Receptor for AGE (RAGE) Signal Transduction in Amyotrophic Lateral Sclerosis: In Vivo Imaging and Novel Therapeutic Approaches
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, and inflammatory mechanisms that cause and sustain damage to the spinal cord and nerves are increasingly recognized as a critical mechanism underlying this devastating incurable disease. Our laboratory has discovered that the molecule known as receptor for advanced glycation endproducts or RAGE is highly expressed in the human and mouse model ALS spinal cord. In this application, we seek to specifically test the concept that RAGE mediates damaging inflammation in ALS. Using novel and specific mouse models and novel small molecule RAGE antagonist drug-like compounds developed in our laboratory, we seek to build evidence for the testing of the RAGE pathway and the advanced development of these drug-like compounds for patients with ALS. Ultimate Applicability for ALS Patients: Preliminary data suggest that blockade of RAGE in the ALS SOD1G93A mouse model prolongs life span and delays neurological deterioration. We predict that antagonists of RAGE hold promise to aid all ALS patients, especially if begun in the early symptomatic stage. Specifically, we postulate that blocking RAGE will significantly suppress the mechanisms that add to brain cell damage and loss in ALS and thus this approach will prolong survival and delay neurological deterioration in this disease. The potential clinical applications are: (1) the ultimate development of orally available drugs to suppress damaging inflammation in the ALS spinal cord and (2) the tracking of the benefits of RAGE blockade by serial imaging of the spinal cord. These imaging studies are painless and akin to a non-invasive radiological test such as an X-ray. We strongly believe that blocking RAGE will have minimal risk and that potential benefits of this approach in ALS greatly outweigh possible risk. We know from many mouse and other animal studies, performed all over the world, that blocking RAGE is safe and well-tolerated. Drug development is a serial methodical process -- tightly overseen by the US Food and Drug Administration (FDA) in order to ensure the best possible chance for benefit with the greatest expectation for lack of harm. In the past few years, together with a talented and experienced medicinal chemist (scientist directly involved in "making drugs"), we have made tremendous strides in the development of the novel small molecule program blocking RAGE. Here, we propose further refinements to take the research one step further and closer for ultimate testing in human ALS subjects. Impactful research often moves from the "laboratory bench" to the "patient bedside" and then back again, so that an iterative process informs the best clinical strategies and expected outcomes for patients. This project is a unique mix of these features: First, using novel RAGE-modified animal models in cells of the spinal cord that cause neuroinflammation to directly test how RAGE functions in this setting to contribute to mediation of damaging inflammation in ALS; second, testing novel small molecules that block RAGE to probe their effect on reduction of damaging inflammation in the ALS mouse spinal cord; and third, using clinically relevant imaging techniques of the spinal cord rounds out the approach as an effort to provide early indices of benefit, or not, of the RAGE molecules in human subjects suffering from ALS. Hence, the basic work directly informs the clinically relevant studies and vice versa. Each step moves the dial closer to clinical testing. Currently available FDA-approved therapies in ALS are limited to the drug riluzole, which offers only marginal benefit to affected subjects. Based on the accumulating basic research data implicating spinal cord inflammation in the cause of ALS, therapeutic targets focused on inflammation are essential to develop and test. Studies in human and murine ALS suggest plausible links between RAGE and the loss of motor function
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710346
Entities
People
- Ann Marie Schmidt
Organizations
- Grossman School of Medicine
- United States Army