Your browser doesn't support javascript.
loading
Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.
Kang, Min Su; Shin, Monica; Ottoy, Julie; Aliaga, Arturo Aliaga; Mathotaarachchi, Sulantha; Quispialaya, Kely; Pascoal, Tharick A; Collins, D Louis; Chakravarty, M Mallar; Mathieu, Axel; Sandelius, Åsa; Blennow, Kaj; Zetterberg, Henrik; Massarweh, Gassan; Soucy, Jean-Paul; Cuello, A Claudio; Gauthier, Serge; Waterston, Michael; Yoganathan, Nathan; Lessard, Etienne; Haqqani, Arsalan; Rennie, Kerry; Stanimirovic, Danica; Chakravarthy, Balu; Rosa-Neto, Pedro.
Afiliação
  • Kang MS; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.
  • Shin M; Douglas Mental Health University Institute, Montreal, Canada.
  • Ottoy J; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.
  • Aliaga AA; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.
  • Mathotaarachchi S; 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.
  • Collins DL; Douglas Mental Health University Institute, Montreal, Canada.
  • Chakravarty MM; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.
  • Mathieu A; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.
  • Sandelius Å; Douglas Mental Health University Institute, Montreal, Canada.
  • Blennow K; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.
  • Zetterberg H; Translational Neuroimaging Laboratory, McGill University Research Centre for Studying in Aging, Montreal, QC, Canada.
  • Massarweh G; Douglas Mental Health University Institute, Montreal, Canada.
  • Soucy JP; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.
  • Cuello AC; Douglas Mental Health University Institute, Montreal, Canada.
  • Gauthier S; Douglas Mental Health University Institute, Montreal, Canada.
  • Waterston M; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
  • Yoganathan N; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
  • Lessard E; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • Haqqani A; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
  • Rennie K; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • Stanimirovic D; UK Dementia Research Institute at UCL, London, UK.
  • Chakravarthy B; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
  • Rosa-Neto P; McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada.
J Cereb Blood Flow Metab ; 42(5): 788-801, 2022 05.
Article em En | MEDLINE | ID: mdl-34378436
ABSTRACT
In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloidpathology 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-ß 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-ß levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-ß42/40 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.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer / Amiloidose Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Animals Idioma: En Revista: J Cereb Blood Flow Metab Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer / Amiloidose Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Animals Idioma: En Revista: J Cereb Blood Flow Metab Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá