A central focus of Isis’ research efforts is the continued advancement of antisense chemistry to improve the potency and therapeutic index of antisense drugs. One way to improve a drug’s therapeutic index is to deliver it selectively to specific tissues and cells of interest. Following systemic administration (e.g., intravenous or subcutaneous), antisense drugs distribute broadly to tissues throughout the body, with highest levels of accumulation in liver, kidneys, spleen and bone marrow. Although antisense drugs do not cross the blood-brain barrier into the central nervous system (CNS), they do distribute broadly in the CNS when delivered into the cerebral spinal fluid by intrathecal administration.
Tissues are made up of different types of cells, and developing the optimal chemistry to maximize delivery and targeting of antisense drugs to the ‘right’ tissue and cell type can further improve the drug’s potency. To this end, Isis scientists have created LICA technology. LICA is a suite of new chemistries designed to enhance targeting of antisense drugs to specific tissues and cells. Results from Isis’ first demonstration of LICA chemistry targeting the liver using an antisense oligonucleotide conjugate prototype chemistry, triantennary N-acetyl galactosamine (GalNAc) conjugation, are published as a ‘Breakthrough Article’ in Nucleic Acids Research. GalNAc is a high affinity ligand for the asialoglycoprotein receptor (ASGPR). ASGPR is highly expressed in hepatocytes and previous preclinical and clinical studies have demonstrated successful targeted delivery of various compounds into hepatocytes using GalNAc conjugation.
In the Nucleic Acids Research article, Isis scientists demonstrated that GalNAc-conjugated antisense drugs exhibited ~10-fold improved potency and increased duration of pharmacological effect in suppressing apolipoprotein C-III and transthyretin protein expression in the liver of transgenic mice. The improved potency is a result of targeted delivery of GalNAc-conjugated antisense compounds to hepatocytes. Because the majority of genes of therapeutic interest are expressed in hepatocytes, GalNAc conjugation can deliver antisense compounds more precisely to hepatocytes, and thereby produce the greatest effect on their intended target.
These results demonstrate the success of Isis’ new LICA technology in improving the potency and duration of effect of antisense drugs. GalNAc conjugation has the potential to significantly improve the therapeutic index, reduce therapy costs, and support a monthly dosing schedule for suppression of liver gene targets in man.
The journal article titled, “Targeted Delivery of Antisense Oligonucleotides to Hepatocytes Using Tri-antennary N-Acetyl Galactosamine Improves Potency 10-fold in Mice” is now available at Nucleic Acids Research.
Prakash, T.P. et al. (2014) Targeted Delivery of Antisense Oligonucleotides to Hepatocytes Using Tri-antennary N-Acetyl Galactosamine Improves Potency 10-fold in Mice. Nucleic Acids Research.