title: Gender differences in serotype 2 adeno-associated virus biodistribution after administration to rodent salivary glands.
abstract: Salivary glands (SGs) have proven useful targets for clinical applications of gene therapeutics. In this toxicology and biodistribution study, which conforms to U.S. Food and Drug Administration Good Laboratory Practice regulations, four doses (10(7)-10(10) particles) of a serotype 2 adeno-associated viral (AAV2) vector encoding human erythropoietin were directly administered to the right submandibular gland of male and female BALB/c mice (n = 21 per gender dose group). Control-treated (saline administered; n = 66) and vector-treated (n = 168) animals did not differ in clinical appearance, morbidity and mortality rates, food and water consumption, weight gain ratios, and final weight. Clinical hematology values also were unaffected by AAV2 administration except for parameters influenced by the expression of the recombinant protein (e.g., hematocrit). Mice were killed on days 3, 30, 55, and 92. No major vector-related toxicity was uncovered after complete pathology and histopathology review. However, a significant gender-related difference in vector biodistribution was revealed by quantitative polymerase chain reaction. In male mice vector (group receiving 10(10) particles/animal) effectively transduced, and was primarily confined within, the SGs (i.e., approximately 800 times more copies in SGs than in liver; day 3) and long lived. In contrast, in female mice, SG transduction was less efficient (260-fold less than in males; day 3) and short lived, and vector was disseminated widely via both the bloodstream (SG:liver copy ratio, approximately 1) and saliva (30-fold greater than in males). The observed vector biodistribution is likely due to differences in AAV2 receptor targets and structural differences affecting SG integrity. Sexual dimorphism is a factor of major significance that could potentially affect gene therapy clinical applications in SGs.
authors.affiliation: Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Voutetakis
authors.forename: C
authors.initials: C
authors.lastname: Zheng
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: C M
authors.initials: CM
authors.lastname: Goldsmith
authors.forename: S
authors.initials: S
authors.lastname: Afione
authors.forename: J A
authors.initials: JA
authors.lastname: Chiorini
authors.forename: M L
authors.initials: ML
authors.lastname: Wenk
authors.forename: M
authors.initials: M
authors.lastname: Vallant
authors.forename: R D
authors.initials: RD
authors.lastname: Irwin
authors.forename: B J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000818:Animals; D001769:Blood / Q000821:virology; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics; D004435:Eating; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007267:Injections; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012463:Saliva / Q000821:virology; D012727:Sex Characteristics; D013363:Submandibular Gland / Q000378:metabolism* / Q000821:virology*; D014018:Tissue Distribution / Q000235:genetics
chemical_list: D004921:Erythropoietin