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Isis Team Publishes 'Breakthrough' Report on GalNAc-conjugated Antisense Oligos

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NEW YORK (GenomeWeb) – Researchers from Isis Pharmaceuticals this week published new data demonstrating the ability of a novel GalNAc conjugate to boost the potency of antisense oligonucleotides (ASOs) — including two it currently has in human trials — by as much as 10 fold in mice.

The report, which appeared in Nucleic Acids Research, has been named as a breakthrough article by the journal's editors.

GalNAc conjugation is based on a sugar modification called N-acetyl galactosamine, which is a high-affinity ligand for the asialoglycoprotein receptors that are expressed on the surface of hepatocytes in all mammals. Efforts to take advantage of this system have long been explored, but heretofore have not been robust enough for clinical utility.

In recent years, however, a number of groups have had success optimizing the GalNAc approach, including Alnylam Pharmaceuticals, which is using its own GalNAc conjugates for siRNA delivery.

But Alnylam is not alone in working in this area, and now it appears that Isis has made significant strides of its own with the delivery technology.

"We had known from Alnylam's presentations at meetings that conjugation of GalNac to duplex RNAs significantly enhanced potency and improved the likelihood of developing successful drugs," David Corey, a professor at the University of Texas Southwestern Medical Center and editor of the Isis paper, told Gene Silencing News in an email.

Isis' paper represents a key milestone as it is the first published example of applying GalNAc to single-stranded RNA, he added. "It is reasonable to believe that antisense oligonucleotides conjugated to GalNac will have advantages for treating disease in the liver and that the conjugates will improve the odds that a suitably modified antisense drug will achieve substantial success."

Isis sees similar promise in GalNAc conjugation. According to Eric Swayze, the company's vice president of chemistry, if the improvement in potency observed in the mouse studies translates to humans, Isis expects it could achieve 20 mg per week, or about 0.3 mg/kg per week, dosing for its second-generation drugs.

"Furthermore, the long duration of action would support longer dosing intervals," he wrote in an email.

In the Nucleic Acids Research paper, the Isis team tested on a variety of different ASOs, including two that are currently under clinical development. These include one designed to silence human apolipoprotein C-III that is in Phase II testing for severe hypertriglyceridemia and familial chylomicronemia syndrometransthyretin; and another that inhibits human transthyretin (TTR) and is in Phase III studies as a treatment for TTR-associated polyneuropathy.

Triantennary N-acetyl galactosamine (GN3) modifications were found to enhance the potency of the company's second-generation ASOs — fully phosphorothioate-modified chimeric antisense molecules with a central gap region of eight to 14 phosphorothioate DNA nucleotides flanked on either end with two to five 5 2'-O-methoxyethyl RNA nucleotides — six to 10 fold in mouse livers.

When combined with next-generation ASO designs comprised of short S-2'-O-Et-2', 4'-bridged nucleic acid, or S-cEt, gapmer ASOs, the scientists observed a roughly 60-fold enhancement in potency relative to 2'-O-methoxyethyl RNA ASOs, according to the paper.

GN3-conjugated ASOs showed high affinity for mouse asialoglycoprotein receptors, resulting in enhanced 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," the Isis team wrote. "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."

Isis is currently working to fully characterize the pharmacokinetics/pharmacodynamics and toxicological properties of GalNAc-conjugated ASOs as it prepares to advance the technology toward human testing, the research team wrote in Nucleic Acids Research. "These enhancements in ASO potency and duration of action could significantly improve the therapeutic index, reduce therapy costs, and support a monthly dosing schedule for suppression of hepatic gene expression in man."

Swayze stated in his email that Isis is "aggressively moving forward with GalNAc technology for certain projects, as appropriate for the target, indication, and stage of development of the program." Specific programs that could feature the technology, however, remain undisclosed.

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