Gene delivery of a modified antibody to Aβ reduces progression of murine Alzheimer’s disease


Autoři: Bradford M. Elmer aff001;  Kurt A. Swanson aff001;  Dinesh S. Bangari aff002;  Peter A. Piepenhagen aff002;  Errin Roberts aff002;  Tatyana Taksir aff002;  Lei Guo aff003;  Maria-Carmen Obinu aff004;  Pascal Barneoud aff004;  Susan Ryan aff002;  Bailin Zhang aff003;  Laurent Pradier aff004;  Zhi-Yong Yang aff001;  Gary J. Nabel aff001
Působiště autorů: Breakthrough Lab, Sanofi, Cambridge, Massachusetts, United States of America aff001;  Global Discovery Pathology, Sanofi, Framingham, Massachusetts, United States of America aff002;  Translational Sciences, Sanofi, Cambridge, Massachusetts, United States of America aff003;  R&D Neuroscience Unit, Sanofi, Chilly-Mazarin, France aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226245

Souhrn

Antibody therapies for Alzheimer’s Disease (AD) hold promise but have been limited by the inability of these proteins to migrate efficiently across the blood brain barrier (BBB). Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies’ own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-β have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. While expression of canonical IgG in the brain led to signs of neurotoxicity, this modified Ab was efficiently secreted from neuronal cells and retained target specificity. Steady state levels in the brain exceeded peak levels obtained by intravenous injection of IgG. AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive β-amyloid plaque accumulation. These findings suggest that CNS gene delivery of a silent anti-Aβ scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer’s disease.

Klíčová slova:

Alzheimer's disease – Central nervous system – Enzyme-linked immunoassays – Hippocampus – Immunohistochemistry techniques – Intravenous injections – Mouse models – Amyloid plaques


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2019 Číslo 12