Preclinical Studies of Bryostatin-1 to Promote Remyelination and Repair in Multiple Sclerosis
Abstract
Focus Area: Central Nervous System (CNS) Regenerative Potential in Demyelinating Conditions Background: In multiple sclerosis (MS), the immune system destroys myelin, the insulating coating around nerve cells that provides nutrients and helps conduct electrical signals. Without myelin, nerve cells cannot function properly and they slowly degenerate. Myelin has the capacity to repair itself, but this process frequently fails in MS, particularly in progressive forms of the disease, contributing to irreversible injury and disease progression. Current therapies for MS prevent new immune attacks (called relapses) but fail to promote myelin repair, and therefore fail to promote recovery from prior demyelination. Therapies that promote myelin repair, thereby reversing disability and preventing progression, remain a major unmet need for MS patients. The precursor cells capable of forming new myelin, called oligodendrocyte precursor cells (OPCs), are abundant in the brains of MS patients but fail to mature into myelinating cells, a failure that has several causes. On one hand, the intrinsic potential of OPCs to mature into myelin-forming cells appears to be altered in MS, particularly in older patients with later stages of disease. One strategy for developing myelin repair therapies has been to identify drugs that act directly on OPCs to augment their maturation. On the other hand, OPC maturation is also critically regulated by cells of the so-called innate immune system (microglia and astrocytes) that persist in MS lesions long after a relapse subsides and can either prevent or promote myelin repair. These brain-resident innate immune cells are not targeted by current therapies. Successful myelin repair therapies will need to address both of these obstacles, combining direct effects on OPCs with beneficial effects on innate immune cells in the brain. Bryostatin-1 (bryo-1) is a naturally occurring, brain-penetrant compound that has gone through phase 2 clinical trials in humans as a treatment for cancer and Alzheimer s disease. Although its benefit for cancer has been limited and its effect in Alzheimer s disease remains uncertain, these trials have established its safety in humans, with reversible muscle pains at excessive doses representing its only common side-effect. We previously published work showing that bryo-1 acts on innate immune cells outside the brain, pushing them toward a beneficial, pro-repair subtype by acting on a protein called protein kinase C (PKC). Using isolated cells and animal models, we now have preliminary evidence that bryo-1 similarly targets innate immune cells (microglia and astrocyte) within the brain, preventing inflammatory functions and promoting repair functions. Preliminary studies, both from our group and another group, further suggest that bryo-1 acts directly on OPCs to promote maturation into myelinating cells. Bryo-1 thus has the potential to promote myelin repair through direct effects on both OPCs and brain-resident innate immune cells. Objectives: Our hypothesis is that bryo-1 augments myelin repair after immune-mediated demyelination through a combination of direct effects on OPCs and modulation of the CNS innate immune response. In this proposal, we plan to rigorously test this hypothesis in cultured cells and animal models of demyelination, in order to establish preclinical evidence supporting the translation of bryo-1 to MS patients. In Aim 1, we will build on our preliminary data to confirm that bryo-1 produces changes in brain-resident innate immune cells (microglia and astrocytes) associated with tissue repair. We will use several animal models that each replicates a distinct aspect of MS pathology, in order to increase the robustness of our results and the translatability to human MS. In Aim 2, we plan to directly evaluate the impact of bryo-1 on remyelination. We will first determine whether bryo-1 has direct effects on isolated OPCs to promote ma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110609
Entities
People
- Michael Kornberg
Organizations
- Johns Hopkins University
- United States Army