Therapeutic Mechanism Documentation
Reference documentation for RNA therapeutics mechanism design — all 9 therapeutic goals
Make or increase
Produce, replace or increase useful RNA or protein.
Reduce
Reduce harmful RNA, protein production or toxic RNA activity.
Modify or correct
Change RNA sequence, processing, isoforms or molecular interactions; expression direction can depend on context.
How to Read a Mechanism Card
Every mechanism entry above carries the same fields. This is what each one means.
Code
The platform's mechanism identifier (A1–A41). Codes can appear under more than one goal — e.g. A2 serves both TG01 (silencing) and TG06 (translation block) — because the same chemistry answers different therapeutic intents.
Name
Common literature name for the approach, including the shorthand used in the field (e.g. TANGO, AntagoNAT, TDMD).
Description
How the mechanism works at the molecular level: what binds what, which endogenous machinery is recruited or blocked, and the downstream effect on RNA or protein.
Required Inputs
Where on the transcript (or elsewhere) the oligo is designed to bind — e.g. mature mRNA CDS, 5' UTR uORF start sites, splice donor/acceptor junctions, promoter-associated RNA, or the mature miRNA itself. Determines whether the designer needs spliced mRNA sequence or pre-mRNA/genomic context.
Current Output
The available research output may be a sequence component or construct proposal. It does not establish complete construct function, activity, safety or delivery.
Goal sections use the same fields per goal: each section shows the mechanisms that arbitrate under that therapeutic goal (TG01–TG09), with the goal's subtitle describing the clinical intent the mechanisms share.
Understanding Mechanism Rankings
The ranking page shows two independent signals to help distinguish general scientific support from fit for the selected design context.
Decision score
A partially identified 0–100 interval over all rankings consistent with the provenance-capped applicability bounds. Every pair is a certified win, certified loss, exact tie, or incomparable. The platform displays the interval and its midpoint, a certified rank range, maximal-set membership, and an abstention when the evidence does not identify a unique winner. None is an efficacy probability.
Evidence rating
A rulebook label describing the level of published and clinical support for the mechanism in general. It is shown separately and is not added to the contextual fit score. A well-established mechanism can therefore have a low fit for a particular target or delivery setting.
Tissue Expression & Delivery
How the platform evaluates tissue-specific ASO delivery, expression data sources, and scoring modifiers.
Expression Data Sources
GTEx Portal v8
Primary source. Median gene expression (TPM) across 54 human tissues. Provides tissue-level and transcript-level expression data via API v2.
Human Protein Atlas
Fallback source. RNA tissue specific nTPM, tissue specificity index, and single-cell type enrichment data from HPA JSON API.
UniProt
Last-resort source. Tissue specificity comments from protein annotations when GTEx and HPA are unavailable.
Expression Level Classification
Exploratory display bins; these thresholds do not establish target suitability or clinical risk.
High
> 25 TPM in target tissue
Medium
5 – 25 TPM in target tissue
Low
< 5 TPM in target tissue
Delivery Contexts
CNS / Intrathecal
Administration into cerebrospinal fluid is one route used for CNS targets. Exposure and cell uptake remain construct and target specific.
Systemic / Subcutaneous
Intravenous or subcutaneous administration; distribution and tissue uptake depend on chemistry, formulation and target.
Liver-Targeted
GalNAc conjugation can support hepatocyte uptake via ASGPR. It does not establish delivery for an arbitrary payload or other liver cell type.
Local / Intramuscular
Injection into target muscle is a local research route. Eteplirsen is administered intravenously; systemic precedent must not be transferred to local injection.
Ocular
Intravitreal administration is an ocular route. Ocular distribution, tolerability and systemic exposure require construct-specific assessment.
Other / TBD
Not yet determined or experimental delivery route.
Overexpression Risk Warnings
Heuristic alert (> 500 TPM)
This is an exploratory expression threshold, not a validated toxicity cutoff. Assess gene dosage and the proposed protein increase.
Heuristic alert (> 200 TPM)
Expression alone cannot establish the risk of overexpression. Tissue-specific dosage and functional assays are required.
ASO Design Parameters
Reference for all configurable fields in the Gene Silencing ASO Design form. These parameters control how candidate oligonucleotides are generated, scored, and ranked.