Skip to content

README.md

Latest commit

 

History

History
247 lines (189 loc) · 8.8 KB

README.md

File metadata and controls

247 lines (189 loc) · 8.8 KB
Raw

Spinal Muscular Atrophy (SMA) — QSP Model

Overview

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)

Disease Mechanism

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

QSP Model Structure

Biological Compartments

Module Components Key Variables
SMN2 Splicing Exon 7 ESE/ESS, ISS-N1, hnRNP A1, SRSF1 E7I (exon-7 inclusion fraction)
SMN mRNA FL-SMN mRNA, SMN-Δ7 mRNA mRNA concentrations
SMN Protein FL-SMN pool, snRNP complex SMN protein (normalized)
Motor Neuron Alpha-MN pool, apoptotic cascade MN fraction (0–1)
NMJ Presynaptic terminal, AChR clustering NMJ maturity score (0–1)
Muscle Fiber mass, atrophy/reinnervation Muscle mass (normalized)
Clinical CMAP, HFMSE, CHOP-INTEND, FVC Clinical endpoint scores

Drug Modules (PK/PD)

Drug Route Mechanism PK Model
Nusinersen (Spinraza) Intrathecal ASO blocks ISS-N1, ↑ exon 7 inclusion 2-compartment CSF (lumbar→cervical→CNS tissue)
Risdiplam (Evrysdi) Oral daily Small molecule enhances SRSF1/Tra2β binding 1-compartment + CNS penetration
Onasemnogene (Zolgensma) IV single dose AAV9 delivers SMN1 transgene to MNs IV → plasma → BBB crossing → MN transduction

Files

File Description
sma_qsp_model.dot Graphviz mechanistic map source (130+ nodes, 12 clusters)
sma_qsp_model.svg Vector image of mechanistic map
sma_qsp_model.png Raster image at 150 dpi
sma_mrgsolve_model.R mrgsolve ODE model with 20 compartments, 6 scenarios
sma_shiny_app.R 8-tab interactive Shiny dashboard
sma_references.md 50 PubMed references with clinical trial summary

Mechanistic Map

SMA QSP Mechanistic Map

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

mrgsolve ODE Model

Compartments (20 ODE states)

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

Treatment Scenarios (6)

Scenario Drug SMA Type Clinical Trial Analogue
1 None Type I Natural history
2 Nusinersen Type I ENDEAR trial
3 Risdiplam Type II SUNFISH trial
4 Zolgensma Presymptomatic SPR1NT trial
5 Nusinersen late Type II Late-start treatment
6 Risdiplam pediatric Type II Weight-based dosing

Running the Model

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)

Shiny App (8 Tabs)

Tab Content
1. Patient Profile Disease type selector, SMA classification table, mechanistic map
2. Pharmacokinetics Drug-specific PK parameters, concentration-time plots
3. SMN Biology (PD) Exon-7 inclusion dynamics, SMN protein, dose-response curves
4. Motor Neuron & NMJ MN pool dynamics, NMJ maturation, muscle mass
5. Clinical Endpoints CMAP, HFMSE, CHOP-INTEND, FVC, RULM value boxes + plots
6. Scenario Comparison Multi-treatment comparison, endpoint selection, summary table
7. Biomarker Dashboard NF-L proxy, SMN protein, correlation matrix
8. Population Variability Virtual population simulation, VPC plots, responder analysis

Launch App

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

Key Parameters

SMN2 Splicing

Parameter Value Description
E7I_base 0.10 Baseline exon-7 inclusion (10%)
Emax_NUS 0.60 Nusinersen max ΔE7I
EC50_NUS 5.0 ng/g Nusinersen EC50 (CNS tissue)
Emax_RIS 0.50 Risdiplam max ΔE7I
EC50_RIS 80 ng/mL Risdiplam EC50 (plasma)

Motor Neuron Dynamics

Parameter Value Description
k_MN_death 0.002–0.004/day MN death rate (type-dependent)
SMN_thresh 0.30 SMN protein threshold
MN_min 0.05 Irreducible MN fraction

Drug PK (Nusinersen)

Parameter Value Description
Dose 12 mg IT Standard adult/pediatric
Loading Day 0,14,28,63 4 loading injections
Maintenance Every 4 months Ongoing
t½ (CNS) 135–177 days Long tissue half-life

Clinical Trial Calibration

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)

Disease Classification Reference

SMA Type Onset SMN2 Copies Maximum Ability Untreated Survival
0 Prenatal/neonatal 1 None <1 month
I (Werdnig-Hoffmann) <6 months 1–2 Never sit <2 years
II (Intermediate) 6–18 months 3 Sit, never stand Adult (reduced)
III (Kugelberg-Welander) >18 months 3–4 Walk (may lose) Normal
IV (Adult) >21 years ≥4 Walk throughout Normal

References

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