, we decided to use pharmacological inducers of autophagy such as mTOR inhibitors but also other already clinically used drugs such as metformin and carbamazepine, or different strategies such as calorie restriction or caffeine intake could be considered . Of note, a single shot of the drug was sufficient to significantly improve the level of transgene products secreted from vector‐transduced hepatocytes not only in mice (Fig.…”

Improving data quality and preserving HCD-generated reporter ions with EThcD for isobaric tag-based quantitative proteomics and proteome-wide PTM studies

“…45,46 Rapamycin has applications in immunosuppression, preventing rejection in organ transplantation. 47 It is one of the most-widely used drugs to prevent restenosis after angioplasty. 48 The progression of restenosis involves enhanced phosphorylation of several key proteins, which can be inhibited by rapamycin.…”

Moonshots for aging

“…Also, these experiments were done in a controlled environment which limits pathogens exposure. This is relevant because rapamycin is an immunosuppressant, used clinically in organ transplantation (12). This suggests in a real-world scenario where people's immune systems would be challenged regularly, it's not clear rapamycin would have a significant beneficial effect on healthspan or lifespan.…”