Drug Development for Dystonia
Abstract
This proposal addresses a major unmet need for an unremitting and disabling movement disorder, known as dystonia. This work addresses Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area of dystonia research within the neuroscience category and the two strategic goals of (1) developing novel therapeutics and (2) identifying biomarkers. Dystonia is characterized by sustained involuntary postures and/or slow twisting movements. Dystonia is an unremitting and poorly treatable movement disorder that causes pain and movement disability. Dystonia can arise in many contexts – limb trauma, traumatic brain injury, stroke, neurodegenerative diseases, antipsychotic medication use, inherited genetic causes, and sporadically. Military personnel are at increased risk to develop dystonia because of exposure to risk factors such as limb trauma, traumatic brain injury, repetitive use tasks, and certain medications. Unfortunately, both the number of treatment options for dystonia and their efficacy are severely limited. Current oral medications are limited by side effects and poor efficacy. Because of limited oral medication benefits, many people seek more invasive options like botulinum toxin injections or deep brain electrode implantation to get relief. However, these procedures are only suitable for specific subsets of dystonia. Lastly, no disease-modifying treatments for dystonia exist; all current treatments are symptomatic. This Expansion Award seeks (1) to develop effective and orally available medications for dystonia with disease-modifying potential and (2) to identify human biomarkers that are needed for successful clinical trial design and outcome interpretation. Our proposal is a direct continuation of successful efforts made during the prior PRMRP Investigator-Initiated Research Award (FY19-FY22). To discover new drug treatments for dystonia, we developed a robust, cell-based, high-throughput assay to monitor dystonia-related cell pathology and screened >40,000 compounds. The top 10 were further studied and modified in order to gain properties that are necessary for a compound to be suitable as a drug for use in people. This effort included medicinal chemistry, testing for drug stability and toxicity, and testing the compound’s effects in advanced disease-relevant models using human cells and mouse models. We now have two leading compounds with promising and distinct opportunities to develop into new oral medications for people with dystonia (one that is a U.S. Food and Drug Administration FDA-approved drug but cannot be simply repurposed because of limited central nervous system access in currently approved dosing/formulation and one with novel chemistry and higher potency). With the Expansion Award, we aim to (1) perform medicinal chemistry to achieve the necessary brain penetrance and drug metabolism properties for the novel lead compound series that has already met high potency and efficacy in dystonia assays and low cytotoxicity milestones, (2) identify the protein that the drugs directly interact with to cause their anti-dystonia effects, and (3) discover biomarkers in human plasma and cerebrospinal fluid that will allow us to identify those subsets of people with dystonia that are most likely to benefit from the drugs’ mechanisms and to monitor target engagement (i.e., that a future drug intervention is causing the intended effect in the brain during clinical trials). The outcome of this effort will be to generate first-in-class dystonia drugs with a comprehensive surrounding preclinical data package in order to attract commercial partners. The advanced novel compound(s) will be ready to address next phases of safety in non-rodent large animals, drug product formulation, and investigational new drug application for human studies. Based on the core biological process that the lead compounds target, we anticipate that both people with rare inherited forms of dystonia (e.g., DYT1, 6,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310386
Entities
People
- Nicole Calakos
Organizations
- Duke University
- United States Army