Antagonizing Neurotoxic Phase Transitions of TDP-43 and FUS with Small RNA Therapeutics
Abstract
One of the 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 any efficacy, but it only very slightly slows progression in some patients. Another approved drug, radicava, also has very limited efficacy. The lack of treatment options is unacceptable, and we are in urgent need of effective therapeutics. Here, we propose to generate short therapeutic RNAs that reverse the clumping of specific proteins (TDP-43 and FUS) that is connected with ~98% of ALS cases. If successful, our studies will provide therapeutic short RNAs to reverse protein clumping and toxicity in ALS and provide new approaches to treat ALS. The studies we propose will enhance our basic understanding of the importance of protein clumping in ALS, and whether targeting this process holds therapeutic potential. Our studies will ultimately increase our understanding of ALS for the ultimate benefit of patients. The therapeutic short RNAs we propose to generate could have clinical applications. Our studies are essential to enhance our understanding of ALS and advance the development of specific therapeutics. Indeed, the therapeutic RNAs we will generate could have game-changing clinical applications as they will be readily deliverable to patients (as with antisense oligonucleotide therapeutics that have been game-changing in spinal muscular atrophy). This project makes important strides toward exploring the development of therapeutic declumping RNAs as a new treatment strategy for ALS. By the end of this project, there will be a clear "go/no go" decision point for introducing therapeutic declumping RNAs into additional rodent ALS models, ALS patient cells in culture, and ultimately ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010242
Entities
People
- James Shorter
Organizations
- United States Army
- University of Pennsylvania