Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

SNAs Are a Hopeful First Step in Boosting the Utility of Oligonucleotides to Treat a Variety of Human Diseases

Gene-silencing oligonucleotides (oligos) offer exciting new prospects for novel therapeutics, including cancer, viral infections, autoimmune diseases, and cardiovascular disorders. But despite their potential role in treating diseases resulting from dysregulated gene expression, the clinical use of oligos and small interfering (siRNAs) remains extremely challenging.

Challenges for Oligo and siRNA Drug Development

Barriers to clinical use of siRNAs, including drug delivery, poor cellular uptake, instability under physiological conditions, off-target effects, and possible immunogenicity, have led some large pharma companies to cut their commitments to siRNA drug development.

Most recently Alnylam announced in October of 2016 that it had halted development of its revusiran, an investigational RNA interference (RNAi) therapeutic targeting transthyretin (TTR), for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). Revusiran employs a siRNA targeting wild-type and all mutant forms of TTR and uses the company’s proprietary N-acetylgalactosamine (GalNAc)-conjugate delivery platform.

This life-threatening disease results from misfolded TTR proteins that accumulate as amyloid fibrils in multiple organs, but specifically in the peripheral nerves and heart. A Phase III trial of revusiran in the rare disease hATTR-CM, which can cause nerve and heart damage, showed that more patients died on the drug than on placebo.

The company continues clinical development of patisiran, a siRNA encapsulated in a lipid nanoparticle (LNP) and delivered intravenously. LNPs are opsonized by apolipoprotein E (ApoE) and are delivered to the liver through interaction with ApoE receptors expressed on hepatocytes. The company’s Phase III APOLLO trial testing patisiran in familial amyloidotic polyneuropathy (FAP) is ongoing, with top-line data anticipated by the middle of 2017.

And on October 20, 2016, Alnylam announced that the Data Monitoring Committee (DMC) for the Phase III APOLLO study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN) met on October 7, 2016, and recommended continuation of the trial without modification.

For this complete article as published in the November 15 issue of GEN click here.

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.

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