Evidence map›Paper›PMID 29459660›Full record

ArticleNature communications2018

Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

Maja M Janas, Mark K Schlegel, Carole E Harbison, Vedat O Yilmaz, Yongfeng Jiang, Rubina Parmar, Ivan Zlatev, Adam Castoreno, Huilei Xu, Svetlana Shulga-Morskaya and 5 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 155 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
155citing papers in PubMed, 1 pooled it
8.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

155 citing papers in PubMed, 1 synthesis or guideline pooled it, 256 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Trial
  4. Trial
  5. Review
  6. Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Review
  12. Article
  13. Review
  14. DNA Nanostructures for siRNA Delivery.Bioconjugate chemistry · 2026
    Review
  15. Divalent siRNA for prion disease.Nucleic acids research · 2026
    Article
  16. Article
  17. Article
  18. Article
  19. Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026
    Article
  20. Review

95 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 1 institution in 1 country.

Maja M JanasAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Mark K SchlegelAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Carole E HarbisonAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Vedat O YilmazAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Yongfeng JiangAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Rubina ParmarAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Ivan ZlatevAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.ORCID http://orcid.org/0000-0003-2797-3032
Adam CastorenoAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Huilei XuAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Svetlana Shulga-MorskayaAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Kallanthottathil G RajeevAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Muthiah ManoharanAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Natalie D KeirsteadAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Martin A MaierAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
Vasant JadhavAlnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA. vjadhav@alnylam.com.
Alnylam Pharmaceuticals (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

Indexed as

AcetylgalactosamineAnimalsLiverMaleRatsRats, Sprague-DawleyRNA InterferenceRNA, Small InterferingAcetylgalactosamineRNA, Small Interfering

Identifiers

PMID29459660
PMCPMC5818625
OpenAlexW2802881274

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.