TY - JOUR
T1 - Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD)
T2 - A Pilot Clinical Trial
AU - Gonzales, Mitzi M.
AU - Garbarino, V. R.
AU - Marques Zilli, E.
AU - Petersen, R. C.
AU - Kirkland, J. L.
AU - Tchkonia, T.
AU - Musi, N.
AU - Seshadri, S.
AU - Craft, S.
AU - Orr, Miranda E.
N1 - Funding Information:
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.
Funding Information:
Funding: This work was made possible by grants through the Alzheimer’s Drug Discovery Foundation, GC-201908-2019443, the Coordinating Center for Claude D. Pepper Older Americans Independence Centers, U24AG059624; the Translational Geroscience Network (R33AG061456); the Institute for Integration of Medicine & Science and the Center for Biomedical Neurosciences at UT Health Science Center in San Antonio (UTHSCSA); and funding from the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, including support made possible by the National Institute on Aging (AG054076 and AG059421). Dr. Gonzales was supported as an RL5 Scholar in the San Antonio Claude D. Pepper Older Americans Independence Center (P30AG044271). Dr. Garbarino is supported by T32AG021890. Dr. Musi also is supported by P30AG044271 and the San Antonio Nathan Shock Center (P30AG013319). Dr. Seshadri Institute is supported by the National Institute on Aging (AG054076 and AG059421). 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; Dr. Orr is also supported by a VA Career Development Award, IK2BX003804.
Publisher Copyright:
© 2021, Serdi and Springer Nature Switzerland AG.
PY - 2022/1
Y1 - 2022/1
N2 - 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).
AB - 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).
KW - Alzheimer’s disease
KW - Clinical trial
KW - cellular senescence
KW - senolytic therapy
KW - tau
UR - http://www.scopus.com/inward/record.url?scp=85117755926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117755926&partnerID=8YFLogxK
U2 - 10.14283/jpad.2021.62
DO - 10.14283/jpad.2021.62
M3 - Article
C2 - 35098970
AN - SCOPUS:85117755926
VL - 9
SP - 22
EP - 29
JO - The journal of prevention of Alzheimer's disease
JF - The journal of prevention of Alzheimer's disease
SN - 2426-0266
IS - 1
ER -