Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential.
Recombinant adenovirus (Ad) vectors are being considered for in vivo delivery of various therapeutic genes. One limiting factor in the development of Ad-based gene therapy is the low efficiency of gene transfer to target tissues such as vascular endothelium, smooth muscle, and airway epithelium. Complexing Ad vector with various polycations has been shown to enhance transduction of cell lines otherwise resistant to Ad infection in vitro. On the basis of this observation, the activity of Ad/polycation complexes was tested in vivo in the mouse lung. The results indicated that several polycations were capable of enhancing transduction of mouse respiratory epithelium, leading to a 1-2 log increase in levels of transgene expression. Poly-L-lysine (PLL) and DEAE-dextran were examined further and were found to increase Ad-mediated gene transfer without any additional toxicity as assessed histologically or through the measurement of inflammatory cytokines in bronchoalveolar lavages. The two polycations also failed to affect the humoral response against Ad vector and were themselves nonimmunogenic under conditions leading to enhanced gene transfer. Moreover, the ability to use reduced doses of vector complexed with polycations resulted in lower levels of Ad-specific antibodies and, thereby, improved readministration of vector. These results suggest that complexing Ad vectors with polycations has the potential to improve the therapeutic index by increasing transgene expression while reducing unwanted responses associated with high doses of vector.
Genzyme Corporation, Framingham, MA 01701-9322, USA.
J M
JM
Kaplan
S E
SE
Pennington
J A
JA
St George
L A
LA
Woodworth
A
A
Fasbender
J
J
Marshall
S H
SH
Cheng
S C
SC
Wadsworth
R J
RJ
Gregory
A E
AE
Smith
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003637:DEAE-Dextran / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D008168:Lung / Q000201:enzymology; D008239:Lysine / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D011108:Polymers / Q000494:pharmacology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D011108:Polymers; D003637:DEAE-Dextran; D001616:beta-Galactosidase; D008239:Lysine