Evidence map›Paper›PMID 41124364›Full record

ArticleBrain : a journal of neurology2026

Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model.

Jinhong Meng, Shunyi Ma, Museer A Lone, Hou Wang Lam, Qiang Zhang, Shuzhi Cheng, Shona Mackie, Emma Graham, Hanna Kedzior, Charalambos Demetriou and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

20 authors.

Jinhong MengGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Shunyi MaGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Museer A LoneInstitute for Clinical Chemistry, University Hospital and University of Zürich, 8006 Zürich, Switzerland.ORCID 0000-0001-9710-775X
Hou Wang LamGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Qiang ZhangGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Shuzhi ChengGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Shona MackieGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Emma GrahamGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Hanna KedziorGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Charalambos DemetriouGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Nicole ZiakInstitute for Clinical Chemistry, University Hospital and University of Zürich, 8006 Zürich, Switzerland.
Laura AndreoliDepartment of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Simon BeggsDepartment of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Stephanie KochDepartment of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Alex J ClarkCentre of Neuroscience, Surgery and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, London E1 2AT, UK.
David L BennettNeural Injury Group, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.ORCID 0000-0002-7996-2696
Thorsten HornemannInstitute for Clinical Chemistry, University Hospital and University of Zürich, 8006 Zürich, Switzerland.ORCID 0000-0002-4218-1087
Francesco MuntoniNIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Mary M ReillyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.ORCID 0000-0003-0686-905X
Haiyan ZhouGenetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.ORCID 0000-0001-8440-3074

Funding

Biomedical Research CentreHarrington Discovery InstituteMedical Research Council MR/X008029/1Medical Research Council MR/Y008405/1NIHR Great Ormond Street HospitalRosetrees Trust PGL24/100137RTW Charitable FoundationUniversity College London
6 · The paper itself

Abstract

Hereditary sensory neuropathy type IA (HSN1A) is a rare neurodegenerative condition caused by dominant mutations in the Serine Palmitoyl Transferase Long Chain base subunit 1 (SPTLC1) gene. There is no treatment available. Allele-specific silencing by antisense oligonucleotides (ASOs) to preferentially silence the mutant transcripts has shown therapeutic promise for dominant gain-of-function genetic disorders. In this study, we validated an allele-specific ASO therapy to selectively silence mutant SPTLC1 (p.S331F) in a disease mouse model carrying a heterozygous p.S331F mutation (S331F mice). Gapmer ASOs, targeting the S331F variant in either 2'-O-methyl (2'-OMe), locked nucleic acid (LNA) or 2'-O-methoxy ethyl (MOE) chemistries, were first studied in cultured mouse skin fibroblasts. The candidate ASOs in LNA or MOE were further evaluated in vivo. Single subcutaneous injection of ASOs into neonatal or adult S331F mice achieved over 90% mutant transcript silencing in liver and dorsal root ganglia (DRG). Weekly subcutaneous injections of LNA-ASOs, either unconjugated or conjugated with N-acetylgalactosamine (GalNAc), into S331F mice showed GalNAc-LNA-ASOs to be more efficient than unconjugated LNA-ASOs at reducing mutant transcripts in liver, DRG and sciatic nerve, without affecting wild-type transcripts. GalNAc-LNA-ASOs also resulted in significantly reduced blood levels of 1-deoxysphingoid bases (1-deoxySL), neurotoxic metabolites used as biomarkers in HSN1A patients. Transcriptomic studies in DRG demonstrated mitochondrial pathway involvement in the pathological changes observed in S331F mice. Quantitative RT-PCR confirmed the differentially expressed genes between S331F and wild-type mice. Furthermore, these aberrantly expressed genes in S331F mice were reversed by GalNAc-LNA-ASO treatment. Our data provide necessary in vivo evidence as proof of concept for ASO-mediated mutant-allele-specific silencing as a therapeutic approach for SPTLC1-related HSN1.

Indexed as

Hereditary Sensory and Autonomic NeuropathiesOligonucleotides, AntisenseSerine C-PalmitoyltransferaseAnimalsDisease Models, AnimalFemaleFibroblastsGanglia, SpinalHumansMaleMiceMice, Inbred C57BLMutationOligonucleotides, AntisenseSerine C-Palmitoyltransferaseallele specific silencingantisense oligonucleotide (ASO)biodistributionmouse modelneurodegenerative disorderperipheral neuropathy

Identifiers

PMID41124364
PMCPMC13233042

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Registered trials

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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.