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Clinical Trial
. 2023 Oct;29(10):2481-2488.
doi: 10.1038/s41591-023-02543-w. Epub 2023 Sep 7.

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

Mitzi M Gonzales  1   2 , Valentina R Garbarino  3   4 , Tiffany F Kautz  3   4 , Juan Pablo Palavicini  4   5 , Marisa Lopez-Cruzan  6 , Shiva Kazempour Dehkordi  3   7 , Julia J Mathews  3 , Habil Zare  3   7 , Peng Xu  8   9 , Bin Zhang  8   9 , Crystal Franklin  10 , Mohamad Habes  3   10   11 , Suzanne Craft  12 , Ronald C Petersen  13 , Tamara Tchkonia  14 , James L Kirkland  14   15 , Arash Salardini  3   16 , Sudha Seshadri  3   16   17 , Nicolas Musi  18 , Miranda E Orr  19   20
Affiliations
Clinical Trial

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

Mitzi M Gonzales et al. Nat Med. 2023 Oct.

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 .

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Conflict of interest statement

Competing interests

M.M.G. reports personal stock in Abbvie. R.C.P. reports personal fees from Roche, no personal fees from Eisai, and personal fees from Genentech, personal fees from Eli Lilly and personal fees from Nestle, outside the submitted work. R.C.P. receives royalties from Oxford University Press and UpToDate and receives fees from Medscape for educational activities. J.L.K. and T.T. have a patent for Killing Senescent Cells and Treating Senescence-Associated Conditions Using an SRC Inhibitor and a Flavonoid with royalties paid to Mayo Clinic by Unity Biotechnologies and a patent for Treating Cognitive Decline and Other Neurodegenerative Conditions by Selectively Removing Senescent Cells from Neurological Tissue with royalties paid to Mayo Clinic by Unity Biotechnologies. S.C. reports Scientific Advisory Board membership for T3D Therapeutics and the Neurodegenerative Consortium, outside the submitted work. M.E.O., H.Z. and S.K.D. have a patent for Biosignature and therapeutic approach for neuronal senescence, which is pending. The remaining authors declare no competing interests.

Figures

Extended Data Fig. 1 |
Extended Data Fig. 1 |. Baseline and Post-Treatment ADRD Plasma and Cerebrospinal Fluid Biomarkers Assessed Using the Simoa® Quanterix HD-X Analyzer.
Baseline and post-treatment values for each analyte color-coded by participant as listed in Table 2. Mean [95% CI]: CSF (a) pTau-181, −12.04 [−34.01 to 9.930]; (b) pTau-231, −1.304 [−25.19 to 22.58]; (c) NfL,−23.20 [−695.6 to 649.2]; (d) GFAP, 2560 [440.9 to 4679]; (e) Aß40, 148.9 [−1359 to 1656]; (f) Aß42, −3.110 [−96.96 to 90.74]. Plasma, mean [95% CI]: (g) pTau-181, −0.0042 [−0.8779 to 0.8695]; (h) NfL, −1.774 [−9.567 to 6.019]; (i) GFAP, 24.29 [−42.74 to 91.32]; ( j) Aß40, −0.6714 [−13.04 to 11.69]; (k) Aß42, −0.1080 [−0.6495 to 0.4335]. Baseline to post-treatment values were assessed using two-sided paired sample t-tests, p < 0.05. 95% CI: 95 percent confidence interval for the post vs baseline mean difference. No correction for multiple comparisons was made due to small sample size (N = 5). CSF: Cerebrospinal fluid.
Fig. 1 |
Fig. 1 |. Study design and timeline.
Primary outcomes were to assess blood–brain barrier penetrance of the senolytic drugs D and Q (D + Q). Secondary outcomes explored target engagement, safety, cognitive and functional outcomes, and neuroimaging and blood and cerebrospinal fluid AD markers.
Fig. 2 |
Fig. 2 |. CONSORT flow diagram.
Participant allocation in the open-label pilot study.
Fig. 3 |
Fig. 3 |. Concentration of D and Q in blood and cerebrospinal fluid before and after oral administration of senolytics.
a–c, Levels of D and Q were quantified by HPLC/MS/MS. a, Baseline and post-treatment levels of D in plasma (n = 5). b, Baseline and post-treatment levels of D in CSF (n = 5). c, Baseline and post-treatment levels of Q in plasma; Q was not detected in CSF at baseline or post-treatment time points. d, Post-treatment D and Q levels in plasma and CSF presented for each participant where applicable with sex and body weight.
Fig. 4 |
Fig. 4 |. Baseline and post-treatment ADRD cerebrospinal fluid biomarkers assessed using Lumipulse.
a–f, Baseline and post-treatment values for each analyte color-coded by the participant as listed in Table 2. Mean (95% CI): a, pTau181: −1.260 (−11.73 to 9.207); b, total tau, −21.00 (−64.90 to 22.90); c, Aß42, 78.00 (−14.62 to 170.6); d, Aß40, 1,149 (−803.9 to 3103); e, Aß42:Aß40, 0.0020 (−0.0032 to 0.0072); f, pTau-181:Aß42, −0.0447 (−0.1328 to 0.0434). Baseline to post-treatment changes were assessed using two-sided paired sample t-tests, P < 0.05. Mean difference = post-treatment–baseline; 95% CI, 95% CI for the post versus baseline mean difference. No correction for multiple comparisons was made due to the small sample size (n = 5).
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