Allele-specific ASO — experiment planner & coverage

Screening simulation

How much of a gene’s global patient population allele-selective ASOs can reach, given how many oligos you screen and how many survive. Coverage is haplotype-level: a patient counts ½ per haplotype carrying a targetable variant allele.

Gene

ASO filtersWhich oligos qualify for each candidate allele. Biallelic, footprint-isolation, frequency 0.05–0.95 and transcriptome off-target filters are already applied.

Selectivity threshold (ΔΔG ≥)

Apply ΔΔG threshold

kcal/mol. No cutoff is applied by default; negative and unavailable values are retained. Enable the threshold to restrict the pool. 4 is the paper's allele-selectivity threshold. At ΔΔG ≥ 4, fewer than 1% of off-target transcripts stay within 5-fold potency of the target (Watt et al. 2020).

Screening and selectionScreen oligos under attrition, then advance the best K winners to the clinic.

Per-ASO success rate (q)

1 in 500, full pipeline 1 in 20, bench hit 1 in 5

Probability a single synthesised ASO clears. An allele is reached if ≥1 of its ASOs clears.

ASO screening budget

How many ASOs you evaluate (simulate pass/fail against, at rate q). Spread across the highest-coverage alleles, fully testing each before the next; an allele is won once one of its ASOs passes, and the K highest-coverage winners are advanced to the clinic.

Min valid ASOs per allele

An allele is only pursued if it has at least this many qualifying ASOs.

Final portfolio (K alleles)

From the alleles whose ASOs pass screening, keep the (up to) K that jointly maximise coverage, re-optimised on whatever cleared, not a fixed ranking.

CostsEach site builds and tests two allelic constructs. Each oligo is synthesised and screened once.

Cost per site

Fixed cost per distinct genomic site screened: both allelic constructs are created and tested for selectivity. The two alleles of a SNP share their constructs, so a site is charged once (see the site count on the "Alleles screened" card).

Cost per ASO

Cost to synthesise and screen one ASO. Multiplied by the ASOs screened.

– expected coverage

ASOs screened

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Alleles screened

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Expected portfolio (≤K)

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Ceiling (best K)

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Total cost

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Coverage distribution 1,000 Monte-Carlo screens under attrition

Coverage against screening budget Expected coverage and the 5–95% spread across screens

Top-K portfolio alleles The jointly-optimal K, if every screened allele passes

rsID	Position	Allele frequency	ASOs	Pass probability	Marginal coverage

Reading q: the bench in-vitro hit-rate (≈1/20 — find a potent, selective ASO among those synthesised) and the full preclinical-to-clinic pass rate (≈1/500) are different stages and swing the answer widely. Ceiling is coverage if every pursued lead yields a working ASO (no attrition). Targetability is heterozygosity for the variant allele; coverage concentrates in a few common, high-LD alleles. Built from ; oofft transcriptome off-target, frequency and isolation filters applied. ΔΔG filtering is optional.