In this seminar, Assistant Professor Luke Larison (Scripps) outlines his laboratory’s approach to treating multiple sclerosis (MS) by promoting remyelination. He begins with a concise overview of MS pathology, emphasizing that disease progression is driven by a failure of oligodendrocyte precursor cells (OPCs) to differentiate into myelinating oligodendrocytes. To address this, his team developed a high‑content imaging assay using primary rat optic‑nerve OPCs, enabling a 200,000‑compound screen. The screen highlighted a class of centrally acting, FDA‑approved neurotransmitter‑receptor modulators, particularly M1 muscarinic receptor antagonists, as potent inducers of OPC differentiation. Collaborative validation (Salk, Scripps immunology, UCSF) demonstrated that these compounds promote functional myelination in vitro, induce remyelination in both inflammatory and non‑inflammatory mouse models, and achieve efficacy comparable to the S1P modulator FTY720. Electron microscopy confirmed true remyelination rather than demyelination blockade, and mechanistic studies pinpointed M1 antagonism as essential. A Phase 2 clinical trial of the M1 antagonist clemastine showed a significant improvement in visual evoked potential latency, marking the first in‑human evidence of a remyelination‑targeting drug. Building on this, Larison’s group is partnering with Frequency Therapeutics to develop fixed‑dose combination therapies, and is exploring additional hit classes from the screen. A parallel metabolomics effort identified taurine as a metabolite that synergistically enhances drug‑induced OPC differentiation, likely by boosting glycosphingolipid synthesis required for myelin. The talk concludes with a forward‑looking vision of combinatorial regimens that could accelerate functional recovery in MS patients.
Chapters
Okay. My name is Luke Larison. I'm an assistant professor in the Chemistry Department at Scripps and I'm going to tell you about our efforts that are ongoing in the field of remyelination for the treatment of multiple sclerosis. So as you are likely aware, multiple sclerosis is a debilitating autoimmune disease that is characterized by the demyelination of axons. And specifically what happens in this disease is the patient's immune cells attack a specialized cell called an oligodendrocyte, which is required for laying down the myelin sheath that wraps the axons of neurons. And this myelin sheath is required for faithful conductance of neuronal signals as well as production or protection of the axon. MS can present in one of multiple forms, but predominantly it initially presents in a relapsing-remitting form of disease in which patients have a flare where they have relapse of disease, the immune system is activated, but then there's remission and disease subsists and you have recovery of neural function. Is that working? It's not going back and forth. Existing treatments for MS are based exclusively on targeting the immunological aspect of the disease. And so we heard earlier about S1P modulators. In addition to that, more recently, B-cell targeting therapies have demonstrated to be incredibly promising in specifically treating relapsing-remitting form of disease. However, unfortunately, even with these disease-modifying agents which decrease the rate of relapse and the degree of severity, unfortunately, even with these therapies, the disease ultimately progresses to a secondary progressive form of disease where there's no longer remission and ultimately the patients die. So a promising complementary treatment approach to MS that could be used in combination with immunosuppression of immunosuppressant therapies is the identification of agents that stimulate a process, a regenerative process known as remyelination. And this regenerative process is what is responsible for disease remission in relapsing-remitting form of disease. And so this appears to be what becomes limiting and causes secondary progression of disease. So what is remyelination? It's a regenerative process that persists throughout adulthood. In humans. It's dependent on a resident precursor cell population called oligodendrocyte precursor cell, which makes up approximately 4% of the CNS in terms of percentage of the cells in the CNS. And so in response to damage where you have immune cell-mediated killing of oligodendrocyte, these OPCs are activated, they proliferate, they migrate to a site of damage, and then they undergo differentiation to form a newly formed oligodendrocyte that can remyelinate that axon, leading to functional recovery. In MS, this process ultimately fails, as I indicated, which leads to the secondary progressive form of the disease. And so this is what we'd like to target. With any regenerative medicine, it's essential to understand what is limiting the ability of your body to regenerate. And so this can either be a limitation of the number of stem cells, the ability of those stem cells to migrate to where they need to go, or to undergo differentiation to form the cell type that's responsible for repair. In MS, based on histopathology data looking at the plaques of chronic MS patients where it's seen that there's an abundance of these precursor cells, as well as preclinical experiments, the consensus is that what is causative in disease progression is the inhibition of these OPCs' ability to differentiate at sites of injury, which causes disease progression. And so the hypothesis is If we can find an agent that overcomes that barrier, we can facilitate remyelination and have a dramatic effect at impacting repair. And so that's the specific objective of this project, was to identify agents and mechanisms that specifically induce the differentiation of this endogenous precursor cell called OPC. To facilitate this, we developed a high-content imaging-based assay using primary rat optic nerve-derived OPCs, which we are able to— using these cells, we can proliferate them ex vivo and get a sufficient number of cells that we could screen on the order of 200,000 compounds in 3D/4L format. The assay is based on a high-content imaging readout where we simply plate these cells, treat with compound for a period of 6 days, and then look for agents that induce the differentiation as read out by the induction of this marker of a mature myelinating oligodendrocyte, MBP. Using this assay, as I mentioned, to date we screened on the order of 200,000 compounds including the Reframe collection of agents that have passed Phase 1 clinical trials. But from our preliminary screening of our bioactives collection, we identified a hit class known as neurotransmitter receptor modulating agents. Agents. We decided to focus on these agents because A, they were FDA-approved drugs. They were centrally acting, which is a major barrier for MS because they need to get into the CNS. And they had no on-tox profiles. And interestingly, this class of drugs had not been previously reported to induce OPC differentiation. We validated the activity of these— of this class of compounds using diverse secondary assays. And critically, in collaboration with Rusty Gage's lab at Salk, showed that these agents induced the differentiation to a functional myelinating cell and that following drug treatment they myelinate the co-cultured axon. In collaboration with Ari Theofilopoulos' lab and Brian Lawson's lab in the immunology department at Scripps, we demonstrated that these compounds work in vivo in both inflammatory and non-inflammatory models of demyelinating disease. And interestingly, and to be honest, quite surprisingly, we found that these agents alone had efficacy in this inflammatory model of relapsing-remitting MS that was comparable to FTY720s, the S1P modulators. We thought that these agents would have to be used in combination. But this demonstrated that this class of compounds works in vivo. Critically, we used electron microscopy in collaboration with the core at Scripps to show that the compounds were actually functioning through the proposed mechanisms. And so specifically, they were inducing remyelination rather than blocking demyelination. So neurotransmitter receptor modulating agents are a notoriously promiscuous class of compounds that are known to hit multiple targets and operate through diverse mechanisms. We use a classical pharmacology approach to determine which of the known targets was potentially responsible for driving OPC differentiation. And without having time to go through the details, essentially we found that M1 receptor antagonism was a required aspect of the mechanism of action for this drug class. Encouragingly, around the same time, Jonah Chan's lab at UCSF had developed a very elegant assay based on a nanofiber in which they look at wrapping of a nanofiber in 3D/4D format. And from a screen of the Lopac collection, identified the same class of compounds, these M1 receptor antagonists, as inducing OPC differentiation. And they did a barrage of in vivo assays to demonstrate that this mechanism translated as potential clinical utility. So two different labs converged on the same class of compounds. And Jonah actually generated M1 through M5 knockout mice and demonstrated that M1 receptor antagonism is very mechanism of this class of compound. So with this data in hand, this actually prompted UCSF to initiate an investigator-led Phase 2 trial of this class of drugs where they evaluated clemastine in relapsing-remitting MS patients. And encouragingly, this study read out at the end of 2017, they found that this drug clemastine, an M1 receptor antagonist, met its primary endpoint of impacting latency delay in a visual evoked potential assay. And so the general consensus in the field is that it's incredibly promising. This is the first example of a drug impacting remyelination in vivo in the clinic. However, there's significant room to improve on this effect. And so that's where we're focused now. But encouragingly, it demonstrates that molecules and mechanisms identified from this high-throughput discovery platform can translate to clinical efficacy. We've partnered this program with a biotech in Boston, Frequency Therapeutics, and we're currently collaborating to identify a fixed-dose combination therapy which we hope to put into the clinic in 2020. So in the brief amount of time I have left, I'll talk about one class of compounds that has potential. Potential here. Okay. So, as I mentioned, we screened the reframe collection, and from those efforts we've identified at least 8 hit classes, which we're currently evaluating in preclinical models to identify an optimal combination therapy. An alternative approach is something that our lab developed in collaboration with Gary Swisdak, where as opposed to screening array collections of compounds, we performed global metabolomics analysis looking at undifferentiated OPC versus mature myelinating oligodendrocyte and then looked for differentially regulated metabolites and then asked the question, what happens if we add those metabolites back or modulate the pathways that are differentially regulated? And somewhat surprisingly, we found that when we added back a specific metabolite called taurine, we saw a dramatic effect at enhancing drug-induced differentiation and maturation. And this metabolite works not only with the M1 receptor antagonist, but even with our most efficacious positive control agent. So this is the profile that we hope to identify, and this demonstrates— so this is what's in the clinic. We hope to get here with our combination therapy in the coming years. I know I'm running out of time, but we've demonstrated that this metabolite enhances functional myelination in that co-culture assay. And the mechanism appears to be by modulating and enhancing the feedstock of the required metabolite that's essential for producing glycosphingolipids that are responsible for myelination. And so taurine might not be the optimal combination therapy, but it demonstrates that there's potential for improving the efficacy of these— this class of drugs. And with that, I'll stop and thank the people that have done the work, primarily Vishal, who was a grad student in Pete's lab that did all the M1 work, and Brittany, who's followed up with them at Town Wilmburysbury. Thank you very much.
