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Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318263/ https://www.ncbi.nlm.nih.gov/pubmed/35890306 http://dx.doi.org/10.3390/pharmaceutics14071412 |
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author | Roshanbin, Sahar Julku, Ulrika Xiong, Mengfei Eriksson, Jonas Masliah, Eliezer Hultqvist, Greta Bergström, Joakim Ingelsson, Martin Syvänen, Stina Sehlin, Dag |
author_facet | Roshanbin, Sahar Julku, Ulrika Xiong, Mengfei Eriksson, Jonas Masliah, Eliezer Hultqvist, Greta Bergström, Joakim Ingelsson, Martin Syvänen, Stina Sehlin, Dag |
author_sort | Roshanbin, Sahar |
collection | PubMed |
description | Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology. |
format | Online Article Text |
id | pubmed-9318263 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93182632022-07-27 Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody Roshanbin, Sahar Julku, Ulrika Xiong, Mengfei Eriksson, Jonas Masliah, Eliezer Hultqvist, Greta Bergström, Joakim Ingelsson, Martin Syvänen, Stina Sehlin, Dag Pharmaceutics Article Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology. MDPI 2022-07-05 /pmc/articles/PMC9318263/ /pubmed/35890306 http://dx.doi.org/10.3390/pharmaceutics14071412 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Roshanbin, Sahar Julku, Ulrika Xiong, Mengfei Eriksson, Jonas Masliah, Eliezer Hultqvist, Greta Bergström, Joakim Ingelsson, Martin Syvänen, Stina Sehlin, Dag Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title | Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title_full | Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title_fullStr | Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title_full_unstemmed | Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title_short | Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody |
title_sort | reduction of αsyn pathology in a mouse model of pd using a brain-penetrating bispecific antibody |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318263/ https://www.ncbi.nlm.nih.gov/pubmed/35890306 http://dx.doi.org/10.3390/pharmaceutics14071412 |
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