Abstract
Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved by the targeted delivery of ASOs to selected tissues. One example is the targeted delivery of ASOs to hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO, which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The activity of GalNAc-conjugated ASOs was superior to that of the unconjugated parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (−) cells. Both human- and mouse-derived HCC displayed reduced levels of ASGR, however, despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both enhanced antisense activity and antitumor activity in the diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced ASO activity in human circulating tumor cells from HCC patients, demonstrating the potential of this approach in primary human HCC tumor cells. Taken together, these results provide a strong rationale for a potential therapeutic use of GalNAc-conjugated ASOs for the treatment of HCC.
Highlights
The incidence of hepatocellular carcinoma (HCC) has been rising, in the western world, partly due to increases in both obesity and alcohol consumption.[1]
To determine if the level of asialoglycoprotein receptor (ASGR) expression influences or limits the activity of GalNAc-conjugated Antisense oligonucleotides (ASOs), we identified a panel of human HCC lines with varying levels
We investigated if the activity of ASO could be improved with GalNAc conjugation in tumor cells growing in culture, as observed in normal liver.[7]
Summary
The incidence of hepatocellular carcinoma (HCC) has been rising, in the western world, partly due to increases in both obesity and alcohol consumption.[1]. The efficacy of multiple ASO drugs has been demonstrated in numerous clinical studies, and, the antisense drugs Spinraza and Tegsedi have recently been approved as treatments for patients with spinal muscular atrophy (SMA) and patients with polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR), respectively.[4,5] liver is one of the primary target organs to nucleic acidbased drugs such as ASOs,[6] a high percentage of ASO is distributed to nonparenchymal cells following systemic administration of the drug.[7,8] the activity of ASO targeted to a hepatocyte gene can be further improved if the ASO is delivered into hepatocytes with greater selectivity
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