Senolytic treatment with Navitoclax alters microglial phenotype and attenuates CNS immune-mediated demyelinating disease in a model of progressive Multiple Sclerosis
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Date
2025-05
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The Ohio State University
Abstract
Multiple Sclerosis (MS) is a multifocal, immune-mediated, demyelinating disease that affects the central nervous system (CNS). MS impacts almost 3.5 million people worldwide, with nearly 1 million of those impacted residing in the United States. MS is additionally the primary cause of nontraumatic disability in young adults in the western hemisphere. Demyelination of CNS axons during MS pathology can occur via a variety of mechanisms, and the exact etiology of MS still remains unknown. However, it is generally held that pathogenic lymphocytes—T cells and B cells—drive immune-mediated demyelination of axons. One mechanism heavily indicated by a vast body of literature is the auto-reactivity of CD4+ T-helper 1 (Th1) and Th17 towards myelin sheath proteins. Overall, demyelination reduces the efficiency and disrupts the continuity of nervous system signal transduction, resulting in a wide variety of neurological deficits.
Individuals with MS are further classified into clinical subtypes based on their course of disease. Patients with RRMS experience a disease course outlined by discrete, self-limited episodes— lasting for weeks to months—of worsening neurological disability, followed by relatively quiescent periods of partial to full recovery. In contrast, patients with progressive forms of MS— both PPMS and SPMS—demonstrate an insidious, gradual decline in neurological function. The physiological mechanisms of MS disease also vary by subtype. RRMS tends to onset in the 20s to 30s and is characterized by focal blood-brain barrier (BBB) breakdown followed by infiltration of hematopoietic leukocytes into the CNS parenchyma, inducing lymphocyte-driven, immune-mediated demyelination. However, these features are often absent in both progressive disease forms, which tend to instead onset around the 40s to 50s and in which the pathology is instead distinguished by widespread microglial activation and slowly expanding lesions characterized by astrogliotic cores and rims of activated microglia. The vast majority of current, FDA-approved disease-modifying therapies (DMTs) for MS are immunomodulators and target peripheral lymphocytes. As follows, while these therapies are highly efficacious in the management of RRMS, they have only a modest impact on progressive forms of MS. The dearth of treatments available for managing progressive forms of MS demands a concerted effort in procuring targeted, applicable treatments tailored for progressive MS pathophysiology. that age may govern the induction of progressive disease.
Our group has developed an age-dependent preclinical model of progressive MS by altering the established Th17-mediated adoptive transfer experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Initial experiments revealed that middle-aged mice compared to young mice experience an exacerbated course of EAE reminiscent of progressive MS. Further investigation demonstrated that the progressive disease phenotype is most likely driven by an aged, CNS-resident cell, prompting a search for pharmacological therapies that could target biologically aged—senescent—CNS-resident cells. Certain hallmarks of biological aging—such as telomere attrition, senescence marker upregulation, and epigenetic inhibition of transcription via DNA methylation—have been shown to be elevated in MS patients. In active inflammatory human MS lesions, BCL2L1-expressing microglia, indicative of a senescent phenotype, were found to be enriched. These microglia also had increased pro-inflammatory gene expression, suggestive of a role in exacerbating disease mechanisms in active lesions. Additional evidence shows the presence of senescent glia in human progressive MS lesions. For these reasons, we hypothesized that senescent microglia contribute to progressive disease and that depletion or modification of senescent microglia using senescence-targeting drugs would ameliorate EAE disease severity in aged mice. Navitoclax is a small molecule BCL2 inhibitor shown in multiple studies to be a powerful senolytic. Overall, we observed that Navitoclax reduces disease severity & increases survival rates in aged mice with EAE, coincident with a shift in the microglial phenotype. Moreover, the immune cell infiltrate was not altered by Navitoclax, supporting the notion that a progressive disease course is driven by CNS-resident cells. Metformin, a senomorphic agent targeting the NF-κB pathway, had no effect on clinical disease during EAE. These findings suggest that senolytics might provide a new line of therapeutics for treating patients with progressive MS, a patient population that has very limited effective options.
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Keywords
Multiple Sclerosis, CNS, Senescence, Senolytic, Microglia, EAE