A Novel Therapeutic Strategy to Reduce TDP-43 Expression in Amyotrophic Lateral Sclerosis (ALS)
Abstract
Kinases are an important class of proteins that are currently targeted by 71 small molecule U.S. Food and Drug Administration (FDA)-approved drugs. More than 85% of these drugs have been designed for oncological indications. Despite this incredible drug development success and their playing essential roles in the brain, not a single kinase drug has been approved to treat a neurological disorder. A lack of focus on targeting kinases in the brain to augment key disease-propagating pathways has left their potential to alter or halt neurological disease progression largely uncharacterized. There is a need for new targets and new approaches to treat amyotrophic lateral sclerosis (ALS). We propose that kinases represent a target class that can be modified using small molecules to develop new ALS drugs. Kinases regulate proteins and pathways that contribute to ALS pathology. The buildup of a specific protein (TDP-43) in the brains of ALS patients, for example, is proposed to be regulated by a few kinases. This particular protein accumulates in patients that suffer from both familial and sporadic ALS. We can use small molecules to specifically inhibit or degrade those kinases that enhance TDP-43 buildup, which will reduce or prevent this harmful process. These small molecules could be developed into drugs and offer new treatment options to ALS patients that currently do not have efficacious drug options available to them. Our early-stage drug candidates would not just address symptoms like the two currently available FDA-approved ALS drugs. Instead, these drugs would eliminate one major cause of patient decline in ALS and thus alter the course of the disease, with the potential to offer more long-term benefits to patients. Since protein buildup is common to nearly all individuals with the disease, our strategy is widely applicable and impacts nearly all ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310286
Entities
People
- Alison D Axtman
Organizations
- United States Army
- University of North Carolina at Chapel Hill