Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models.
A detailed comparison of recombinant adeno-associated viral (rAAV) vectors of serotypes 2, 5, and 8 was performed in mice and nonhuman primates. Differences within the capsid proteins and viral terminal repeats of rAAV-2 and -5 did not significantly influence their ability to transduce murine liver. However, vectors pseudotyped with AAV-8 capsid (rAAV-2/8) mediated transgene expression more rapidly and from lower doses than possible with rAAV-2 and -5, although expression declined from peak values in a distinct dose-dependent manner prior to reaching steady-state levels. Nevertheless, at all time points and vector doses, rAAV-2/8 transgene levels were 17- to 84-fold higher than with rAAV-2 or -5 due to a more rapid conversion of the single-stranded genome to transcriptionally active stable duplex DNA. In nonhuman primates, liver-targeted administration of rAAV-5 and rAAV-2/8 vectors established therapeutic levels of transgene expression. The importance of preexisting serotype immunity was highlighted by the inability to achieve successful transduction in the presence of serotype-specific antibodies, although this impediment was successfully avoided through the use of alternative serotypes. In summary, serotype-specific differences in transduction biology and the appreciation of preexisting immunity will likely influence the selection of the rAAV serotype for future clinical trials.
Davidoff
Andrew M
AM
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
Gray
John T
JT
Ng
Catherine Y C
CY
Zhang
Youbin
Y
Zhou
Junfang
J
Spence
Yunyu
Y
Bakar
Yusura
Y
Nathwani
Amit C
AC
D000818:Animals; D000917:Antibody Formation; D036022:Capsid Proteins / Q000276:immunology*; D004279:DNA, Viral / Q000032:analysis; D000229:Dependovirus / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology; D002836:Hemophilia B / Q000628:therapy; D022781:Hepatocytes / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D012703:Serotyping; D014161:Transduction, Genetic; D019076:Transgenes
D036022:Capsid Proteins; D004279:DNA, Viral