Development of a Small-Molecule Anti-Misfolding Drug for Frontotemporal Degeneration
Abstract
Frontotemporal degeneration (FTD) results in many different brain disorders that fall under the heading of frontotemporal dementia. Difficulties with language, behavior, and memory are reported by these patients, and these difficulties get progressively worse. FTD is one of the most common forms of dementia reported by those younger than 60 years. To date, there is no cure for FTD and there are no treatments for FTD that affect the disease progression. FTD can be difficult to categorize, but the different varieties of FTD seem to be caused by an overabundance of certain proteins that can clump and cause damage to the nerve cells in the brain. One of these proteins is called tau. Tau is known to be a very important part of Alzheimer’s disease. Other proteins implicated in FTD include TDP-43 and FUS. It seems that certain FTD patients (especially people with behavioral problems) develop certain symptoms because they have too much tau. Led by researchers skilled in drug design for clumping proteins, this research project is aimed at developing a drug that can halt the progression of FTD caused by tau. After years of drug discovery work, a new, drug-like small molecule has been established as a candidate drug for FTD. This candidate has shown significant effects on the rate of tau clumping in animal models of the disease, and it has been shown to get into the brain and seems to be well tolerated by mice and rats. This candidate is ready to be moved into preclinical development as required by the Food and Drug Administration (FDA) prior to being used in humans. Thus, in this proposed research project, the candidate will be tested in various additional tests required by the FDA before it can be used in humans. The candidate will also be manufactured in a special facility certified by the FDA to produce drugs usable by humans. Moreover, the candidate will be further tested in animal models of tau and in models of TDP-43 or FUS to see if it could be useful to FTD patients whose FTD is caused by those proteins instead. During this project, there will be a planning and designing phase for testing in humans to FDA standards. No human testing will take place during the project itself. By the end of the project, there will be enough information about the candidate to put together an Investigational New Drug application to the FDA, which will enable entry into a first-time-in-humans clinical trial for the candidate. The FDA requires three phases of clinical trials, for which the phase 1 will be ready to begin at project end. Ultimately, provided the candidate moves through phase 2 and 3 successfully, then it could be approved as a drug for FTD. Such a drug could have high impact for FTD patients. It could potentially be an entirely new kind of treatment (disease-modifying, rather than just covering symptoms for a while). Indeed, if it can halt progression, then as early diagnosis improves, it has potential to be curative for FTD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210746
Entities
People
- Donald Weaver
Organizations
- United States Army