Developing a Novel Neurotrophin-Based Strategy to Promote Myelin Repair in Multiple Sclerosis
Abstract
Background and Rationale: This project aims to establish a novel reparative strategy that targets nervous system repair in multiple sclerosis (MS). MS is a devastating disease in which the body s own immune system appears to attack myelin, the insulating coat that surrounds nerve cells in the brain. The myelin loss impairs nerve cell function by disrupting the passage of electrical impulses along the nerve fibres, which is the major cause of clinical disability, ranging from impaired vision, to numbness in the limbs, to an inability to coordinate, and, ultimately, paralysis. At early stages of disease, these effects are often temporary and resolve, as the brain has an innate capacity to replace the lost myelin. However, at later stages of the disease the brain loses the capacity to repair itself, and these symptoms return and progressively worsen, resulting in long-term physical impairment and dramatically reduced quality of life. A key component of the degenerative process in MS involves autoimmune mechanisms, where the body s own immune system attacks myelin. While early research to find therapies for MS focused on developing ways to dampen the immune system in order to prevent the loss of myelin, it is now understood that this approach does little to prevent the myelin loss and nerve damage that ultimately determines the severity of disease. Many human MS brains contain both nerve cells and myelin-producing cells. But for reasons we do not understand, the formation of new myelin after injury "stalls", which has led to a search for novel therapeutic strategies that are directed toward initiating myelin repair and protecting nerve cells from cumulative long-term damage. Research Objective and Plan: Our ultimate goal is to develop reparative therapies that directly target nerve cells within MS lesions for enhancing myelin repair to restore nerve function. This is essential for optimal control of this progressive and devastating disease. In order to achieve this goal, research from my laboratory has focused on studying molecular targets that control myelin repair after injury. Recently, we pioneered discoveries concerning the role of a molecule called TrkB in the brain myelin repair process. We subsequently adopted a structure-based drug design approach and developed a small molecule drug that targets this TrkB gene. Our recent unpublished data demonstrates that this TrkB-based small molecule drug significantly enhances myelin repair in an animal model of MS disease. This is an exciting and significant finding as it suggests that activating this gene may be a promising strategy for promoting repair in patients with MS. Outcomes and Significance: In this project, we will determine the long-term therapeutic potential and selectivity of this small molecule drug in enhancing nerve repair and protecting against further damage in different preclinical models of MS disease. This project is also expected to identify novel derivatives of this small molecule drug with improved potency and brain uptake. Outcomes of this project will be transformational, allowing us to identify a suite of compounds that we can use, then move forward with as potential therapeutic agents in future larger-scale experiments. This will serve to establish the feasibility and utility of using TrkB-activating drugs as a novel means directed toward promoting myelin repair to limit cumulative nerve degeneration, ultimately, in clinical trials of MS. Research that would delay or prevent the progression of MS would bring substantial rewards in terms of both reducing the financial burden and increasing quality of life. Outcomes of this project will not only significantly advance current MS research focusing on neurobiology but also ultimately benefit patients with MS and their family via improving their quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810555
Entities
People
- Junhua Xiao
Organizations
- United States Army
- University of Melbourne