Gene therapy vectors based on adeno-associated virus type 1.
The complete sequence of adeno-associated virus type 1 (AAV-1) was defined. Its genome of 4,718 nucleotides demonstrates high homology with those of other AAV serotypes, including AAV-6, which appears to have arisen from homologous recombination between AAV-1 and AAV-2. Analysis of sera from nonhuman and human primates for neutralizing antibodies (NAB) against AAV-1 and AAV-2 revealed the following. (i) NAB to AAV-1 are more common than NAB to AAV-2 in nonhuman primates, while the reverse is true in humans; and (ii) sera from 36% of nonhuman primates neutralized AAV-1 but not AAV-2, while sera from 8% of humans neutralized AAV-2 but not AAV-1. An infectious clone of AAV-1 was isolated from a replicated monomer form, and vectors were created with AAV-2 inverted terminal repeats and AAV-1 Rep and Cap functions. Both AAV-1- and AAV-2-based vectors transduced murine liver and muscle in vivo; AAV-1 was more efficient for muscle, while AAV-2 transduced liver more efficiently. Strong NAB responses were detected for each vector administered to murine skeletal muscle; these responses prevented readministration of the same serotype but did not substantially cross-neutralize the other serotype. Similar results were observed in the context of liver-directed gene transfer, except for a significant, but incomplete, neutralization of AAV-1 from a previous treatment with AAV-2. Vectors based on AAV-1 may be preferred in some applications of human gene therapy.
Xiao
W
W
Institute for Human Gene Therapy and Departments of Molecular and Cellular Engineering and of Medicine, University of Pennsylvania, and The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. cousc@mri.sari.ac.uk
Chirmule
N
N
Berta
S C
SC
McCullough
B
B
Gao
G
G
Wilson
J M
JM
D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D004279:DNA, Viral; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D016679:Genome, Viral; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid
D004279:DNA, Viral