Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle.
Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders.
Asokan
Aravind
A
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. aravind_asokan@med.unc.edu
Conway
Julia C
JC
Phillips
Jana L
JL
Li
Chengwen
C
Hegge
Julia
J
Sinnott
Rebecca
R
Yadav
Swati
S
DiPrimio
Nina
N
Nam
Hyun-Joo
HJ
Agbandje-McKenna
Mavis
M
McPhee
Scott
S
Wolff
Jon
J
Samulski
R Jude
RJ
D000818:Animals; D000229:Dependovirus / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000097:blood; D051379:Mice; D008958:Models, Molecular; D009132:Muscles / Q000378:metabolism* / Q000821:virology; D009928:Organ Specificity; D011991:Receptors, Virus / Q000235:genetics*; D013329:Structure-Activity Relationship; D056189:Viral Tropism
D011991:Receptors, Virus