Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic
| Autor: | A. Claudio Cuello, Sulantha Mathotaarachchi, Julie Ottoy, Kerry Rennie, Arturo Aliaga, D. Louis Collins, Danica Stanimirovic, Nathan Yoganathan, Serge Gauthier, Pedro Rosa-Neto, Etienne Lessard, Tharick A. Pascoal, Balu Chakravarthy, Monica Shin, Axel Mathieu, Min Su Kang, Kely Quispialaya, Kaj Blennow, M. Mallar Chakravarty, Arsalan S. Haqqani, Michael Waterston, Jean-Paul Soucy, Henrik Zetterberg, Åsa Sandelius, Gassan Massarweh |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 42:788-801 |
| ISSN: | 1559-7016 0271-678X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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