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

Abstract

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.

Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

“…FcR-mediated endocytosis [28,[43][44][45][46], internalisation mediated by electrostatic interactions with the plasma membrane [47] and through lipid rafts on the surface of the plasma membrane [48]. However, neurons are not specialised to express nor do they cope well with high intracellular concentrations of IgG, as has been shown by Elmer and colleagues, where viralmediated expression of IgG antibodies resulted in glycoprotein accumulation and subsequent neuronal degeneration [49]. While RNF5 was not expressed intracellularly in our study, it is possible that forcing large amounts of IgG into cells can be detrimental to neuronal health due to neurons being incapable of processing large quantities of glycoprotein.…”

The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy

“…Other gene therapy approaches attempt to produce antibodies against β-amyloid. 254 Focal transgene expression (ie, in the proximity of amyloid plaques), has been investigated in mouse models of AD 255 …”

“…Other gene therapy approaches attempt to produce antibodies against β-amyloid. 254 Focal transgene expression (ie, in the proximity of amyloid plaques), has been investigated in mouse models of AD 255 Multimodal AD therapy includes gliotherapy Many different approaches have been considered to fight against AD (neuronal defense/repair, gliotherapies, AD preventive approaches) (Figure 1). Pharmacological and nopharmacological therapies have been proposed.…”

Genetic Therapies for Alzheimer’s Disease: A Scoping Review

“…As a way of addressing these issues, Elmer et al ( 2020) [36] performed intrahippocampal injections of an AAV vector encoding a transcript for anti-Aβ IgG into 2-month-old APP mutation mice, just prior to the time of Aβ plaque deposition in this model. They found that CNS expression of anti-Aβ IgG was maintained at levels higher than peak concentration achieved with IV injection and that it resulted in reduced cortical and hippocampal Aβ load.…”