title: Assessment of the safety and biodistribution of a regulated AAV2 gene transfer vector after delivery to murine submandibular glands.
abstract: Clinical gene transfer holds promise for the treatment of many inherited and acquired disorders. A key consideration for all clinical gene transfer applications is the tight control of transgene expression. We have examined the safety and biodistribution of a serotype 2, recombinant adeno-associated viral (AAV2) vector that encodes a rapamycin-responsive chimeric transcription factor, which regulates the expression of a therapeutic transgene (human erythropoietin [hEpo]). The vector, AAV2-TF2.3w-hEpo (2.5 × 10(7)-2.5 × 10(10) particles), was administered once to a single submandibular gland of male and female mice and mediated hEpo expression in vivo following a rapamycin injection but not in its absence. Control (saline treated) and vector-treated animals maintained their weight, and consumed food and water, similarly. Vector delivery led to no significant toxicological effects as judged by hematology, clinical chemistry, and gross and microscopic pathology evaluations. On day 3 after vector delivery, vector copies were not only abundant in the targeted right submandibular gland but also detected in multiple other tissues. Vector was cleared from the targeted gland much more rapidly in female mice than in male mice. Overall, our results are consistent with the notion that administration of the AAV2-TF2.3w-hEpo vector to salivary glands posed no significant risk in mice.
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, 20892, USA.
authors.forename: Changyu
authors.initials: C
authors.lastname: Zheng
authors.forename: Antonis
authors.initials: A
authors.lastname: Voutetakis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goldstein
authors.forename: Sandra
authors.initials: S
authors.lastname: Afione
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Martin L
authors.initials: ML
authors.lastname: Wenk
authors.forename: Molly
authors.initials: M
authors.lastname: Boyle
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: John A
authors.initials: JA
authors.lastname: Chiorini
authors.forename: Molly
authors.initials: M
authors.lastname: Vallant
authors.forename: Richard D
authors.initials: RD
authors.lastname: Irwin
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000818:Animals; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics*; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018570:Risk Assessment; D012737:Sex Factors; D020123:Sirolimus / Q000494:pharmacology; D013363:Submandibular Gland / Q000378:metabolism / Q000821:virology*; D018675:Toxicity Tests
chemical_list: D004921:Erythropoietin; D020123:Sirolimus