School of Medicine Publications and Presentations

Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial

Document Type

Article

Publication Date

9-7-2023

Abstract

Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7–73.5 ng ml−1 for D and 3.29–26.3 ng ml−1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml−1 with a CSF to plasma ratio of 0.422–0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, P = 0.008 and t(4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels (t(4) = −2.338, P = 0.079). In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124.

Comments

University of Texas Health Science Center at San Antonio

Reprints and Permissions

https://rdcu.be/dtJDj

Publication Title

Nature Medicine

DOI

10.1038/s41591-023-02543-w

Academic Level

faculty

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