Senolytics for Secondary Progressive MS

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory and neurodegenerative disorder of the central nervous system (CNS), which afflicts approximately one million people in the United States. Age is the strongest driver of disease course in MS. With increasing age, most older adults with MS develop a progressive disease phenotype characterized by gradual accrual of irreversible neurological disability, for which there are no effective treatments that reliably slow disease progression. Cellular senescence is a hallmark of aging, whereby senescent cells accumulate with age and produce mediators of inflammation through the senescence-associated secretory phenotype (SASP). In MS, senescent cells have been identified in both the central nervous system and peripheral immune compartments contributing to SASP expression, promoting chronic inflammation, axonal damage, and failure of myelin repair, and ultimately leading to functional decline. Senescent cells can be selectively removed by senolytic drugs, which delay age-related dysfunction in animal models and show potential for improving functional outcomes in human clinical trials. The senolytic drug combination of dasatinib and quercetin (D+Q) selectively induces apoptosis of senescent cells in human tissue. Our pilot data shows D+Q treatment improves function and survival in experimental autoimmune encephalomyelitis, the widely used animal model of MS. Emerging evidence from early phase clinical trials of D+Q in age-related diseases shows improvement of gait speed in idiopathic pulmonary fibrosis and CNS penetrance of dasatinib in Alzheimer's disease. However, studies of senolytic therapy for people with MS have yet to be conducted. The investigators hypothesize that treatment with D+Q will be well tolerated, improve physical and cognitive function, reduce circulating biomarkers of senescence and neurodegeneration, and attenuate T-cell immune exhaustion. The investigators will test this hypothesis through a single arm, open label, study to 1) determine the feasibility of 3 months of intermittent D+Q treatment in 30 older adults age 50-85 with secondary progressive MS and 2) to obtain preliminary data of D+Q treatment on physical and cognitive function and 3) serum biomarkers of senescence, neurodegeneration, and the circulatory T cell repertoire. Targeting cellular senescence represents a novel strategy for treating progressive MS, and results from the study will lay the foundation for a future randomized controlled trial of senolytics to treat progressive MS.

Inclusion criteria

• Individuals aged 50-85 with SPMS diagnosed using the 2024 McDonald Criteria
• Not treated with a DMT for MS within the last 6 months or have used alemtuzumab, cladribine, or mitoxantrone.
• Evidence of MS progression over the past 12 months.

Exclusion criteria

• Unstable coronary artery disease (myocardial infarction within 6 months or angina)
• Hospitalization within 6 months
• Stroke or transient ischemic attack in the past 6 months
• Pulmonary arterial hypertension
• Current or chronic history of liver disease
• Alzheimer's or Parkinson's disease
• Drug or alcohol abuse in the previous 5 years
• History of coagulation disorders, central nervous system hemorrhage, or gastrointestinal hemorrhage
• History of angina or myocardial infarction, arrhythmia, or heart failure at any time
• QTc prolongation
• Anemia (Hgb<9), thrombocytopenia (platelets<50,000 per microliter), or neutropenia (ANC< 1000 per microliter)
• Moderate hypokalemia (2.9 mmol/L) and moderate hypomagnesemia (0.9-1.1 mg/dL or 0.37-0.45 mmol/L)
• ALT/AST >1.5x ULN, total bilirubin >ULN, and alkaline phosphatase >2x ULN
• Chronic renal disease (glomerular filtration rate < 30 mL/min/1.73 m2)
• Alcohol intake greater than 2 drinks/day for men and greater than 1 drink/day for women
• Anti-arrhythmic medications known to cause QTc prolongation
• Antipsychotics and anxiolytics
• Anti-platelet or anti-coagulant medications other than aspirin
• Quinolone antibiotics
• Pregnant or lactating subjects or subjects intending to become pregnant or to donate egg/sperm
• Participants with p16INK4a below the median of SPMS patients in the OSU Aging and MS Cohort
• Use of drugs metabolized by the same liver enzymes as D or Q