Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway.
A systematic evaluation of the influence of sex on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver-targeted delivery of vector particles was between 5- to 13-fold higher in male mice compared with female mice, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the sex difference in transduction was observed with AAV-2- and AAV-5-based vectors, which use distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV inverted terminal repeat (ITR) in males compared with females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5alpha dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, sex did not have a significant effect on AAV gene transfer into nonhepatic tissue, indicating that there are distinct tissue- and sex-specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver.
Davidoff
Andrew M
AM
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA. andrew.davidoff@stjude.org
Ng
Catherine Y C
CY
Zhou
Junfang
J
Spence
Yunyu
Y
Nathwani
Amit C
AC
D000728:Androgens / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D000229:Dependovirus / Q000235:genetics*; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000494:pharmacology; D004343:Drug Implants; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000821:virology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009919:Orchiectomy; D009928:Organ Specificity; D010052:Ovariectomy; D011991:Receptors, Virus / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012727:Sex Characteristics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
D000728:Androgens; D004343:Drug Implants; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D013196:Dihydrotestosterone; D040301:Vascular Endothelial Growth Factor Receptor-2