Assessing Hybridization-Dependent Off-Target Risk for Therapeutic Oligonucleotides: Updated Industry Recommendations.

Patrik Andersson¹, Sebastien A Burel², Heather Estrella³, Jeffrey Foy⁴, Peter H Hagedorn⁵, Tod A Harper³, Scott P Henry², Jean-Christophe Hoflack⁶, Erle M Holgersen⁷, Arthur A Levin⁸, Eliot Morrison⁹, Adam Pavlicek¹⁰, Luca Penso-Dolfin⁹, Utsav Saxena¹¹

¹AstraZeneca R&D, Gothenburg, Sweden.

²Ionis Pharmaceuticals, Carlsbad, California, USA.

³Amgen, Thousand Oaks, California, USA.

⁴PepGen Inc., Boston, Massachusetts, USA.

⁵Contera Pharma, Hørsholm, Denmark.

⁶Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.

⁷Deep Genomics, Toronto, Canada.

⁸Avidity Biosciences, San Diego, California, USA.

⁹Silence Therapeutics, Berlin, Germany.

¹⁰Monoceros Biosystems, San Diego, California, USA.

¹¹Dicerna Pharmaceuticals, a Novo Nordisk Company, Lexington, Massachusetts, USA.

PubMed DOI

Abstract

Hybridization-dependent off-target (OffT) effects, occurring when oligonucleotides bind via Watson-Crick-Franklin hybridization to unintended RNA transcripts, remain a critical safety concern for oligonucleotide therapeutics (ONTs). Despite the importance of OffT assessment of clinical trial ONT candidates, formal guidelines are lacking, with only brief mentions in Japanese regulatory documents (2…

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