Toward Pharmacological Rescue of TSC Loss of Function
Abstract
Background: The tuberous sclerosis complex (TSC) complex is a protein found in human cells that acts as a hand brake for another protein known as mTORC1. Activated mTORC1 is the main driver of cellular growth, and the role of the TSC complex is to provide guidance as to when growth should be permitted, such that our body does not get too much or too little growth at any given point in time. Genetic mutations in TSC patients weaken the ability of the TSC complex to regulate mTORC1, and hence the growth in cells impacted by those mutations is completely out of control. In the last 20 years, scientists have succeeded in turning a natural product, rapamycin, into a medicine that can be administered orally or topically to TSC patients. Rapamycin is a powerful medicine – it dampens the activity of mTORC1 in cells, and therefore provides the missing hand brake in cells affected by TSC mutations. However, what makes rapamycin so powerful is also its biggest limitation – it directly targets the mTOR subunit of mTORC1. By directly deactivating mTOR, rapamycin also affects a related protein complex, called mTORC2, which is responsible for other important functions in the cell. That lack of specificity can be problematic from a therapeutic perspective, because it can produce unwanted side effects. In the short term, the abnormal growth problems of the affected cells are fixed; however, a prolonged treatment with rapamycin will affect other useful processes in the body, such as balance of sugar levels, which is controlled by mTORC2. Scientific Objective: The main goal of this project is to lay the foundation for the development of a first-in-class drug that only acts on the hyperactive mTORC1 in TSC patients. To do so, we plan to take a novel approach, and instead of targeting the front gate, we will go for the back door. Such back door in the context of mTORC1 is its ability to anchor on cellular structures called lysosomes. These lysosomes are the standard location where mTORC1 does its job in the cell, and where in the absence of a functional TSC complex it becomes hyperactivated. Our goal is to limit the number of mTORC1 molecules that can anchor on lysosomes by developing drugs that interfere with that process. Such drugs will conceptually serve as a substitute for the defective hand brake normally provided by the TSC complex, and they will only act on mTORC1, and not any other mTOR that does other things in the cell – like in the case of rapamycin. Applicability of This Research: The ultimate goal of this project is to make a drug that alleviates all symptoms of TSC, and that TSC patients can take daily, like aspirin, and experience none or very limited side effects. Developing pharmaceuticals is a long process due to many requirements a drug candidate needs to fulfill in order to be approved by a federal agency. In this 2-year project, we want to produce a selection of tangible alternative drug leads that we can study in a test tube, and show that they are effective in stopping mTORC1 from docking at lysosomes. At this stage, such drug leads will potentially gain interest of a mainstream pharmaceutical company that can develop them further into treatments. Such process can take several years, but it has a major advantage over short-term, quick solutions. The strength of this project lies in its exploration of novel drug modalities that work via a completely different mechanism than rapamycin or any other drugs that are currently in clinical trials. By diversifying, we have a better chance of succeeding. Expected Contributions: In the short term, this project will deliver a number of chemical probes for the immediate benefit of the TSC research community. Those probes will have the ability to specifically turn off mTORC1’s ability to land on lysosomes, and although not immediately suitable as therapeutic agents, these chemical probes will facilitate further research into the cellular connection between TSC and mTOR. And
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110260
Entities
People
- David M. Sabatini
Organizations
- United States Army
- Whitehead Institute