Abstract
Triantennary N-acetyl galactosamine (GalNAc, GN3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6–10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2′-O-Et-2′,4′-bridged nucleic acid) gapmer ASOs, ∼60-fold enhancement in potency relative to the parent MOE (2′-O-methoxyethyl RNA) ASO was observed. GN3-conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3-ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3-ASO conjugate was detected in plasma suggesting that GN3 acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.
Highlights
Antisense oligonucleotides (ASOs) are short chemically modified oligonucleotides that bind to complementary RNA in cells via Watson-Crick base-pairing and modulate RNA function to produce a pharmacological effect [1]
We examined if GalNAc conjugation could be utilized for targeted delivery of second-generation ASOs to hepatocytes and if this could enhance ASO potency in animal models
SRB1M is a fully PS-modified ASO with a 10-base DNA gap flanked on each end with 5 MOE nucleotides targeting scavenger receptor B1 (SRB1) mRNA
Summary
Antisense oligonucleotides (ASOs) are short chemically modified oligonucleotides that bind to complementary RNA in cells via Watson-Crick base-pairing and modulate RNA function to produce a pharmacological effect [1]. There are currently over 30 second-generation ASOs at various stages of clinical development for the treatment of cardiovascular, diabetes, cancer and several rare and orphan disease indications. Half of these ASOs target genes that are predominantly expressed by hepatocytes in the liver––an organ that plays a central role in metabolism and in the synthesis and secretion of carrier proteins, coagulation factors, hormones and apolipoproteins [6]. PS ASOs accumulate preferentially in the non-parenchymal (np) cells of the liver [8], which do not express majority of the gene targets of therapeutic interest
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