Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial

M M Gonzales, V R Garbarino, E Marques Zilli, R C Petersen, J L Kirkland, T Tchkonia, N Musi, S Seshadri, S Craft, M E Orr, M M Gonzales, V R Garbarino, E Marques Zilli, R C Petersen, J L Kirkland, T Tchkonia, N Musi, S Seshadri, S Craft, M E Orr

Abstract

Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).

Keywords: Alzheimer’s disease; Clinical trial; cellular senescence; senolytic therapy; tau.

Conflict of interest statement

Dr. Gonzales reports grants from ADDF, grants from UTHSCA Center for Biomedical Neuroscience, grants from the Coordinating Center for Claude D. Pepper Older Americans Independence Centers, during the conduct of the study. Drs. Zilli and Garbarino have nothing to disclose. Dr. Petersen reports grants from Alzheimer’s Drug Discovery Foundation, during the conduct of the study; personal fees from Roche, personal fees from Merck, personal fees from Biogen, personal fees from Eisai, personal fees from Genentech, outside the submitted work. Dr. Kirkland reports grants from ADDF, during the conduct of the study. In addition, Dr. Kirkland has a patent Killing Senescent Cells and Treating Senescence-Associated Conditions Using a SRC Inhibitor and a Flavonoid with royalties paid to Unity Biotechnologies, and a patent Treating Cognitive Decline and Other Neurodegenerative Conditions by Selectively Removing Senescent Cells from Neurological Tissue with royalties paid to Unity Biotechnologies. Dr. Tchkonia reports grants from ADDF, during the conduct of the study. In addition, Dr. Tchkonia has a patent Killing Senescent Cells and Treating Senescence-Associated Conditions Using a SRC Inhibitor and a Flavonoid with royalties paid to Unity Biotechnologies, and a patent Treating Cognitive Decline and Other Neurodegenerative Conditions by Selectively Removing Senescent Cells from Neurological Tissue with royalties paid to Unity Biotechnologies. Dr. Musi reports grants from ADDF, grants from UTHSCSA Center for Biomedical Neuroscience, grants from the Coordinating Center for Claude D. Pepper Older Americans Independence Centers, during the conduct of the study. Dr. Seshadri reports grants from ADDF, grants from UTHSCSA Center for Biomedical Neuroscience, during the conduct of the study. Dr. Craft reports grants from ADDF, grants from the Coordinating Center for Claude D. Pepper Older Americans Independence Centers, during the conduct of the study; other from vTv Therapeutics, other from Cylcerion, other from T3D Therapeutics, from Cognito Therapeutics, outside the submitted work. Dr. Orr reports grants from ADDF, grants from UTHSCSA Center for Biomedical Neuroscience, grants from the Coordinating Center for Claude D. Pepper Older Americans Independence Centers, during the conduct of the study. In addition, Dr. Orr has a patent Biosignature and therapeutic approach for neuronal senescence pending.

Figures

Figure 1
Figure 1
Outline of study timeline and major measures collected at each visit Primary and secondary outcomes are indicated by black checkmarks under each relevant visit where their collection falls. Outcomes, relevant to safety monitory measures are indicated by the gray arrow across the top, and will be assessed at every study visit (V(-1)-V10). BBB= blood brain barrier, Tx = Treatment, EOS= End of Study.

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