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

In the paper

“The SASP triggers immune cells to clear senescent cells, which is beneficial; however as senescent cells accumulate, the SASP exerts paracrine effects on adjacent cells, becoming the precipitant for broader cellular conversion to the senescent phenotype (17, 20).”

What the sources say

• Not checked yetcites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
• Not checked yetcites [20] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source

In the paper

“Cellular senescence is a dynamic molecular process induced by stressors such as DNA and mitochondrial damage, telomere shortening, protein accumulation and metabolic dysfunction (17, 20).”

What the sources say

• Not checked yetcites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
• Not checked yetcites [20] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source

In the paper

“Cellular senescence is a hallmark feature of aging and contributes to numerous age-related chronic medical conditions including AD (10–19).”

What the sources say

• Not checked yetcites [10] Lewis-McDougall, 2019, Aged-senescent cells contribute to impaired heart regeneration, Aging Cell source
• Not checked yetcites [11] Nath, 2018, The murine dialysis fistula model exhibits a senescence phenotype: pathobiologic mechanisms and therapeutic potential, Am J Physiol Renal Physiol source
• Not checked yetcites [12] Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun source
• Not checked yetcites [13] Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab source
• Not checked yetcites [14] Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell source
• Not checked yetcites [15] Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell source
• Not checked yetcites [16] Schafer, 2017, Cellular senescence mediates fibrotic pulmonary disease, Nat Commun source
• Not checked yetcites [17] Tchkonia, 2018, Aging, cell senescence, and chronic disease: emerging therapeutic strategies, JAMA source
• Not checked yetcites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
• Not checked yetcites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source

In the paper

“The SASP consists of a noxious secretome comprised of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins (24–27).”

What the sources say

• Not checked yetcites [24] Acosta, 2013, A complex secretory program orchestrated by the inflammasome controls paracrine senescence, Nat Cell Biol source
• Not checked yetcites [25] Chen, 2015, MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype, Mol Cell source
• Not checked yetcites [26] Hoare, 2016, NOTCH1 mediates a switch between two distinct secretomes during senescence, Nat Cell Biol source
• Not checked yetcites [27] Weichhart, 2018, mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review, Gerontology source

In the paper

“The strong association between aging and AD suggests overlapping molecular and cellular processes (9), which may serve as viable treatment targets to prevent or alleviate neurodegenerative diseases.”

What the sources say

• Not checked yetcites [9] Xia, 2018, Aging and Alzheimer's disease: comparison and associations from molecular to system level, Aging Cell source

In the paper

“The burden of senescent cells in the brain increases with advanced chronological age and neurodegenerative diseases, and occurs across cell types including neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells (28–32).”

What the sources say

• Not checked yetcites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
• Not checked yetcites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
• Not checked yetcites [30] Zhang, 2019, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci source
• Not checked yetcites [31] Blasko, 2004, How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes, Aging Cell source
• Not checked yetcites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source

In the paper

“Microglia and astrocytes can acquire a senescent phenotype themselves (28, 31, 32), promoting further diffusion of the SASP and the conversion of healthy cells to the senescent phenotype.”

What the sources say

• Not checked yetcites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
• Not checked yetcites [31] Blasko, 2004, How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes, Aging Cell source
• Not checked yetcites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source

In the paper

“To date, research conducted across six transgenic AD mouse models has demonstrated that orally administered senolytic drugs ablate senescent cells in the brain and alleviate AD-relevant pathogenesis (28–30, 32).”

What the sources say

• Not checked yetcites [28] Baker, 2018, Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives, J Clin Invest source
• Not checked yetcites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source
• Not checked yetcites [30] Zhang, 2019, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci source
• Not checked yetcites [32] Gerdes, 2020, Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases, Int Rev Neurobiol source

In the paper

“D+Q target multiple senescent cell types; the combination of the two agents has been demonstrated to effectively clear senescent cells and alleviate numerous chronic medical conditions in preclinical models, including physical frailty, muscle weakness, vascular stiffness, osteoporosis, and hepatic stenosis (12–15, 18, 34).”

What the sources say

• Not checked yetcites [12] Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun source
• Not checked yetcites [13] Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab source
• Not checked yetcites [14] Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell source
• Not checked yetcites [15] Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell source
• Not checked yetcites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
• Not checked yetcites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source

In the paper

“Importantly, D+Q have been well tolerated and demonstrated benefits in first-in-human clinical trials of other conditions (i.e., idiopathic pulmonary fibrosis (40) followed by diabetic kidney disease (34).”

What the sources say

• Not checked yetcites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source
• Not checked yetcites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source

In the paper

“Both D and Q have demonstrated blood-brain barrier penetrance in rodent models with some supportive data in clinical studies of individuals undergoing cancer treatment (41, 42).”

What the sources say

• Not checked yetcites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
• Not checked yetcites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source

In the paper

“Brain MRI indicated that senolytic treatment mitigated pathogenic ventricular enlargement, aberrant blood flow, and the SASP.”

What the sources say

• Not checked yetcites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source

In the paper

“Our pilot study evaluating a novel therapeutic agent for AD is a direct follow-up to the preclinical studies and clinical trials utilizing D+Q for other age-related conditions, which demonstrated an encouraging safety profile coupled with modest but promising therapeutic outcomes (18, 34, 40–42).”

What the sources say

• Not checked yetcites [18] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source
• Not checked yetcites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
• Not checked yetcites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source
• Not checked yetcites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
• Not checked yetcites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source

In the paper

“Similarly, in an open-label trial of D+Q for diabetic kidney disease, short-term treatment effectively reduced senescent cell burden in adipose tissue and attenuated plasma levels of key SASP factors, including IL-2 and IL-6 (34).”

What the sources say

• Not checked yetcites [34] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source

In the paper

“The first clinical trial of senolytic treatment, published in 2019, showed D+Q was generally well tolerated and suggested improvements in physical function in an open-label trial for individuals with idiopathic pulmonary fibrosis, a fatal disease, providing encouraging first evidence for further clinical testing (40).”

What the sources say

• Not checked yetcites [40] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source

In the paper

“We will track occurrence of adverse events (AEs) and serious adverse events (SAEs) from the screening visit to the end of the study.”

In the paper

“AEs and SAEs will be defined according to the International Conference on Harmonization Guidance for Clinical Safety Data Management.”

What the sources say

• Not checked yetcites International Conference on Harmonization Guidance for Clinical Safety Data Management

In the paper

“While it has been shown that D and/or Q can cross the blood barrier in rodent models and individuals undergoing cancer treatment, the central nervous system drug penetrance in individuals with AD remains unknown (41, 42).”

What the sources say

• Not checked yetcites [41] Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood source
• Not checked yetcites [42] Ishisaka, 2011, Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats, Free Radic Biol Med source

In the paper

“Incidence of AEs and SAEs will be reviewed by the UTHSCSA Data Safety Monitoring Board (DSMB).”

In the paper

“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.”

In the paper

“One of the major challenges to our trial and related studies as this field moves forward is the lack of a universally accepted definition and biomarkers of cellular senescence (57).”

What the sources say

• Not checked yetcites [57] DiBattista, 2020, NIA workshop on senescence in brain aging and Alzheimer's disease and its related dementias, GeroScience source

In the paper

“Preclinical and clinical trials have identified various cellular and molecular features of cellular senescence (58).”

What the sources say

• Not checked yetcites [58] Tuttle, 2020, Cellular senescence and chronological age in various human tissues: a systematic review and meta-analysis, Aging Cell source

In the paper

“The intermittent administration of senolytics in other study populations has been shown to attenuate side effects and effectively circumvent potential off-target effects induced by continuous receptor occupancy.”

What the sources say

• Not checked yetcites [19] Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source
• Not checked yetcites [43] Zhu, 2016, Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors, Aging Cell source

In the paper

“Senolytic treated mice had lower tau deposition, which correlated with favorable clinically relevant outcomes.”

What the sources say

• Not checked yetcites [29] Musi, 2018, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell source

In the paper

“As such, the SToMP-AD vanguard is critical in that it will provide the first proof-of-concept AD-relevant data utilizing a senescence-associated pharmacotherapy.”

In the paper

“CSF tau levels demonstrate elevation prior to tau PET imaging, suggesting that it may be a sensitive marker of early change (59).”

What the sources say

• Not checked yetcites [59] Mattsson, 2017, (18)F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease, EMBO Mol Med source

In the paper

“The senescence markers included in the secondary aim were selected a priori based on the literature.”

In the paper

“Though there are obvious benefits to being able to repurpose a FDA approved chemotherapeutic medication, D, with a well-established side effect profile (53), there is a need to carefully evaluate safety and the equipoise of treatment in our vulnerable target population, especially as D+Q are utilized in combination to achieve broader targeting of senescent cell survival mechanisms (19).”

What the sources say

• Not checked yetcites [53] Sprycel prescribing information, 2018