Systemic AAV9 Gene Therapy: SMA Motor Neuron Rescue

Infusion Parameters

Vector dose 1.10 ×10¹⁴ vg/kg

Age at infusion 6 months

Pre-existing anti-AAV9 titer 1:0 (seronegative)

Live Readouts

Motor neurons transduced0%

CNS vector dose0 vg/kg

Predicted CHOP-INTEND score0 / 64

Particle Fate

Circulating in blood Sequestered by liver Crossed BBB → CNS Neutralized by antibody

How it works

This models the pharmacology behind IV-infused AAV9 gene therapy for spinal muscular atrophy (the mechanism used by the approved drug Zolgensma): a single dose of self-complementary AAV9 carrying a working SMN1 transgene is infused into the bloodstream and must survive three filters before it can rescue a motor neuron.

block   = titer / (titer + 50)            neutralizing-antibody screen
avail   = dose × (1 − block)               dose that actually reaches tissue
liver   = avail × 0.65                     AAV9 is strongly hepatotropic
remain  = avail × 0.35
bbbPerm = 0.30·e^(−age/10) + 0.04           blood-brain-barrier permeability falls with age
cns     = remain × bbbPerm                 vector genomes reaching the CNS
%MN     = 100 · cns^1.4 / (K^1.4 + cns^1.4)   Hill-type transduction curve, K = 0.03

Dose — total infused vector, in ×10¹⁴ viral genomes per kilogram; the approved clinical dose is 1.1×10¹⁴ vg/kg.
Age at infusion — the blood-brain barrier is far more permeable to AAV9 in the first months of life; older, heavier patients dilute the same vg/kg dose across more capillary length and neuronal loss becomes progressively less reversible.
Pre-existing anti-AAV9 titer — many people already carry neutralizing antibodies from natural AAV exposure; real trials exclude patients above roughly 1:50, because bound vector is cleared by the immune system before it ever reaches a cell.
Most of the dose is captured by the liver regardless of settings — this is the biodistribution trade-off that limits how much can be pushed across the BBB, and the reason liver enzymes are monitored after every infusion.
The CHOP-INTEND readout is a simplified proxy for the real 64-point infant motor function scale used in SMA trials — its achievable ceiling falls with age at treatment, reflecting motor neurons already lost before the infusion, which gene therapy cannot bring back.

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