About the Model
What is ASO Therapy?
Antisense oligonucleotides (ASOs) are short synthetic nucleic acids that bind to mRNA to modulate gene expression. They can correct aberrant splicing, silence toxic genes, or upregulate insufficient protein production. Several ASO drugs are FDA-approved, including Nusinersen (for SMA) and Eteplirsen (for DMD).
How Predictions Work
This tool uses a two-level machine learning pipeline trained on 105 known ASO-amenable genes and 504,000+ pathogenic ClinVar variants:
- Gene-level PU learning: Nine Positive-Unlabeled (Elkan-Noto) classifiers predict amenability per ASO mechanism using gene constraint metrics (pLI, LOEUF), exon structure, expression data, and inheritance patterns.
- Variant-level XGBoost: Four mechanism-specific classifiers score individual variants based on molecular consequence, location, and gene-level priors.
- Combined score: Gene-level (40%) and variant-level (60%) scores are weighted to produce a final amenability score (0–100%).
Confidence Tiers
High (75-100%): Strong evidence of ASO amenability. Gene and variant features align with known ASO targets.
Medium (40-74%): Moderate evidence. Some features suggest amenability but with less certainty.
Low (0-39%): Limited evidence. The variant/gene is unlikely to be a strong ASO candidate with current approaches.
ASO Mechanisms
- Splice-Switching: Redirects spliceosome to correct aberrant splicing patterns.
- Exon-Skipping: Skips a mutated exon to produce a shorter but functional protein.
- Pseudoexon-Blocking: Blocks cryptic exon inclusion from deep intronic mutations.
- Gene-Silencing: Degrades mRNA of toxic gain-of-function genes.
- Gene-Silencing (Toxic RNA): Targets toxic repeat-expansion RNA aggregates.
- Upregulation (Poison Exon): Blocks NMD-inducing poison exons to increase expression.
- Upregulation (AntagoNAT): Inhibits natural antisense transcripts to de-repress gene.
- Gene Unsilencing: Reactivates epigenetically silenced genes.
Data Sources
- ClinVar pathogenic/likely pathogenic variants (NCBI)
- gnomAD gene constraint metrics (pLI, LOEUF, missense Z)
- Ensembl gene structure (exon counts, sizes) via BioMart
- GTEx median tissue expression (brain, liver)
- 105 curated ASO-amenable genes from published literature
Limitations
This is a research tool. Predictions should not be used for clinical decision-making without expert review. The model is trained primarily on known ASO targets and may underperform for novel mechanisms. Variant-level scoring requires the variant to be present in ClinVar.