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Title: NOVEL CAPRINE ADENO-ASSOCIATED VIRUS (AAV) CAPSID (AAV-GO.1) IS CLOSELY RELATED TO THE PRIMATE AAV-5 AND HAS UNIQUE TROPISM AND NEUTRALIZATION PROPERTIES

Author
item ARBETMAN, ALEJANDRA - AVIGEN, INC.
item LOCHRIE, MICHAEL - AVIGEN, INC.
item SHANGZHEN, ZHOU - AVIGEN, INC.
item WELLMAN, JENNIFER - AVIGEN, INC.
item SCALLAN, CIARAN - AVIGEN, INC.
item DOROUDCHI, MOHAMMAD - AVIGEN, INC.
item LEHMKUHL, HOWARD
item HOBBS, LEA
item PIERCE, GLENN - AVIGEN, INC.
item COLOSI, PETER - AVIGEN, INC.

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/16/2005
Publication Date: 9/22/2005
Citation: Arbetman, A.E., Lochrie, M., Shangzhen, Z., Wellman, J., Scallan, C., Doroudchi, M.M., Lehmkuhl, H.D., Hobbs, L.A., Pierce, G.F., Colosi, P. 2005. Novel caprine adeno-associated virus (AAV) capsid (AAV-GO.1) is closely related to the primate AAV-5 and has unique tropism and neutralization properties. Journal of Virology. 79(24):15238-15245.

Interpretive Summary: Preexisting humoral immunity to adeno-associated virus (AAV) vectors may limit their clinical utility in gene delivery. We describe a novel caprine AAV (AAV-Go.1) capsid with unique biological properties. AAV-Go.1 also demonstrated a marked tropism for lung when administered intravenously. The pulmonary tropism and high neutralization resistance to human preexisting antibodies suggest novel therapeutic uses for AAV-Go.1 vectors, including targeting diseases such as cystic fibrosis. Nonprimate sources of AAVs may be useful to identify additional capsids with distinct tropisms and high resistance to neutralization by human preexisting antibodies.

Technical Abstract: Preexisting humoral immunity to adeno-associated virus (AAV) vectors may limit their clinical utility in gene delivery. We describe a novel caprine AAV (AAV-Go.1) capsid with unique biological properties. AAV-Go.1 capsid was cloned from goat-derived adenovirus preparations. Surprisingly, AAV-Go.1 capsid was 94% identical to the human AAV-5, with differences predicted to be largely on the surface and on or under the spike-like protrusions. In an in vitro neutralization assay using human immunoglobulin G (IgG) (intravenous immune globulin [IVIG]), AAV-Go.1 had higher resistance than AAV-5 (100-fold) and resistance similar to that of AAV-4 or AAV-8. In an in vivo model, SCID mice were pretreated with IVIG to generate normal human IgG plasma levels prior to the administration of AAV human factor IX vectors. Protein expression after intramuscular administration of AAV-Go.1 was unaffected in IVIG-pretreated mice, while it was reduced 5- and 10-fold after administration of AAV-1 and AAV-8, respectively. In contrast, protein expression after intravenous administration of AAV-Go.1 was reduced 7.1-fold, similar to the 3.8-fold reduction observed after AAV-8 administration in IVIG-pretreated mice, and protein expression was essentially extinguished after AAV-2 administration in mice pretreated with much less IVIG (15-fold). AAV-Go.1 vectors also demonstrated a marked tropism for lung when administered intravenously in SCID mice. The pulmonary tropism and high neutralization resistance to human preexisting antibodies suggest novel therapeutic uses for AAV-Go.1 vectors, including targeting diseases such as cystic fibrosis. Nonprimate sources of AAVs may be useful to identify additional capsids with distinct tropisms and high resistance to neutralization by human preexisting antibodies.