A Novel Stress-Activated Inhibitor of Myelination
Abstract
Describe the objectives and rationale for the proposed research Rationale: In Multiple Sclerosis (MS) immune cells and inflammation cause destruction of myelin and axons, the long neuronal cell cables that transmit information throughout the brain. In most cases at the beginning of the disease, the brain can repair itself by "remyelination" of damaged axons. For this reason, patients with Relapsing-Remitting MS have symptoms only during active relapses, but may be asymptomatic during the inactive phases. With time, however, the repair ability of the brain deteriorates, and remyelination is no longer efficient or sometimes even possible. This is also true in Progressive MS, where, for unknown reasons, the protection from myelin cells to axons is less efficient from the beginning, and axon damage starts even earlier. Our objective is to discover drugs, procedures, or lifestyle modifications that promote remyelination and protect axons. We have discovered a novel inhibitor, or remyelination, that is present in MS plaques. In this proposal, we will determine if blocking this inhibitor improves remyelination and axonal protection in animal models. If this works, we will design drugs or evaluate procedures applicable to patients that also are able to inactivate the inhibitor. What are the potential clinical applications, benefits, and risks? The current available drugs for MS are effective at targeting inflammation and immune attacks that cause active relapses, but no drugs have been approved yet that significantly enhance repair by remyelination. A few such drugs have been discovered and currently hold promising results in clinical trials. The hope is that these drugs will be able to promote repair by blocking the action of factors in the cells that prevent remyelination. Because experience in the pharmaceutical field indicates that only one in many drugs will be effective and have no side effects in patients, alternative drugs must be developed and tested. Here we have identified a new cell factor that inhibits remyelination but has no other deleterious effect as shown in mice. The experiments in our proposal aim to establish if this novel inhibitory factor represents a viable target for developing a new class of drugs that favors repair in Multiple Sclerosis. As such, our proposal addresses the "obstacles to remyelination and axonal protection" focus area. There are no risks. What types of patients could it potentially help, and how? The development of a class of drugs that promotes remyelination will benefit patients with Relapsing-Remitting MS. We will test the hypothesis that the cell factor that we have identified also protects axons in two models of demyelination. If this hypothesis is true, then our work will also benefit patients with Progressive MS. What is the projected time it may take to achieve a patient-related outcome? After this 3-year project, we would partner with medicinal chemistry and industry to develop an inhibitor of our cell factor. The development and testing of such inhibitors in animal models could take between 3-5 years, followed by approximately 5 years each for Phase I, II, and III clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810311
Entities
People
- M. Laura Feltri
Organizations
- United States Army
- University at Buffalo