Targeted delivery of antisense DNA in woodchuck hepatitis virus-infected woodchucks.
An asialoglycoprotein-based DNA delivery system containing an antisense oligo DNA against the polyadenylation region and adjacent upstream sequences of woodchuck hepatitis virus (WHV) was prepared. Experimental woodchucks were inoculated neonatally with the woodchuck virus 23 weeks before initiating the study, and all animals subsequently developed hepatitis as evidenced by the presence of measurable levels of circulating viral DNA. Animals were injected intravenously (i.v.) with asialoorosomucoid (AsOR)-poly-L-lysine complexes containing 0.1 mg kg-1 antisense DNA for five consecutive days. Levels of surface antigen did not differ substantially between treated and control animals. However, intravenous administration of complexed antisense DNA significantly decreased viraemia, as shown by a five- to 10-fold decrease in circulating viral DNA 25 days post treatment. The decline lasted for at least 2 weeks, after which there was a gradual increase in DNA levels. Antisense DNA alone or a complex containing a random oligo DNA of the same size and linkage failed to have any significant effect on viral DNA levels. We conclude that antisense oligo DNA can be targeted to the liver in vivo, resulting in a substantial and prolonged decrease in viral DNA levels in WHV-infected woodchucks.
Bartholomew
R M
RM
Department of Gene Therapy, TargeTech, Inc./The Immune Response Corporation, Carlsbad, CA, USA.
Carmichael
E P
EP
Findeis
M A
MA
Wu
C H
CH
Wu
G Y
GY
D000818:Animals; D001212:Asialoglycoproteins / Q000008:administration & dosage; D001483:Base Sequence; D016373:DNA, Antisense / Q000008:administration & dosage* / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015967:Gene Expression Regulation, Viral; D018963:Hepatitis Antigens / Q000032:analysis; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology*; D017919:Hepatitis B Virus, Woodchuck; D006515:Hepatitis B virus / Q000737:chemistry*; D008297:Male; D008392:Marmota; D008969:Molecular Sequence Data; D014779:Virus Replication
D001212:Asialoglycoproteins; D016373:DNA, Antisense; D004279:DNA, Viral; D018963:Hepatitis Antigens