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PreprintCited by 335Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchTelomeres, Telomerase, and Senescence

The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.

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 access
Orr, Miranda, Gonzales, Mitzi, Garbarino, Valentina, Kautz, Tiffany, Palavicini, Juan, Lopez-Cruzan, Marisa, Dehkordi, Shiva Kazempour, Mathews, Julia, Zare, Habil, Xu, Peng, Zhang, Bin, Franklin, Crystal, Habes, Mohamad, Craft, Suzanne, Petersen, Ronald, Tchkonia, Tamara, Kirkland, James, Salardini, Arash, Seshadri, Sudha, Musi, Nicolas·2023·Nature Medicine
DOI 10.21203/rs.3.rs-2809973/v1PMC PMC10875739

Preprint — published as 10.1038/s41591-023-02543-w · Paper page

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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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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
Publisher
Springer Science and Business Media LLC
Published
2023-04-24
Volume
29
Issue
10
Pages
2481-2488
ISSN
1078-8956 (ISSN-L)
DOI
10.21203/rs.3.rs-2809973/v1
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
Licence
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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