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Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD) – Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease
Open accessPreprint — published as 10.1038/s41591-023-02543-w · Paper page
Abstract
Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.
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Cites
The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment
Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., Cummings, J. L., & Chertkow, H. (2005) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2005.53221.x · Cited by 25,553
Dietary Intake and Bioavailability of Polyphenols
Scalbert, A., & Williamson, G. (2000) · The Journal of Nutrition · doi:10.1093/jn/130.8.2073s · Cited by 3,658
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584
Self-citationA complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278
(2015) · HAL · Cited by 2,238
Health effects of quercetin: From antioxidant to nutraceutical
Boots, A. W., Haenen, G. R. M. M., & Bast, A. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.03.008 · Cited by 2,121
Jack, C. R., Albert, M. S., Knopman, D. S., McKhann, G. M., Sperling, R. A., Carrillo, M. C., Thies, B., & Phelps, C. H. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.004 · Cited by 2,042
Morris, J. C. (1997) · International Psychogeriatrics · doi:10.1017/s1041610297004870 · Cited by 1,641
Benedict, R. H. B., Schretlen, D., Groninger, L., & Brandt, J. (1998) · The Clinical Neuropsychologist · doi:10.1076/clin.12.1.43.1726 · Cited by 1,597
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Metadata
- Authors
- Orr, M., Gonzales, M., Garbarino, V., Kautz, T., Palavicini, J., Lopez-Cruzan, M., Dehkordi, S. K., Mathews, J., Zare, H., Xu, P., Zhang, B., Franklin, C., Habes, M., Craft, S., Petersen, R., Tchkonia, T., Kirkland, J., Salardini, A., Seshadri, S., & Musi, N.
- Affiliations
- W. G. (Bill) Hefner VA Medical Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Texas Health Science Center
- Icahn School of Medicine at Mount Sinai (US)
- Wake Forest University Health Sciences (US)
- Mayo Clinic (US)
- Mayo Clinic
- Boston University (US)
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Orr, Miranda
- Gonzales, Mitzi
- ORCID
- Venue
- Nature Medicine
- Published
- 2023-04-24
- Volume
- 29
- Issue
- 10
- Pages
- 2481-2488
- ISSN
- 1078-8956 (ISSN-L)
- PMC
- PMC10875739
- OpenAlex
- W4386499275
- Cited by
- 319
- References
- 64
- Citations by year
- 2026: 100 · 2025: 116 · 2024: 82 · 2023: 21
- FWCI
- 56.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Medicine (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by)
- ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
- Funders
- Hevolution Foundation
- U.S. Department of Health and Human Services (TR002647, RF1AG059421, T32-AG021890, P30 AG062677, R01AG068293, R37AG13925, U01AG22307, R01AG080821, UF1 NS125417, R21NS125171, U19AG024904, R01AG069690, P30 AG066546, U54AG07594, R33AG061456, U01 AG046170, 1R01AG065301, R01AG054076, R01NS017950, P01AG062413, P30-AG013319, R01AG077472, R01AG068030, R01AG075684, R01AG033193, U01 AG006786, U24AG059624, PG30AG044271, U19NS115388, P30AG044271, R01AG066524, 1R01AG0665241A, P30AG072947, R01AG057896, U24 AG057437, 1RF1AG063507, RF1NS112391)
- U.S. Department of Veterans Affairs (I01 BX005717, P30AG013319)
- Alzheimer's Association (PTC REG-20-651687)
- American Federation for Aging Research
- Alzheimer's Drug Discovery Foundation (AG059421, GC-201908-2019443)
- Cure Alzheimer's Fund
- McGill University
- GHR Foundation
- Noaber Foundation
- National Heart and Lung Institute (R01HL105756)
- National Institutes of Health (4r01ag065301-03, TL1TR002647)
- University of Texas Health Science Center at San Antonio (TR002647)
- National Institute on Aging (R24AG073199, 1R01AG0665241A, RF1AG065301, U01AG22307, AG054076, U01AG046170, R01AG066524, R01AG069690, U01AG006786, R37 AG13925, R01AG068030, U54AG07594, R01AG057896, R01AG054076, R01AG065839, R01AG013925, 1R01AG065301, R01 AG065301, AG059421, PG30AG044271, RF1AG063507, R01AG033193, T32AG021890, RF1AG059421, R33AG061456, P30AG013319, U01AG022307, R37AG013925, R01AG080821, R01AG077472, U24AG057437, U19AG024904, U24AG059624, U54AG079754, P01AG062413, P30AG062677, R01AG068293, P30AG044271, P30AG072947, R01AG075684, P30AG066546)
- National Heart, Lung, and Blood Institute (R01HL105756)
- National Institute of Neurological Disorders and Stroke (R21NS125171, U19NS115388, RF1NS112391, UF1NS125417, R01NS017950)
- National Center for Advancing Translational Sciences (TR002647)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- senolytic therapy, Alzheimer's disease, cellular senescence, dasatinib, quercetin, oral drug delivery, CNS penetration, cerebrospinal fluid drug concentration, drug safety and tolerability, interleukin-6, glial fibrillary acidic protein, amyloid-beta 42, aging biomarkers, early Alzheimer's disease
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