Identification and validation of small molecules targeting the amyloidogenic core of TDP-43 as therapeutics for ALS/FTLD
University of Toronto, University Health Network
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that affects motor neurons of the brain and spinal cord causing paralysis and death within 2-5 years from diagnosis. There is no known cure or effective treatment. Aggregation of TAR DNA Binding Protein (TDP-43) is the most common disease pathology present in the diseased motor neurons of over 95% of ALS patients and correlates with the areas of neurodegeneration. It is our hypothesis that preventing and/or reversing this aggregation of TDP-43 will have therapeutic benefit. Our aim is to identify small molecules that target a region of TDP-43, called the amyloidogenic core, which plays a role in its aggregation. To achieve this goal we will use computer based modeling to identify small molecules that target the amyloidogenic core of TDP-43 then test these small molecules for their ability to prevent and/or reverse TDP-43 aggregation in a series of increasingly complex model systems. This is an iterative process that will ultimately lead to the identification of a small molecule(s) that will be will be used in preclinical studies for proof of efficacy in animal models of TDP-43 aggregation.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
50% of ALS patients succumb to the disease within 18 months, 80% within 2-5 years. Despite numerous studies, to date there is no cure or effective treatment for ALS. Abnormal aggregation of TDP-43 is common to ~95% ALS cases and has been linked with causing motor neuron degeneration. Our goal is to identify small molecules targeting TDP-43 aggregation as a therapeutic approach for ALS.
Through this study we will identify small molecules that can prevent and/or reverse TDP-43 aggregation, fully characterizing these small molecules to create a Target Product Profile as part of the drug development process, with the goal of providing a drug(s) for testing in the clinic.