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Mar 24, 2016
 |  BC Innovations  |  Product R&D

Liver-bound

Ionis sweetens hepatocyte uptake of its liver-targeting antisense oligos

Ionis Pharmaceuticals Inc. is retooling its antisense technology with a sugar-based conjugate that boosts uptake into liver cells. By tapping the power of GalNAc sugars to latch onto hepatocyte receptors, the company believes it can increase the activity of its liver-targeting portfolio. Next, it plans to find new targeting handles to extend the strategy to other tissues.

Last month, the company published details of the new technology in the Journal of Medicinal Chemistry. The Ionis team screened N-acetylgalactosamine (GalNAc) conjugates with a variety of scaffold, spacer and ASO linker chemistries, and selected THA-GN3 to promote tissue-specific delivery by linking it to the 5' end of liver-targeted ASOs.

THA-GN3 contains a tris(hydroxymethyl)aminomethane scaffold that branches into three N-hexylamine spacer chains, each capped by a GalNAc sugar. The scaffold is conjugated to an ASO via a hexylamino phosphodiester linker (see Figure: Key to the liver).

Ionis' antisense oligonucleotide (ASO) compounds suppress target gene expression by hybridizing to mRNA, leading to mRNA inactivation via degradation of other mechanisms. The company is incorporating THA-GN3 into at least eight of its liver-targeted compounds, covering a wide range of disease indications (see Table: Ionis' sweetened goods).In November, Ionis showed one of these compounds, IONIS-APO(a)-LRx, had a more than 30-fold higher potency in Phase I/IIa testing for cardiovascular disease than its parent molecule.

Earlier iterations of Ionis' technology have involved enhancing the ASO itself by introducing chemical modifications such as phosphorothioate chemistry that boosts ASO stability, and 2'-O-methoxyethyl (2'MOE) chemistry that increases ASO affinity for RNA targets.

According to VP of Medicinal Chemistry Eric Swayze, the THA-GN3 conjugate is the start of a new tissue-targeting strategy for the company's platform, dubbed ligand-conjugated antisense (LICA) technology.

"LICA is a concept where you could target an oligonucleotide to a specific cell population or tissue, and GalNac is one means to do that, to get it specifically to a hepatocyte," Swayze told BioCentury. "We view LICA as the genus, and the...

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