From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization.

Animals Rats RNA, Small Interfering / genetics

Journal

Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011

Informations de publication

Date de publication:
08 07 2022
Historique:
accepted: 09 06 2022
revised: 02 06 2022
received: 01 02 2022
pubmed: 24 6 2022
medline: 15 12 2022
entrez: 23 6 2022
Statut: ppublish

Résumé

Preclinical mechanistic studies have pointed towards RNA interference-mediated off-target effects as a major driver of hepatotoxicity for GalNAc-siRNA conjugates. Here, we demonstrate that a single glycol nucleic acid or 2'-5'-RNA modification can substantially reduce small interfering RNA (siRNA) seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established hepatotoxicity driven by off-target effects, these novel designs with seed-pairing destabilization, termed enhanced stabilization chemistry plus (ESC+), demonstrated a substantially improved therapeutic window in rats. In contrast, siRNAs thermally destabilized to a similar extent by the incorporation of multiple DNA nucleotides in the seed region showed little to no improvement in rat safety suggesting that factors in addition to global thermodynamics play a role in off-target mitigation. We utilized the ESC+ strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient and asymptomatic alanine aminotransferase elevations in healthy volunteers. The redesigned ALN-HBV02 (VIR-2218) showed improved specificity with comparable on-target activity and the program was reintroduced into clinical development.

Identifiants

DOI: 10.1093/nar/gkac539 PMID: 35736224 PMC: PMC9262600
pubmed: 35736224
pii: 6613918
doi: 10.1093/nar/gkac539
pmc: PMC9262600
doi:

Substances chimiques

RNA, Small Interfering 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

6656-6670

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

Auteurs

Mark K Schlegel (MK)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
ORCID: 0000-0002-0127-608X

Maja M Janas (MM)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Yongfeng Jiang (Y)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Joseph D Barry (JD)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Wendell Davis (W)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Saket Agarwal (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Daniel Berman (D)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Christopher R Brown (CR)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
ORCID: 0000-0001-6076-4035

Adam Castoreno (A)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Sarah LeBlanc (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Abigail Liebow (A)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Tara Mayo (T)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Stuart Milstein (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Tuyen Nguyen (T)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Svetlana Shulga-Morskaya (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Sarah Hyde (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Sally Schofield (S)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

John Szeto (J)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Lauren Blair Woods (LB)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Vedat O Yilmaz (VO)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Muthiah Manoharan (M)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
ORCID: 0000-0002-7931-1172

Martin Egli (M)

Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
ORCID: 0000-0003-4145-356X

Klaus Charissé (K)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Laura Sepp-Lorenzino (L)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Patrick Haslett (P)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Kevin Fitzgerald (K)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Vasant Jadhav (V)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
ORCID: 0000-0002-6666-0250

Martin A Maier (MA)

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
ORCID: 0000-0002-4987-0184

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › From bench to bedside: Improving the clinical...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › From bench to bedside: Improving the clinical...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › From bench to bedside: Improving the clinical...