WFRF:(Chelsky D.)
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| Fältnamn | Indikatorer | Metadata |
|---|---|---|
| 000 | 05477naa a2200673 4500 | |
| 001 | oai:gup.ub.gu.se/302536 | |
| 003 | SwePub | |
| 008 | 240528s2021 | |||||||||||000 ||eng| | |
| 024 | 7 | a https://gup.ub.gu.se/publication/3025362 URI |
| 024 | 7 | a https://doi.org/10.1002/alz.123022 DOI |
| 040 | a (SwePub)gu | |
| 041 | a eng | |
| 042 | 9 SwePub | |
| 072 | 7 | a ref2 swepub-contenttype |
| 072 | 7 | a art2 swepub-publicationtype |
| 100 | 1 | a Izzo, N. J.4 aut |
| 245 | 1 0 | a Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification |
| 264 | c 2021-02-08 | |
| 264 | 1 | b Wiley,c 2021 |
| 520 | a Introduction: Amyloid beta (A beta) oligomers are one of the most toxic structural forms of the A beta protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block A beta oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on A beta oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). Methods: Experiments were performed to measure the impact of CT1812 versus vehicle on A beta oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APP(S)(we)/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on A beta oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPP(Swe/Lnd+) and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. Results: CT1812 significantly and dose-dependently displaced A beta oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of A beta oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. Discussion: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and A beta oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812. | |
| 650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe |
| 650 | 7 | a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng |
| 653 | a Abeta oligomers | |
| 653 | a Alzheimer's disease | |
| 653 | a clinical trial | |
| 653 | a sigma-2 receptor | |
| 653 | a synapse | |
| 653 | a Neurosciences & Neurology | |
| 700 | 1 | a Yuede, C. M.4 aut |
| 700 | 1 | a LaBarbera, K. M.4 aut |
| 700 | 1 | a Limegrover, C. S.4 aut |
| 700 | 1 | a Rehak, C.4 aut |
| 700 | 1 | a Yurko, R.4 aut |
| 700 | 1 | a Waybright, L.4 aut |
| 700 | 1 | a Look, G.4 aut |
| 700 | 1 | a Rishton, G.4 aut |
| 700 | 1 | a Safferstein, H.4 aut |
| 700 | 1 | a Hamby, M. E.4 aut |
| 700 | 1 | a Williams, C.4 aut |
| 700 | 1 | a Sadlek, K.4 aut |
| 700 | 1 | a Edwards, H. M.4 aut |
| 700 | 1 | a Davis, C. S.4 aut |
| 700 | 1 | a Grundman, M.4 aut |
| 700 | 1 | a Schneider, L. S.4 aut |
| 700 | 1 | a DeKosky, S. T.4 aut |
| 700 | 1 | a Chelsky, D.4 aut |
| 700 | 1 | a Pike, I.4 aut |
| 700 | 1 | a Henstridge, C.4 aut |
| 700 | 1 | a Blennow, Kaj,d 1958u Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology4 aut0 (Swepub:gu)xbleka |
| 700 | 1 | a Zetterberg, Henrik,d 1973u Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology4 aut0 (Swepub:gu)xzethe |
| 700 | 1 | a LeVine, H.4 aut |
| 700 | 1 | a Spires-Jones, T. L.4 aut |
| 700 | 1 | a Cirrito, J. R.4 aut |
| 700 | 1 | a Catalano, S. M.4 aut |
| 710 | 2 | a Göteborgs universitetb Institutionen för neurovetenskap och fysiologi4 org |
| 773 | 0 | t Alzheimers & Dementiad : Wileyx 1552-5260x 1552-5279 |
| 856 | 4 | u https://doi.org/10.1002/alz.12302 |
| 856 | 4 8 | u https://gup.ub.gu.se/publication/302536 |
| 856 | 4 8 | u https://doi.org/10.1002/alz.12302 |
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