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Combined CP0 Systems Model — Dietary Rosmarinic Acid + Engineered DAF SCR1-4 (Computational, comp-029)

Frozen analysis lives at ./etc/experiments/comp-029-combined-cp0-systems-model/ — README + analyze.py + inputs/ + outputs/ all committed for reproducibility. This wiki page is the interpretive layer; the analysis script is stdlib-only Python 3 and reproduces deterministically with RNG seed 29.

The question

complement-c5a-gout.md §9.7 added the combined-CP0-coverage hypothesis on 2026-05-15: two CP0 threads (dietary rosmarinic acid + engineered DAF SCR1-4) operate at different geometric scales (fluid-phase / gut-luminal vs. MSU crystal surface), use different mechanisms (covalent C3b modification vs. decay-acceleration), and might therefore compose into additive CP0 coverage without relying on avacopan (the only OE CP0 candidate with serious clinical-development infrastructure, but expensive and on-patent).

Does the predicted combined-effect range, with explicit confidence bounds over published priors, meaningfully exceed either intervention alone?

Verdict: YELLOW

DAF accessibility prior DAF α RA alone median DAF alone median Combined median Combined/better-singleton ratio Verdict
Low 0.05 0.886 0.568 0.956 1.08 YELLOW
Medium 0.20 0.886 0.815 0.979 1.10 YELLOW
High 0.80 0.886 0.914 0.989 1.08 YELLOW

Per the comp-029 brief decision rule (GREEN needs combined ≥ 1.5× the better singleton AND combined 95% CI strictly above singleton 95% CI), none of the three accessibility priors clears either threshold. The combined median is only 1.08-1.10× the better singleton, and the combined 95% CI overlaps both singleton CIs.

Why YELLOW, mechanistically

Both arms individually saturate at their operative concentrations. RA in the gut-luminal regime (50-1100 μM after 50-200 mg oral dose) hits the C3 convertase IC50 range (5-180 μM) hard — median inhibition fraction 0.886. DAF SCR1-4 at 10-500 nM secreted concentration with even modest accessibility hits decay fraction 0.5-0.9 across the three accessibility priors. When two interventions each already produce 60-90% reduction independently, multiplicative composition (the standard treatment of two independent fractional reductions: f_combined = 1 - (1-f_RA)(1-f_DAF)) has structurally little room to grow — the combined ratio against the better singleton is mathematically capped near 1.1×.

This is not a refutation of the combined-coverage hypothesis. It's a mathematical feature of saturated singletons. The two interventions DO compose as the §9.7 hypothesis claimed; the issue is that under current input uncertainty, the combined effect is probably larger than either alone but not provably-large-enough to justify wet-lab co-administration cost.

What comp-029 rules OUT

The RED verdict path is closed. No interaction blocker found at any of three candidate failure modes:

  1. RA covalently inactivates DAF SCR1-4 via the catechol / α,β-unsaturated ester — no published evidence. RA's covalent chemistry targets activated C3b nucleophilic acceptor sites; SCR/CCP-domain proteins do not present the same chemistry, and DAF binds C3b through reversible protein-protein interaction.
  2. DAF degraded under gut-luminal RA-bioavailable conditions — comp-012 explicitly verified DAF SCR1-4 LOW protease risk in shio-koji and gut-luminal conditions. RA does not alter pH or protease activity in a way that would compromise DAF stability.
  3. RA + DAF compete for C3b binding — RA modifies C3b post-deposition (covalent); DAF accelerates C2a/Bb dissociation from already-assembled C3b complexes. The two operate at different time points on different C3b states. Mechanistically complementary, not competitive.

(Mechanistic Extrapolation.)

What comp-029 rules IN

  1. The two interventions hit the geometric scales the §9.7 hypothesis claimed. RA contributes via the gut-luminal transient, not systemic plasma — Baba 2004 free plasma Cmax of 20 nM is ~1700× below the central IC50 (34 μM), giving essentially 0% inhibition (median 0.0007). The gut-luminal regime at 252-1100 μM (Kang 2021) DOES reach mechanistically active concentrations — median 0.886. This sharpens the wet-lab framing: the right RA readout is a gut-luminal complement-activation assay, not a plasma-based one. (Mechanistic Extrapolation over In Vitro Sahu 1999 + Clinical Trial Baba 2004 anchors.)

  2. DAF SCR1-4 contributes via MSU-surface decay-acceleration, with effective concentration in the 10-500 nM range and accessibility α as the single load-bearing wet-lab unknown (comp-012's explicit Limitations section).

  3. The combined-effect distribution is broadly higher than either singleton, just not separated under current prior uncertainty. The wide singleton CIs (RA p5=0.44, DAF p5=0.18-0.77 depending on α) leak into the combined CI.

Dominant uncertainty drivers

Input Spearman r vs combined (α=0.20) Prior spread
RA gut-luminal IC50 -0.658 (largest) 36× (5-180 μM)
RA gut-luminal [RA] +0.552 22× (50-1100 μM)
DAF effective [DAF] +0.480 50× (10-500 nM); accessibility α adds another 16×

Top wet-lab measurement that would tighten the prediction most:

Measure DAF SCR1-4 MSU-surface engagement fraction. This is the load-bearing wet-lab unknown per comp-012's explicit Limitations section and the dominant uncertainty driver in comp-029's sensitivity analysis. One experiment, one parameter, currently a 16× prior spread.

validation-experiments.md §1.25 DAF SCR1-4 expression screen already provides the right functional readout (zymosan or MSU-crystal C5a-generation assay ± DAF). The §1.25 functional arm directly resolves α as a side product of its primary experimental aim. No new wet-lab experiment is gated by comp-029 — only an optional co-treatment arm WITHIN the already-planned §1.25 experiment, gated on §1.25's own functional readout.

Wet-lab handoff to §1.25

If §1.25 returns α ≥ 0.5 (mid-to-high MSU-surface engagement), comp-029 re-runs to GREEN — DAF alone saturates and the combined ratio improves. The marginal-cost RA co-treatment arm is then justified:

Optional co-treatment arm (gated on §1.25 functional readout showing DAF SCR1-4 mid-to-high MSU-surface engagement): Add a co-treatment condition to the §1.25 zymosan / MSU-crystal C5a-generation assay: DAF SCR1-4 expressed material (mature, ELISA-quantified) + rosmarinic acid at 100 μM (gut-luminal regime; matches the median Sahu 1999 C3b-deposition IC50) co-incubated 30 min at 37°C with complement-competent serum + MSU crystals. Compare C5a + C5b-9 generation across (i) DAF SCR1-4 alone, (ii) RA alone, (iii) DAF + RA combined, (iv) vehicle. Marginal cost: one additional condition per plate; readout: same ELISA already in the §1.25 plan.

If §1.25 returns α < 0.2, comp-029 stays YELLOW and the combined-strategy thesis is parked. RA alone via the gut-luminal regime survives as a stand-alone dietary intervention; engineered DAF SCR1-4 survives as a stand-alone CP0 candidate at the MSU surface; the combined-coverage claim is shelved until a new mechanism or geometry surfaces.

Pass 3 softening discipline honored

This page explicitly does not claim:

  1. The two interventions are "mechanistically additive." Multiplicative composition of independent fractional reductions is the standard treatment; super-additivity would require coupling we did NOT find.
  2. Rosmarinic acid "saturates fluid-phase and gut-luminal C3 convertase." It saturates the GUT-LUMINAL regime (post-meal, transient), and contributes essentially 0% at SYSTEMIC free-RA concentrations. The two are 4-5 orders of magnitude apart.
  3. Downstream clinical effect size. Even if the mechanism prediction holds, downstream clinical SUA / IL-1β effect-sizes are gated by the H08-class clinical-translation question covered separately.

Evidence levels

  • In silico systems composition over published kinetic constants: Mechanistic Extrapolation.
  • Sahu 1999 / Englberger 1988 IC50 values: In Vitro.
  • Baba 2004 human plasma Cmax: Clinical Trial (single-dose human PK).
  • Wang 2017 rat oral absolute bioavailability: Animal Model.
  • Kang 2021 gut-luminal concentration calculation: Mechanistic Extrapolation (calculation from oral dose + intestinal volume assumptions).
  • Fischer 1981 C4b2a half-life: In Vitro.
  • Medof 1984 DAF effective threshold: In Vitro.

Cross-references