Evidence map›Paper›PMID 41994868›Full record

ArticleNucleic acids research2026

Acyclic serinol nucleic acid modification of siRNAs overcomes seed region mediated off-target effects while maintaining potency.

Tyler Chickering, Joel M Harp, Yongfeng Jiang, June Qin, Guo He, Sarah Hyde, Audrey Ihlefeld, Maja Janas, Derek K O'Flaherty, Sally Schofield and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nucleic acids research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed.

  1. Review
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

18 authors.

Tyler ChickeringAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Joel M HarpDepartment of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232, United States.
Yongfeng JiangAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
June QinAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Guo HeAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Sarah HydeAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Audrey IhlefeldAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Maja JanasAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Derek K O'FlahertyAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0000-0003-3693-6380
Sally SchofieldAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
John SzetoAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Christopher S TheileAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.
Klaus CharisséAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0009-0002-7836-259X
Vasant JadhavAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0000-0002-6666-0250
Martin A MaierAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0000-0002-4987-0184
Muthiah ManoharanAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0000-0002-7931-1172
Martin EgliDepartment of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232, United States.ORCID 0000-0003-4145-356X
Mark K SchlegelAlnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, United States.ORCID 0000-0002-0127-608X

Funding

Alnylam Pharmaceuticals
6 · The paper itself

Abstract

Similar in structure to both glycol nucleic acid (GNA) and peptide nucleic acid (PNA), serinol nucleic acid (SNA) combines the acyclic flexibility of GNA with the amide bond found in PNA and can form stable heteroduplexes with DNA and RNA. While the thermal and metabolic stability of SNA and SNA-modified heteroduplexes has been previously reported, we here describe the application of SNA in RNA interference (RNAi) using GalNAc-conjugated small interfering RNAs (siRNAs). Single incorporations were evaluated at each position across both the guide and passenger strands and subsequently evaluated at key positions in mice. Additionally, the off-target potential of siRNAs containing SNA was assessed. We demonstrate the position-dependent tolerance of SNA inside both the guide and passenger strands, and more specifically, high tolerance of SNA incorporation in the seed region of the guide strand, preserving on-target activity while mitigating microRNA-like off-target effects. Furthermore, the crystal structure of an RNA dodecamer containing a single SNA nucleotide was obtained and the resulting SNA structure was used to explain the activity of SNA containing siRNAs. Thus, SNA constitutes another viable modification in the siRNA toolbox for the development of potent and specific RNAi therapeutics.

Indexed as

RNA InterferenceRNA, Small InterferingAcetylgalactosamineAnimalsMiceModels, MolecularPropanolaminesPropylene GlycolsAcetylgalactosaminePropanolaminesPropylene GlycolsRNA, Small Interferingserinol

Identifiers

PMID41994868
PMCPMC13096799

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
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.