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

Autor: Gonzales, Mitzi M., Garbarino, Valentina R., Kautz, Tiffany F., Palavicini, Juan Pablo, Lopez-Cruzan, Marisa, Dehkordi, Shiva Kazempour, Mathews, Julia J., Zare, Habil, Xu, Peng, Zhang, Bin, Franklin, Crystal, Habes, Mohamad, Craft, Suzanne, Petersen, Ronald C., Tchkonia, Tamara, Kirkland, James L., Salardini, Arash, Seshadri, Sudha, Musi, Nicolas, Orr, Miranda E.
Zdroj: Nature Medicine; October 2023, Vol. 29 Issue: 10 p2481-2488, 8p
Abstrakt: 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−1for D and 3.29–26.3 ng ml−1for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml−1with 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.
Databáze: Supplemental Index
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