Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.
| Title: | Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic. |
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| Authors: | Kang MS; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Shin M; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; Ottoy J; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Aliaga AA; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Mathotaarachchi S; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; Quispialaya K; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Pascoal TA; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; Collins DL; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Chakravarty MM; Douglas Mental Health University Institute, Montreal, Canada.; Mathieu A; Douglas Mental Health University Institute, Montreal, Canada.; Sandelius Å; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Blennow K; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Zetterberg H; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; UK Dementia Research Institute at UCL, London, UK.; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.; Massarweh G; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Soucy JP; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Cuello AC; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.; Gauthier S; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.; Waterston M; Centre for Imaging Technology Commercialization, London, ON, Canada.; Yoganathan N; KalGene Pharmaceuticals Inc., Montreal, Canada.; Lessard E; Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.; Haqqani A; Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.; Rennie K; Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.; Stanimirovic D; Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.; Chakravarthy B; Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.; Rosa-Neto P; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.; Douglas Mental Health University Institute, Montreal, Canada.; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada. |
| Source: | Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2022 May; Vol. 42 (5), pp. 788-801. Date of Electronic Publication: 2021 Aug 11. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: SAGE Publications Country of Publication: United States NLM ID: 8112566 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-7016 (Electronic) Linking ISSN: 0271678X NLM ISO Abbreviation: J Cereb Blood Flow Metab Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2016- : Thousand Oaks, CA : SAGE Publications; Original Publication: New York : Raven Press, c1981- |
| MeSH Terms: | Alzheimer Disease*/diagnostic imaging ; Alzheimer Disease*/drug therapy ; Alzheimer Disease*/metabolism ; Amyloidosis*; Amyloid beta-Peptides/metabolism ; Animals ; Biomarkers ; Longitudinal Studies ; Mice ; Positron-Emission Tomography ; Rats |
| Abstract: | In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials. |
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| Contributed Indexing: | Keywords: Alzheimer’s disease; anti-amyloid-beta therapeutic; longitudinal in vivo biomarkers; preclinical study; protein-based treatment |
| Substance Nomenclature: | 0 (Amyloid beta-Peptides); 0 (Biomarkers) |
| Entry Date(s): | Date Created: 20210811 Date Completed: 20220413 Latest Revision: 20220716 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9014686 |
| DOI: | 10.1177/0271678X211035625 |
| PMID: | 34378436 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't