title: Systemic Vascular Transduction by Capsid Mutant Adeno-Associated Virus After Intravenous Injection.
abstract: The ability to effectively deliver genetic material to vascular endothelial cells remains one of the greatest unmet challenges facing the development of gene therapies to prevent diseases with underlying vascular etiology, such as diabetes, atherosclerosis, and age-related macular degeneration. Herein, we assess the effectiveness of an rAAV2-based capsid mutant vector (Y272F, Y444F, Y500F, Y730F, T491V; termed QuadYF+TV) with strong endothelial cell tropism at transducing the vasculature after systemic administration. Intravenous injection of QuadYF+TV resulted in widespread transduction throughout the vasculature of several major organ systems, as assessed by in vivo bioluminescence imaging and postmortem histology. Robust transduction of lung tissue was observed in QuadYF+TV-injected mice, indicating a role for intravenous gene delivery in the treatment of chronic diseases presenting with pulmonary complications, such as α1-antitrypsin deficiency. The QuadYF+TV vector cross-reacted strongly with AAV2 neutralizing antibodies, however, indicating that a targeted delivery strategy may be required to maximize clinical translatability.
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .|2 Nuffield Laboratory of Ophthalmology, Department of Clinical Neuroscience, University of Oxford , Oxford, United Kingdom .
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Lipinski
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .
authors.forename: Chris A
authors.initials: CA
authors.lastname: Reid
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .
authors.forename: James J
authors.initials: JJ
authors.lastname: Peterson
authors.affiliation: 3 Department of Ophthalmology, Indiana University School of Medicine, Indiana University , Indianapolis, Indiana.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
authors.affiliation: 3 Department of Ophthalmology, Indiana University School of Medicine, Indiana University , Indianapolis, Indiana.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.affiliation: 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida .
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D014161:Transduction, Genetic; D014652:Vascular Diseases / Q000235:genetics / Q000628:therapy*
chemical_list: D036022:Capsid Proteins