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PMID: 15960598 Published · ppublish English Evaluation Study Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Evaluation of biodistribution and safety of adenovirus vectors containing group B fibers after intravenous injection into baboons.

Human gene therapy ·Vol. 16 ·No. 6 ·2005-06-00 ·Pages 664-77

Ni S, Bernt K, Gaggar A, Li ZY, Kiem HP, Lieber A

Abstract

Vectors containing group B adenovirus (Ad) fibers are able to efficiently transduce gene therapy targets that are refractory to infection with standard Ad serotype 5 (Ad5) vectors, including malignant tumor cells, hematopoietic stem cells, and dendritic cells. Preliminary studies in mice indicate that, after intravenous injection, B-group fiber-containing Ads do not efficiently transduce most organs and cause less acute toxicity than Ad5 vectors. However, biodistribution and safety studies in mice are of limited value because the mouse analog of the B-group Ad receptor, CD46, is expressed only in the testis, whereas in humans, CD46 is expressed on all nucleated cells. Unlike mice, baboons have CD46 expression patterns and levels that closely mimic those in humans. We conducted a biodistribution and toxicity study of group B Ad fiber-containing vectors in baboons. Animals received phosphate-buffered saline, Ad5-bGal (a first-generation Ad5 vector), or B-group fiber-containing Ads (Ad5/35-bGal and Ad5/11-bGal) at a dose of 2 x 10(12) VP/kg, and vector biodistribution and safety was analyzed over 3 days. The amount of Ad5/35-bGal and Ad5/11-bGal vector genomes was in most tissues one to three orders of magnitude below that of Ad5. Significant Ad5/35- and Ad5/11-mediated transgene (beta-galactosidase) expression was seen only in the marginal zone of splenic follicles. Compared with the animal that received Ad5-bGal, all animals injected with B-group fiber-containing Ad vectors had lower elevations in serum proinflammatory cytokine levels. Gross and histopathology were normal in animals that received B-group Ad fiber-containing Ads, in contrast to the Ad5-infused animal, which showed widespread endothelial damage and inflammation. In a further study, a chimeric Ad5/35 vector carrying proapoptotic TRAIL and Ad E1A genes under tumor-specific regulation was well tolerated in a 30-day toxicity study. No major clinical, serologic, or pathologic abnormalities were noticed in this animal.

MeSH Terms
Adenoviridae/genetics Animals Bone Marrow Cells/drug effects,metabolism DNA Helicases/genetics Escherichia coli Proteins Genetic Vectors/administration & dosage,pharmacokinetics Injections, Intravenous Male Papio Tissue Distribution Toxicity Tests beta-Galactosidase/blood,genetics,pharmacokinetics
Chemicals
Escherichia coli Proteins beta-Galactosidase TraI protein, E coli DNA Helicases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ni Shaoheng
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Bernt Kathrin
Gaggar Anuj
Li Zong-Yi
Kiem Hans-Peter
Lieber André
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Article Info
Journal
Human gene therapy
Abbr.
Hum Gene Ther
ISSN
1043-0342
DOI
10.1089/hum.2005.16.664
Published
2005-06-00
Pages
664-77
Language
English
Region
United States
NLM ID
9008950
PMCID
PMC1351080
Subset
IM
Grants
NHLBI NIH HHS · P01 HL53750 · United States
NHLBI NIH HHS · U01 HL066947 · United States
NHLBI NIH HHS · P01 HL053750 · United States
NHLBI NIH HHS · HL-00-008 · United States
NHLBI NIH HHS · R01 HL078836 · United States
NCI NIH HHS · R01 CA144057 · United States
External Links
PubMed source DOI: 10.1089/hum.2005.16.664 PMC Full Text View journal details
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