Combination Therapy Demonstrates Ability to Clear Senescent Cells in Alzheimer Disease

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At the conclusion of a 12-weel treatment period, biomarker data provided mechanistic insights of senolytic effects using dasatinib and quercetin that need to be confirmed in fully powered, placebo-controlled studies.

Miranda Orr, PhD, associate professor of gerontology and geriatric medicine, Wake Forest University School of Medicine

A recently published small-scale study in Nature showed that a combination of dasatinib, an FDA-approved therapy designed to clear cancer cells, and quercetin, a plant-derived antioxidant, was safe in patients with Alzheimer disease (AD) and resulted in central nervous system penetration. Treated patients also showed an increase in inflammation in cerebrospinal fluid (CSF) biomarkers, which investigators concluded could have been a result of senescent cells being cleared.

Led by Mitzi M. Gonzales, PhD, ABPP-CN, clinical research core director at UT Health San Antonio, the trial featured 5 individuals with early-stage AD who received oral dasatinib plus quercetin over 2 consecutive days, followed by 2 weeks of no drugs. This cycle repeated 6 times over a 12-week period with the primary goals of assessing CNS penetrance, safety, feasibility, and efficacy. A proof-of-concept study, the phase 1 trial built on previous evidence of senescent cells and their interactions with cell loss, inflammation, and memory impairment in human AD.

At the conclusion of the trial period, patients saw increases in dasatinib (12.7-73.5 ng ml-1) and quercetin (3.29-26.3 ng ml-1) levels in blood. In CSF, dasatinib levels were detected in 4 participants (80%) ranging from 0.281 to 0.536 ml-1 with a CSF to plasma ratio of 0.422%-0.919%. Of note, quercetin was not detected in the CSF in any of the treated participants.

Secondary cognitive and neuroimaging end points, did not change significantly after patients underwent treatment, further supporting a favorable safety profile. Investigators also observed changes in relevant biomarkers, most notably, increases in CSF levels of interleukin-6 (IL-6; t(4) = 3.913; P = .008) and glial fibrillary acidic protein (t(4) = 3.354; P = .028). In addition, investigators observed trending decreases in senescence-related cytokines and chemokines, with a trend toward higher amyloid-ß42 levels (t(4)= ­–2.338; P = .079).

"There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further," Miranda Orr, PhD, associate professor of gerontology and geriatric medicine, Wake Forest University School of Medicine, said in a statement.1 "However, we shouldn’t over-interpret these results. There was a small number of people enrolled, there was no placebo arm to compare results."

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Orr and her team are in the process of a larger, phase 2 trial assessing the effects of the combination therapy and its effects on clearing senescent cells. Looking to build upon the results of this study, the new trial is supported by a $3 million donation by the Alzheimer’s Drug Discovery Foundation (ADDF).

"Dr. Orr’s research is a critical part of this pivotal moment in Alzheimer’s research as the focus shifts from amyloid and tau, the classic disease hallmarks, toward how the biology of aging underlies the disease," Howard Filit, MD, cofounder and chief science officer, ADDF, said in a statement.1 "Aging is the leading risk factor for Alzheimer’s, and it is important that the field explores new approaches for developing therapeutics, like senolytics, that target biological aging. Alzheimer disease is a multifaceted disease, and similar to cancer, we will need multiple treatment options that can be combined and personalized to improve the outlook for millions of patients living with Alzheimer disease."

In July 2022, the Mayo Clinic started ALSENLITE (NCT04785300), a third phase 1/2 open-label pilot study assessing the effects of the combination therapy in cohort of 20 patients aged over 55 years old with mild cognitive impairment or AD. Those included have Mini-Mental State Examination scores between 26 to 15, are not on cholinesterase inhibitors or memantine, and have a diagnosis of AD confirmed by with a positive tau-PET scan.

REFERENCES
1. Phase 1 clinical trial shows treatment designed to clear senescent cells in Alzheimer’s disease is safe. News release. Atrium Health Wake Forest Baptist. September 7, 2023. Accessed October 2, 2023. https://www.eurekalert.org/news-releases/1000588
2. Gonzales MM, Garbarino VR, Kautz TF, et al. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nat Med. Published online September 7, 2023. doi:10.1038/s41591-023-02543
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