Small-Molecule Enhancers of the Human Protein-Disaggregase Machinery for ALS
Abstract
One of greatest biomedical challenges of our era lies in the morbid reality that there are still no effective therapies for any of the inexorably lethal nerve degeneration disorders associated with the clumping of specific proteins into aggregated structures. One of these debilitating disorders, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease, is the most common adult motor neuron disease afflicting ~2 individuals per 100,000 with a typical age of onset between 50-60 years of age. Upon progression, ALS is characterized by an unrelenting devastation of motor neurons. This degeneration leads to progressive weakness, muscular wasting, and spasticity, which typically culminate in paralysis, denervation of respiratory muscles, and death within 3-5 years. There are no effective therapies for ALS, and patients have extremely few treatment options. So far only one drug, riluzole, has shown efficacy, but it only very slightly slows progression in some patients. The lack of treatment options is unacceptable and we are in urgent need of effective therapeutics. Here, we propose to isolate small-molecule drugs that stimulate natural enzymes throughout the nervous system and human body to reverse the clumping of proteins that is connected with all forms of ALS. If successful, our studies could provide new drugs to reverse protein clumping in ALS and provide important foundations for new approaches to treat all forms of ALS. The studies we propose will enhance our basic understanding of the importance of protein clumping in ALS and help determine whether targeting the reversal of this process with specific drugs holds therapeutic potential. Although we are a few years away from the clinic, our studies will ultimately increase our understanding of ALS for the ultimate benefit of patients. The small-molecule drugs we will isolate that stimulate the activity of natural human therapeutic enzymes could have broad clinical applications to several other common neurodegenerative disorders, including Alzheimer s disease, Parkinson s disease, and frontotemporal dementia. This project makes important strides toward exploring the development of small-molecule therapeutics that enhance the activity of endogenous human declumping enzymers as a new treatment strategy for ALS. By the end of this project, there will be a clear "go/no go" decision point for moving small-molecule candidates into the most pertinent rodent models and ultimately ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710237
Entities
People
- James Shorter
Organizations
- United States Army
- University of Pennsylvania