Spinal Muscular Atrophy (SMA) is a severe autosomal recessive neuromuscular disease caused by homozygous deletion or mutation of the SMN1 gene on chromosome 5q13.2. Loss of full-length Survival Motor Neuron (SMN) protein leads to progressive alpha motor neuron degeneration, denervation of skeletal muscle, and in severe cases respiratory failure and death in infancy.

This QSP model captures the complete mechanistic cascade from SMN2 pre-mRNA alternative splicing through motor neuron degeneration and skeletal muscle atrophy, integrated with three FDA-approved disease-modifying therapies.

ICD-10: G12.0 (infantile SMA), G12.1 (other inherited SMA), G12.9 (SMA unspecified)

SMN1 deletion (5q13.2)
        │
        ▼
SMN2 gene (backup)                 SMN2 copies: 1–4 (higher = milder)
        │
        ├─ Pre-mRNA alternative splicing ──────────────────────────────────┐
        │   ├─ C840T transition disrupts exon 7 ESE                        │
        │   ├─ ISS-N1 (intronic silencer) represses exon 7 inclusion       │
        │   └─ Baseline 10% exon 7 inclusion → 10% FL-SMN mRNA            │
        │                                                                   │
        ├─ FL-SMN mRNA → FL-SMN protein (full function)          Drug target: ISS-N1 & ESE
        └─ SMN-Δ7 mRNA → SMN-Δ7 protein (rapidly degraded)
                │
                ▼
         SMN protein pool < threshold
                │
                ▼
        snRNP assembly defect → mRNA splicing dysregulation
        Axonal transport defect → β-actin mRNA mis-targeting
                │
                ▼
         Alpha motor neuron degeneration (apoptosis)
                │
                ▼
         Neuromuscular junction immaturity + denervation
                │
                ▼
         Skeletal muscle atrophy (neurogenic)
                │
                ▼
         Loss of motor milestones → Respiratory failure → Death

The mechanistic map contains 130+ nodes organized in 12 subgraph clusters:

1. Genetic & Chromosomal Basis (5q13.2)
2. SMN2 Pre-mRNA Alternative Splicing
3. SMN Protein & snRNP Assembly Complex
4. Motor Neuron Biology & Degeneration
5. Neuromuscular Junction (NMJ) Biology
6. Skeletal Muscle Pathology
7. Clinical Endpoints & Biomarkers
8. Nusinersen (Spinraza) PK/PD
9. Risdiplam (Evrysdi) PK/PD
10. Onasemnogene (Zolgensma) PK/PD
11. SMA Disease Types & Natural History
12. Systemic Effects & Comorbidities

Nusinersen PK (3): CSF lumbar, CSF cervical, CNS tissue
Risdiplam PK (3): GI tract, plasma, CNS
Zolgensma PK (3): Plasma vector, transduced MN vg load, transgene mRNA
Disease Biology (6): FL-SMN mRNA, SMN-Δ7 mRNA, SMN protein, MN pool, NMJ score, Muscle mass
Cumulative (2): AUC-SMN, MN lost

library(mrgsolve)
library(dplyr)
library(ggplot2)

source("sma_mrgsolve_model.R")

# Build model
mod <- sma_model()

# Run single scenario: nusinersen in SMA Type I
mod_t1 <- param(mod, list(SMN2_copies = 2, k_MN_death = 0.004))
out <- mrgsim(mod_t1, ev_nusinersen(), delta = 1, end = 730)
plot(out, SMN_protein + MN_fraction + CMAP + CHOP_INTEND ~ time)

# Run all 6 scenarios
df_all <- run_scenarios()

# Virtual population (n=100)
vpc <- virtual_population(n = 100)

library(shiny)
runApp("sma_shiny_app.R")

Model parameters calibrated to reproduce key outcomes from:

• ENDEAR (NCT02193074): 51% motor milestone response vs 0% sham at Day 183
• CHERISH (NCT02292537): +4.0 HFMSE (nusinersen) vs −1.9 (sham) at 15 months
• FIREFISH (NCT02913482): 61% sitting ≥5 s at 12 months (risdiplam)
• STR1VE (NCT03461289): 91% alive without permanent ventilation at 14 months (Zolgensma)

See sma_references.md for 50 curated PubMed references covering:

• Disease pathophysiology & genetics (1–8)
• SMN protein biology & splicing (9–14)
• Motor neuron biology (15–18)
• NMJ pathology (19–21)
• Nusinersen clinical trials & PK (22–27)
• Risdiplam clinical trials & PK (28–32)
• Zolgensma gene therapy (33–37)
• Biomarkers (38–41)
• QSP & pharmacometric models (42–45)
• Supportive care & outcomes (46–50)

Model built: 2026-06-23 | Disease: Spinal Muscular Atrophy | Category: Neuromuscular