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

Nature Medicine volume 29, pages 2481–2488 (2023)Cite this article

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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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Fig. 1: Study design and timeline.
Fig. 2: CONSORT flow diagram.
Fig. 3: Concentration of D and Q in blood and cerebrospinal fluid before and after oral administration of senolytics.
Fig. 4: Baseline and post-treatment ADRD cerebrospinal fluid biomarkers assessed using Lumipulse.

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Data availability

The minimum datasets necessary to interpret, verify and extend the research in the article are available within the paper and its Supplementary Information. The trial was registered on ClinicalTrials.gov: NCT04063124 and the full study protocol was published29.

Change history

  • 14 December 2023

    In the version of the article initially published, part of Extended Data Table 3 was missing but has now been added.

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Acknowledgements

We would like to thank the volunteers, study participants and the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio and the South Texas Alzheimer’s Disease Research Center (P30AG066546 to S.S.) research staff who conducted the study recruitment and assessments. This work was made possible by pilot funding from the Institute for Integration of Medicine & Science and the Center for Biomedical Neurosciences at UT Health Science Center in San Antonio (to M.M.G., N.M. and M.E.O.); the Alzheimer’s Drug Discovery Foundation (GC-201908-2019443 to M.E.O.), pilot funding from the Coordinating Center for Claude D. Pepper Older Americans Independence Centers (U24AG059624 to M.E.O. and M.M.G.); the Translational Geroscience Network (R33AG061456 to J.L.K.). We also acknowledge philanthropic support from the JMR Barker Foundation, Bill Reed Endowment for Precision Medicine, the Kleberg/McGill Foundation and UT STARS award. M.M.G., S.S., V.R.G., T.F.K., J.J.M., H.Z., C.F., M.H. and A.S. are supported by the South Texas Alzheimer’s Disease Research Center (P30AG066546). Additionally, M.M.G. was supported as an RL5 Scholar in the San Antonio Claude D. Pepper Older Americans Independence Center (P30AG044271) and the National Institute on Aging (R01AG077472 and P30AG066546). V.R.G. was supported by a National Institute on Aging Training Grant on the Biology of Aging (T32AG021890) and a National Center for Advancing Translational Sciences NRSA Training Core (TR002647). M.L.C. was supported by the San Antonio Claude D. Pepper Older Americans Independence Center (PG30AG044271) and by the National Institute on Aging (P30AG013319 and U01AG22307). H.Z. and S.K.D. were supported by the National Institute on Aging (R01AG057896, 1RF1AG063507, R01AG068293, 1R01AG0665241A, 1R01AG065301 and P30AG066546) and the National Institute of Neurological Disorders and Stroke (RF1NS112391 and U19NS115388). J.P.P. was supported by the San Antonio Claude D. Pepper Older Americans Independence Center (RL5 Scholar, P30AG044271), the American Federation of Aging Research and the Cure Alzheimer’s Fund. B.Z. was supported by the National Institute on Aging (U01AG046170 and R01AG068030). M.H. was supported by the National Institute on Aging (R01AG080821). S.C. was supported by the National Institute on Aging (P30AG072947). R.C.P. was supported by the National Institute on Aging (P30 AG062677, U01 AG006786, U24 AG057437 and U19 AG024904), National Institute of Neurological Disorders and Stroke (UF1 NS125417) and the GHR Foundation. T.T. and J.L.K. were supported by the National Institute on Aging (R37AG13925 and P01AG062413), the Alzheimer’s Association (PTC REG-20-651687), the Connor Fund, Robert J. and Theresa W. Ryan, and the Noaber Foundation. S.S. was supported by the National Institute on Aging (R01AG066524, R01AG054076, R01AG033193 and RF1AG059421), National Institute of Neurological Disorders and Stroke (R01NS017950) and the National Heart, Lung and Blood Institute (R01HL105756). N.M. was supported by the National Institute on Aging (P30AG044271, P30AG013319, U54AG07594, R01AG069690 and R01AG075684). M.E.O. was supported by the US Department of Veterans Affairs (I01BX005717), National Institute on Aging (R01AG068293), National Institute of Neurological Disorders and Stroke (R21NS125171), Cure Alzheimer’s Fund and Hevolution Foundation/American Federation of Aging Research. The sponsors had no role in the design and conduct of the study; in the collection, analysis and interpretation of data; in the preparation of the manuscript or in the review or approval of the manuscript.

Author information

Authors and Affiliations

  1. Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Mitzi M. Gonzales, Valentina R. Garbarino, Tiffany F. Kautz, Shiva Kazempour Dehkordi, Julia J. Mathews, Habil Zare, Mohamad Habes, Arash Salardini & Sudha Seshadri

  2. Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Mitzi M. Gonzales, Arash Salardini & Sudha Seshadri

  3. Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Valentina R. Garbarino, Tiffany F. Kautz & Juan Pablo Palavicini

  4. Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA

    Juan Pablo Palavicini

  5. Department of Psychiatry & Behavioral Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Marisa Lopez-Cruzan

  6. Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Shiva Kazempour Dehkordi & Habil Zare

  7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Peng Xu & Bin Zhang

  8. Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Peng Xu & Bin Zhang

  9. Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Crystal Franklin & Mohamad Habes

  10. Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Mohamad Habes

  11. Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Suzanne Craft & Miranda E. Orr

  12. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Ronald C. Petersen

  13. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Tamara Tchkonia & James L. Kirkland

  14. Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    James L. Kirkland

  15. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Sudha Seshadri

  16. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Nicolas Musi

  17. Salisbury VA Medical Center, Salisbury, NC, USA

    Miranda E. Orr

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  1. Mitzi M. Gonzales
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Contributions

M.M.G. and M.E.O. conceived the project, acquired funding, analyzed and interpreted data, drafted and submitted the manscript. M.M.G. provided study oversight and supervision. N.M. and A.S. provided medical oversight of the trial. V.R.G. recruited study participants, collected data, and drafted the manuscript. T.F.K. and J.J.M. performed Simoa®, Lumipulse and MSD assays, as well as analyses. J.P.P., S.K.D., H.Z., P.X., and B.Z. conducted statistical analyses and interpreted biofluid data. T.T. contributed to biofluid analyses and interpretation. M.L.C. performed HPLC–MS/MS study design, oversight, and analyses. C.F. and M.H. conducted MRI image acquisition and analyses. S.S., S.C., R.C.P. and J.K.L contributed to data interpretation. All authors edited and approved the final manuscript.

Corresponding authors

Correspondence to Mitzi M. Gonzales or Miranda E. Orr.

Ethics declarations

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.

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Peer review information

Nature Medicine thanks Frank Longo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Extended data

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.

Extended Data Table 1 Baseline and post-treatment cognitive and functional status assessments
Full size table
Extended Data Table 2 Baseline and post-treatment neuroimaging outcomes
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Extended Data Table 3 Significantly differentially expressed proteins in plasma and cerebrospinal fluid from baseline to post-treatment
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Gonzales, M.M., Garbarino, V.R., Kautz, T.F. et al. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nat Med 29, 2481–2488 (2023). https://doi.org/10.1038/s41591-023-02543-w

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