Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease.
Miranda E OrrMitzi GonzalesValentina GarbarinoTiffany KautzJuan Pablo PalaviciniMarisa Lopez-CruzanShiva Kazempour DehkordiJulia MathewsHabil ZarePeng XuBin ZhangCrystal FranklinMohamad HabesSuzanne CraftRonald C PetersenTamara TchkoniaJames L KirklandArash SalardiniSudha SeshadriNicolas MusiPublished in: Research square (2023)
Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.
Keyphrases
- clinical trial
- cerebrospinal fluid
- open label
- early stage
- high performance liquid chromatography
- tandem mass spectrometry
- emergency department
- combination therapy
- blood brain barrier
- randomized controlled trial
- radiation therapy
- phase ii
- type diabetes
- endothelial cells
- mouse model
- oxidative stress
- mesenchymal stem cells
- cognitive decline
- risk assessment
- double blind
- simultaneous determination
- squamous cell carcinoma
- multiple sclerosis
- adverse drug
- ultra high performance liquid chromatography
- neoadjuvant chemotherapy
- cancer therapy
- cell death
- climate change
- gas chromatography
- insulin resistance
- high intensity
- deep learning
- solid phase extraction
- big data
- phase ii study
- metabolic syndrome