Evidence map›Paper›PMID 28436437›Full record

ArticleScientific reports2017

Allele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells.

James R C Miller, Edith L Pfister, Wanzhao Liu, Ralph Andre, Ulrike Träger, Lori A Kennington, Kimberly Lo, Sipke Dijkstra, Douglas Macdonald, Gary Ostroff and 2 more

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

Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.9field-weighted citation impact, top 16% 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

15 citing papers in PubMed, 26 citations in OpenAlex.

  1. Article
  2. Article
  3. Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.International journal of molecular sciences · 2024
    Review
  4. Review
  5. Full-Length Transcript Phasing with Third-Generation Sequencing.Methods in molecular biology (Clifton, N.J.) · 2023
    Article
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Review
  14. Review
  15. Gene suppression approaches to neurodegeneration.Alzheimer's research & therapy · 2017
    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

12 authors at 4 institutions in 3 countries.

James R C MillerDepartment of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
Edith L PfisterRNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Wanzhao LiuRNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Ralph AndreDepartment of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
Ulrike TrägerDepartment of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
Lori A KenningtonRNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Kimberly LoCharles River, Leiden, The Netherlands.
Sipke DijkstraCharles River, Leiden, The Netherlands.
Douglas MacdonaldCHDI Management/CHDI Foundation, Los Angeles, CA, USA.
Gary OstroffProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Neil AroninRNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Sarah J TabriziDepartment of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
University of Massachusetts Chan Medical School · USUniversity College London · GBCharles River Laboratories (Netherlands) · NLCHDI Foundation · US

Funding

Medical Research Council MR/L02053X/1Medical Research Council MR/P007015/1Wellcome Trust 200181/Z/15/Z
6 · The paper itself

Abstract

Post-transcriptional gene silencing is a promising therapy for the monogenic, autosomal dominant, Huntington's disease (HD). However, wild-type huntingtin (HTT) has important cellular functions, so the ideal strategy would selectively lower mutant HTT while sparing wild-type. HD patients were genotyped for heterozygosity at three SNP sites, before phasing each SNP allele to wild-type or mutant HTT. Primary ex vivo myeloid cells were isolated from heterozygous patients and transfected with SNP-targeted siRNA, using glucan particles taken up by phagocytosis. Highly selective mRNA knockdown was achieved when targeting each allele of rs362331 in exon 50 of the HTT transcript; this selectivity was also present on protein studies. However, similar selectivity was not observed when targeting rs362273 or rs362307. Furthermore, HD myeloid cells are hyper-reactive compared to control. Allele-selective suppression of either wild-type or mutant HTT produced a significant, equivalent reduction in the cytokine response of HD myeloid cells to LPS, suggesting that wild-type HTT has a novel immune function. We demonstrate a sequential therapeutic process comprising genotyping and mutant HTT-linkage of SNPs, followed by personalised allele-selective suppression in a small patient cohort. We further show that allele-selectivity in ex vivo patient cells is highly SNP-dependent, with implications for clinical trial target selection.

Indexed as

Polymorphism, Single NucleotideAdultAgedAllelesCells, CulturedCohort StudiesGenotypeHumansHuntingtin ProteinHuntington DiseaseMiddle AgedMutant ProteinsMyeloid CellsRNA InterferenceHTT protein, humanHuntingtin ProteinMutant Proteins

Identifiers

PMID28436437
PMCPMC5402279
OpenAlexW2607684571

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.