Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".