Targeting TSC2 S1366 (mouse, rat) S1365 (human) by gene engineering or phosphorylation to Regulate mTOR Signaling Cascades for Therapeutic Indications

Unmet Need
The mechanistic target of rapamycin complex-1 (mTORC1) coordinates cellular processes and regulates recycling pathways in order to control cell growth and metabolic homeostasis. Additionally, in immune cells when the T-cell receptor is activated, the mTORC1 signaling pathway is also engaged and thus plays an important role in T-cell activation, cytokine release, regulation, and memory. Despite its role in maintaining normal physiology and the immune response, mTORC1 signaling can also contribute to various diseases including autoimmune disorders, cancer, and heart failure. In fact, one potential therapeutic target for these disorders is the hyperactivation of mTORC1. However, broadly suppressing mTORC1 signaling can have important consequences for its role in overall homeostatic regulation. Consequently, a more targeted suppression is needed for mTORC1 to serve as a therapeutic target for cancer and other diseases and disorders. The protein tuberin (TSC2), a GTPase-activating protein, is an important, intrinsic regulator of mTORC1 signaling, as its phosphorylation status can activate or suppress mTORC1 activity. At steady state, TSC2 is constitutively inhibitory and gene deletion or loss-of-function mutations drive mTORC1 hyperactivation, causing tumors and neurological disorders. Alteration of the phosphorylation of TSC2 at specific residues could serve as the needed potential therapeutic target for diseases with abnormal mTORC1 activity and could also be used to enhance and alter T-cell responses for cancer immunotherapy.
 
Technology Overview
Johns Hopkins researchers have developed various TSC2 polypeptides, a regulator of mTORC1, in which two serine residues that can be phosphorylated are altered to be either gain- or loss-of-function mutations. These mutations serve to either prevent phosphorylation or cause the protein to be constitutively phosphorylated. The researchers have also generated two knock-in mouse models enabling the investigation of how mutating two residues on TSC2 and altering its phosphorylation status impact mTORC1 signaling in vivo and the implications of these changes for potential therapeutic indications in cancer, neurological disorders, or heart disease/failure.
 
Stage of Development
The inventors have developed a potentially novel method for modifying mTORC1 signaling as a way to treat diseases and disorders that result from aberrant mTORC1 signaling. In particular, it could be employed as a potential immunotherapy treatment for cancer due to its ability to enhance the role of T-cells. While initial investigation in vitro and also in vivo in mice has been conducted, further investigation is required to optimize the correct mutation(s) needed to alter phosphorylation and signaling for eventual testing and application in human patients.
 
Publications
Ranek MJ, et al. Nature 566, 264-269, 2019
 

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