title: Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo.
abstract: Recently adeno-associated virus (AAV) became the first clinically approved gene therapy product in the western world. To develop AAV for future clinical application in a widespread patient base, particularly in therapies which require intravenous (i.v.) administration of vector, the virus must be able to evade pre-existing antibodies to the wild type virus. Here we demonstrate that in mice, AAV vectors associated with extracellular vesicles (EVs) can evade human anti-AAV neutralizing antibodies. We observed different antibody evasion and gene transfer abilities with populations of EVs isolated by different centrifugal forces. EV-associated AAV vector (ev-AAV) was up to 136-fold more resistant over a range of neutralizing antibody concentrations relative to standard AAV vector in vitro. Importantly in mice, at a concentration of passively transferred human antibodies which decreased i.v. administered standard AAV transduction of brain by 80%, transduction of ev-AAV transduction was not reduced and was 4000-fold higher. Finally, we show that expressing a brain targeting peptide on the EV surface allowed significant enhancement of transduction compared to untargeted ev-AAV. Using ev-AAV represents an effective, clinically relevant approach to evade human neutralizing anti-AAV antibodies after systemic administration of vector.
authors.affiliation: Department of Neurology, The Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, USA.
authors.forename: Bence
authors.initials: B
authors.lastname: György
authors.affiliation: Department of Neurology, The Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, USA; Louisiana State University, Baton Rouge, LA, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fitzpatrick
authors.affiliation: Department of Neurology, The Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, USA; Neuro-oncology Research Group, Department of Neurosurgery, Cancer Center Amsterdam, and VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Matheus H W
authors.initials: MH
authors.lastname: Crommentuijn
authors.affiliation: Department of Neurology, The Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, USA.
authors.forename: Dakai
authors.initials: D
authors.lastname: Mu
authors.affiliation: Department of Neurology, The Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, USA. Electronic address: cmaguire@mgh.harvard.edu.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014161:Transduction, Genetic
chemical_list: D057134:Antibodies, Neutralizing
keywords: Adeno-associated virus; Exosomes; Extracellular vesicles; Gene delivery; Gene therapy; Microvesicles