Pulmonary delivery of adenovirus vector formulated with dexamethasone-spermine facilitates homologous vector re-administration.
Gene transfer to lung has been hindered by inflammatory and immunological responses activated to the gene-transfer agent or transgene products. In prior work, adenovirus vector delivered to the lung with the cationic glucocorticoid, dexamethasone-spermine (DS) had improved targeting to conducting airway epithelium and reduced cellular infiltration. In this study, the effect of formulation on homologous adenovirus vector re-administration was studied in C57Bl/6 mice. Formulation of an adenovirus vector expressing LacZ with DS/dioleoylphosphatidylethanolamine (DOPE) delivered at day 0 allowed re-administration of adenovirus vector expressing alkaline phosphatase at day 21. Formulation with 3beta [N-(N', N'-dimethylaminoethane) carbamoy] cholesterol (DC-Chol) DC-cholesterol (DC-Chol))/DOPE or dexamethasone in the first dosing at day 0 resulted in moderate alkaline phosphatase expression at day 24. Neutralizing antibodies against adenovirus vector in serum at day 28 were greatly reduced by all three formulations in mice receiving a single dose of adenovirus at day 0. Also, homologous adenovirus vector re-administration at day 14 produced less neutralizing antibody at day 28 when adenovirus was formulated with DS/DOPE at day 0. The use of DS/DOPE at day 0 dramatically reduced CD4 and CD8 T-cell infiltration in mice receiving adenovirus at day 0 followed by vector re-administration at day 14. Transgene-specific T-cell activation was markedly reduced by the DC-Chol/DOPE formulation. Overall, DS/DOPE) facilitated homologous vector re-administration through a combination of liposomal and glucocorticoid mechanisms.
Price
A R
AR
Department of Bioengineering, Institute for Medicine and Engineering, Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA.
Limberis
M P
MP
Wilson
J M
JM
Diamond
S L
SL
D000256:Adenoviridae / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000097:blood; D002784:Cholesterol / Q000031:analogs & derivatives; D003550:Cystic Fibrosis / Q000276:immunology / Q000628:therapy*; D003907:Dexamethasone; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents; D008081:Liposomes; D008168:Lung / Q000201:enzymology* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010714:Phosphatidylethanolamines; D013096:Spermine; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000906:Antibodies; D007166:Immunosuppressive Agents; D008081:Liposomes; D010714:Phosphatidylethanolamines; C070648:3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol; D013096:Spermine; D003907:Dexamethasone; D002784:Cholesterol; D000469:Alkaline Phosphatase