Method2Model—ALD mRNA Therapy — Stage 3 Core Model (Mouse Branch, Python Package)

This record archives the Stage 3 Core Model for a dual-platform (LNP + EV) mRNA therapy program in X-linked adrenoleukodystrophy (ALD), implemented as a reusable Python package and delivered as a versioned ZIP snapshot.

The package encodes the mouse branch (Blocks A–E) of the ALD mechanistic model defined in Stage 1 (architecture) and Stage 2 (Formula Pack and I/O Contract). It includes:

• Block A — Delivery & Exposure: 5-compartment coarse-grained PBPK (plasma, liver, periphery, CNS, CSF), saturable uptake into multiple cell types, and a time-dependent BBB flux controlled by a focused ultrasound (FUS) window.

• Block B — Expression & Peroxisomal Targeting: endosomal escape, cytosolic mRNA, ALDP protein, partitioning into peroxisomal vs. non-peroxisomal pools, and an effective peroxisomal β-oxidation capacity Vβ(t).

• Block C (mouse PD): VLCFA (C26:0) dynamics in plasma and CNS, CNS inflammation, axonal injury, and mouse endpoints (NfL, FA, Rotarod) derived algebraically from axon injury.

• Block D — Safety & Immunogenicity: cytokine response, hepatic injury markers (ALT/AST), and anti-drug antibodies (ADA_k), driven by flexible exposure-based driver functions.

• Block E — CMC / Batch Variability: batch-level CMC metrics Q_{k,b} mapped to algebraic factors, with φ_k,b(Q) already wired for dose scaling and ψ_k,b(Q), θ_mRNA,b(Q) reserved for future tuning of η_esc and k_deg,m.

All inputs (PBPK/PD/safety parameters, CMC metrics, initial conditions, and dose schedules) are provided as YAML configuration files in the configs/ folder. The ZIP also contains:

• ald_model/core.py — the main Stage-3 core implementation.

• examples/example_run_mouse.py — an end-to-end baseline mouse example.

• RUNBOOK.md — installation and execution instructions.

• verification/TRACEABILITY_MATRIX.md, ACCEPTANCE_TESTS.md, SCENARIO_EQUIVALENCE.md, VERSION_LINKS.md — scaffolding for “Proof of Match” between architecture, formulas, and code.

This Stage-3 core is intentionally scoped to the mouse branch only: the human projection branch (clinical endpoints), explicit complement activation state, full ψ/θ wiring, and scenario/VOI engine (Blocks F–G) are not included and are intended to be built on top of this core.

The software is released for research and educational use only under a non-commercial Method2Model research license (see the GitHub README). It is a modeling prototype, not a medical device or clinical decision support tool.

The upstream Stage-2 Formula Pack is archived under DOI 10.5281/zenodo.18093206, and the actively maintained code repository is hosted at:
https://github.com/RamyarAzar/ALD_mRNA_Therapy.