This is a mechanism module, not a specific disease, and conformance is node-level consistency rather than inheritance. Scope: use this module for treatments whose operative mechanism is Argonaute-mediated cleavage of a target mRNA by an exogenous double-stranded siRNA. Exclude single-stranded antisense oligonucleotides, which belong to antisense_oligonucleotide_therapy even when they knock a transcript down - the effector is RNase H1, not RISC. Exclude endogenous miRNA biology, miRNA mimics and antimiRs, shRNA expressed from a viral vector (the delivery node below assumes a synthetic duplex administered as a drug), and CRISPR interference. The delivery node is deliberately part of the chain rather than a module of its own. Delivery is what makes an RNAi drug organ-specific, so it is the node a conforming disorder entry specializes - hepatocyte ASGR1 uptake of a GalNAc conjugate for a liver target, intrathecal or lipid-conjugate delivery for a CNS target. The chemistry of a given platform is not itself a pathophysiology claim: record it on the treatment via oligonucleotide_details (delivery_platform, conjugation, oligonucleotide_chemistry) rather than as additional nodes here. Node granularity: RISC loading is described inside the Argonaute-2 cleavage node rather than modeled as a node of its own. It was one initially, and was folded in on review: the cached sources here describe the Argonaute slicer degrading the transcript, but none of them mention RISC, the passenger strand, or guide-strand selection, so a separate loading node asserted three claims and its ontology bindings (GO:0016442, GO:0035197) carried no evidence at all. The step is textbook biology, and if a source that states it is later cached the node can be split back out; until then the module does not claim a step it cannot cite. ATTR_Amyloidosis, the only conformer, already collapses loading and cleavage into one node. Evidence discipline: every node below is supported by a source that describes the step in a named, marketed or trialed siRNA drug. The mechanism is well established, but a conforming disorder entry must still cite its own disease-specific evidence that the named transcript is the pathogenic one and that silencing it produces the claimed protein reduction - a modality tag and a plausible target are not sufficient. Where a conformer's siRNA is preclinical or allele-selective proof of concept (several are), say so rather than inheriting this module's approved-drug evidence. Where a clinical-outcome trial is cited as validation of the mechanism it targets rather than as a measurement of the node itself, keep supports: SUPPORT and record directness: INDIRECT. Every delivery-to-effector edge is conditional on administration of the sequence-matched siRNA and must say so explicitly.
How much of an administered siRNA dose actually escapes the endosome, and does the escape fraction differ enough between delivery platforms to explain their different dosing intervals?
KNOWLEDGE GAP
gap_sirna_endosomal_escape_fraction
Attached to:
Target-Cell siRNA Delivery
Endosomal escape is the least characterized step in the chain above. It is widely reported to be inefficient for unassisted conjugate uptake, and the catalytic nature of RISC is invoked to explain why that is nonetheless sufficient. But the module's delivery node cites platform identity, not a measured escape fraction, and the cached sources here do not quantify it. The dosing intervals recorded on the treatments above are label facts; attributing the difference between them specifically to escape kinetics rather than to duplex stability or tissue residence would be an inference this module does not currently support.
Pathogenic Transcript Abundance
trigger
The disease-causing transcript is transcribed and translated at a level that produces harmful amounts of the encoded protein, or produces a protein whose intrinsic properties are pathogenic. The transcript is usually structurally normal - it is the abundance of its product, or that product's toxicity, that drives disease - which makes reducing the message, rather than inhibiting the protein after it is made, the upstream therapeutic target. This is the same upstream state that the RNase H branch of antisense_oligonucleotide_therapy addresses; it is restated here so an RNAi conformer has an anchor that does not imply an ASO effector. Worked targets include TTR mRNA in ATTR amyloidosis, PCSK9 mRNA in familial hypercholesterolemia, ALAS1 mRNA in acute intermittent porphyria, and APOC3 mRNA in familial chylomicronemia syndrome.
Downstream
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Target-Cell siRNA Delivery
Conditional on administration of a sequence-matched siRNA drug, the duplex is carried to the cell that expresses the pathogenic transcript.
Show evidence (1 reference)
"Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis."
Establishes reduction of synthesis of the pathogenic protein - rather than action on the protein once made - as a distinct therapeutic target, which is the state this trigger node represents.
Target-Cell siRNA Delivery
effector
A chemically stabilized siRNA duplex reaches the cytosol of the cell that transcribes the target gene. Naked siRNA cannot do this unaided: it is degraded by serum nucleases, cannot cross the plasma membrane, and is digested in the endosome after uptake. Two platforms solve this in approved drugs. An ionizable lipid nanoparticle encapsulates the duplex and, on endosomal acidification, becomes positively charged and destabilizes the endosomal membrane (patisiran). Alternatively, a tri-antennary GalNAc conjugate on a nuclease-resistant duplex engages the asialoglycoprotein receptor on hepatocytes, driving receptor-mediated endocytosis, after which a small fraction escapes the endosome - enough, because RISC-mediated cleavage is catalytic (vutrisiran, inclisiran, givosiran). This is the node a conforming disorder entry specializes to its own target organ; the two platforms above are the liver-directed case, not the general one.
Downstream
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Argonaute-2 Cleavage of the Target Transcript
Once in the cytosol, the duplex is handed to the RNA-induced silencing complex, whose guide strand directs Argonaute-2 to the matching transcript.
Show evidence (2 references)
"Patisiran is formulated in a lipid nanoparticle to ensure delivery to the hepatocyte."
Documents the lipid-nanoparticle delivery platform in an approved siRNA drug.
"Revusiran is conjugated to N-acetylgalactosamine (GalNAc), which promotes the interaction with the asialoglycoprotein receptor, widely expressed on hepatocytes."
Documents the GalNAc-asialoglycoprotein-receptor route as the alternative delivery platform. Revusiran itself was discontinued in development; the quote is cited for the conjugate-uptake mechanism, which is shared by the approved GalNAc siRNAs, not as evidence for that drug.
Argonaute-2 Cleavage of the Target Transcript
central effector
The cytosolic siRNA duplex is loaded into the RNA-induced silencing complex, the passenger strand is discarded, and the retained guide strand directs the complex by Watson-Crick base pairing to the transcript carrying the matching sequence. That guide-strand selection is what makes the platform programmable: the protein machinery is endogenous and constant, and only the loaded sequence changes between one disease and the next. Loading is described here as setup rather than modeled as its own node - see the note on node granularity below. Argonaute-2, the sole catalytically competent human Argonaute, endonucleolytically cleaves the guide-paired transcript. The cleaved fragments are degraded by cytoplasmic exonucleases and the guide-loaded complex is released to engage another transcript, so silencing is catalytic rather than stoichiometric. That catalytic turnover is what allows the very small fraction of an administered dose that escapes the endosome to produce a therapeutic effect, and is the proximate reason GalNAc siRNAs can be dosed quarterly or twice yearly. This is the RNAi counterpart of the antisense_oligonucleotide_therapy#RNase H-Mediated Transcript Degradation node. Both degrade the target message; the effector differs, and a disorder entry should conform to the one that matches its drug rather than treating them as interchangeable.
Downstream
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Sustained Reduction of the Encoded Protein
Loss of the message removes the template for translation, lowering the steady-state level of the encoded protein.
Show evidence (2 references)
"Binding triggers activation of the Argonaute slicer protein, which degrades the mRNA, thereby inhibiting TTR synthesis"
Directly attributes transcript degradation, and the resulting block on protein synthesis, to Argonaute slicer activity.
"Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin."
Confirms in a phase 3 human trial that the RNA-interference mechanism specifically suppresses synthesis of the targeted protein.
Sustained Reduction of the Encoded Protein
consequence
Steady-state levels of the encoded protein fall in proportion to the degree of transcript knockdown, and remain suppressed for as long as the guide-loaded complex persists. The reduction is deep - typically 80% or more of circulating protein for a liver-expressed target - and long-lived, which is what converts a molecular effect into an interval-dosed medicine. Because silencing is reversible and does not alter the genome, protein levels recover when dosing stops; this distinguishes RNAi from gene editing and is the reason these are chronic therapies. Downstream disease benefit is not asserted here. It depends on whether the silenced protein is genuinely causal in the disease at hand and on how much irreversible damage has already accrued, so a conforming disorder entry must carry its own outcome evidence.
Show evidence (3 references)
"Vutrisiran achieved a dose-dependent TTR knockdown; a single 25 mg subcutaneous dose resulted in a maximum TTR reduction of 80%, which was sustained for 90 days"
Quantifies both the depth and the duration of protein reduction after a single dose of a GalNAc-conjugated siRNA, which is the property this node claims.
"a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia."
Demonstrates the same sustained-knockdown consequence for a different gene and a different disease, which is what makes this a module rather than a disease-specific mechanism.
"The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo."
A third gene and disease showing rapid and sustained transcript-level knockdown with a downstream biochemical consequence.
Patisiran
Platform:
siRNA
RNAi knockdown
Delivery: Lipid nanoparticle
Targeting: Unconjugated
Dosing:
once every 3 weeks
every 21 days
The first approved RNAi therapeutic, and the worked example of the lipid-nanoparticle delivery platform: an unconjugated siRNA against TTR mRNA encapsulated in an ionizable lipid nanoparticle and infused intravenously every three weeks.
Vutrisiran
Platform:
siRNA
RNAi knockdown
Delivery: Ligand conjugate
Targeting: GalNAc
Dosing:
once every 3 months
every 90 days
The GalNAc-conjugate counterpart of patisiran against the same transcript: a stabilized siRNA given subcutaneously once every three months without premedication. The contrast between the two is the clearest illustration in the KB of what the delivery platform, rather than the targeting sequence, determines.
Inclisiran
Platform:
siRNA
RNAi knockdown
Delivery: Ligand conjugate
Targeting: GalNAc
Dosing:
once every 6 months
every 182.5 days
A GalNAc-conjugated siRNA against PCSK9 mRNA, dosed twice yearly after loading. Included here because it demonstrates that the platform transfers to a different gene and a common disease with the chemistry held constant.
Givosiran
Platform:
siRNA
RNAi knockdown
Delivery: Ligand conjugate
Targeting: GalNAc
Dosing:
once monthly
every 30 days
A GalNAc-conjugated siRNA against ALAS1 mRNA, dosed monthly as prophylaxis in acute intermittent porphyria. A third gene, a third disease, and a metabolic rather than a structural or lipid target.