An adenovirus serotype 5 vector with fibers derived from ovine atadenovirus demonstrates CAR-independent tropism and unique biodistribution in mice.
Many clinically important tissues are refractory to adenovirus (Ad) infection due to negligible levels of the primary Ad5 receptor the coxsackie and adenovirus receptor CAR. Thus, development of novel CAR-independent Ad vectors should lead to therapeutic gain. Ovine atadenovirus type 7, the prototype member of genus Atadenovirus, efficiently transduces CAR-deficient human cells in vitro, and systemic administration of OAdV is not associated with liver sequestration in mice. The penton base of OAdV7 does not contain an RGD motif, implicating the long-shafted fiber molecule as a major structural dictate of OAdV tropism. We hypothesized that replacement of the Ad5 fiber with the OAdV7 fiber would result in an Ad5 vector with CAR-independent tropism in vitro and liver "detargeting" in vivo. An Ad5 vector displaying the OAdV7 fiber was constructed (Ad5Luc1-OvF) and displayed CAR-independent, enhanced transduction of CAR-deficient human cells. When administered systemically to C57BL/6 mice, Ad5Luc1-OvF reporter gene expression was reduced by 80% in the liver compared to Ad5 and exhibited 50-fold higher gene expression in the kidney than the control vector. To our knowledge, this is the first report of a fiber-pseudotyped Ad vector that simultaneously displays decreased liver uptake and a distinct organ tropism in vivo. This vector may have future utility in murine models of renal disease.
Nakayama
Masaharu
M
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, 901 19th Street South BMR2-572, Birmingham, AL 35294-2180, USA. mnakayam@uab.edu
Both
Gerald W
GW
Banizs
Boglarka
B
Tsuruta
Yuko
Y
Yamamoto
Seiji
S
Kawakami
Yosuke
Y
Douglas
Joanne T
JT
Tani
Kenzaburo
K
Curiel
David T
DT
Glasgow
Joel N
JN
D000818:Animals; D046808:Atadenovirus / Q000235:genetics* / Q000502:physiology*; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006321:Heart / Q000821:virology; D006801:Humans; D007668:Kidney / Q000821:virology; D008099:Liver / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010051:Ovarian Neoplasms; D011991:Receptors, Virus / Q000378:metabolism; D012756:Sheep / Q000821:virology; D013154:Spleen / Q000821:virology
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus