Antisense Oligonucleotide의 간으로의 송달 = Hepatic Delivery of Antisense Oligonucleotide

다국어 초록 (Multilingual Abstract)

Chronic viral hepatitis caused by hepatitis B, C or D virus may lead to cirrhosis, hepatocellular failure and hepatocellular carcinoma. Gene therapy using antisense oligonucleotides are currently being evaluated for the treatment of viral diseases such as hepatitis B.
Antisense oligonucleotides are short sequences of nucleic acid that bind to (hybridize) cytosolic mRNA sense strand through hydrogen bonding to complementary nucleic acid bases and interfere with mRNA sense strand to regulate the synthesis of a specific protein. As a result, antisense oligonucleotides may inhibit the expression of the HBV genes. However major limitations in the effective use of antisense nucleic acids as inhibitors of gene expression in the clinic include their poor biological stability and their inefficient delivery to target cells. Strategies available for oligonucleotide delivery to target cells include : (a) high concentration : (b) modification of structure : and (c) conjugation to a transport vector via high affinity binding such as avidin-biotin binding.
The present studies describe attempts to elevate the stability and targeting of antisense oligonucleotide by biotinylation, avidin-biotin system and lactosylation via receptor-mediated endocytosis. The stability of antisense oligonucleotide was tested by ELISA based on the secreted hepatitis B virus surface antigen (HBsAg) in PLC/PRF/5 cell line.
Antisense-HBsAg (15 mer) reduced in a dose-dependent manner the secretion of HBsAg in PLC/PRF/5 cell line. Similarly biotinylated antisense-HBsAg resulted in HBsAg inhibition. But Lactosylated avidin-biotinylated antisense complex was more effective on HBsAg inhibition than antisense or biotinylated antisense.
The results indicate that the increased HBsAg inhibition effect of antisense resulted in enhanced stability of oligonucleotide.