TY - JOUR
T1 - Senolytic therapy in mild Alzheimer’s disease
T2 - a phase 1 feasibility trial
AU - Gonzales, Mitzi M.
AU - Garbarino, Valentina R.
AU - Kautz, Tiffany F.
AU - Palavicini, Juan Pablo
AU - Lopez-Cruzan, Marisa
AU - Dehkordi, Shiva Kazempour
AU - Mathews, Julia J.
AU - Zare, Habil
AU - Xu, Peng
AU - Zhang, Bin
AU - Franklin, Crystal
AU - Habes, Mohamad
AU - Craft, Suzanne
AU - Petersen, Ronald C.
AU - Tchkonia, Tamara
AU - Kirkland, James L.
AU - Salardini, Arash
AU - Seshadri, Sudha
AU - Musi, Nicolas
AU - Orr, Miranda E.
N1 - Publisher Copyright:
© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/10
Y1 - 2023/10
N2 - 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 .
AB - 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 .
UR - https://www.scopus.com/pages/publications/85169921353
U2 - 10.1038/s41591-023-02543-w
DO - 10.1038/s41591-023-02543-w
M3 - Article
C2 - 37679434
AN - SCOPUS:85169921353
SN - 1078-8956
VL - 29
SP - 2481
EP - 2488
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -