Mechanism of action

ZOLGENSMA is a gene therapy designed to treat the genetic root cause of SMA1

Spinal muscular atrophy (SMA) is caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene. The SMN1 gene produces survival motor neuron (SMN) protein that is critical for normal function of motor neurons. Patients with SMA have an insufficient amount of SMN protein, which leads to permanent loss of motor neurons.2-4 

ZOLGENSMA is designed to enable rapid and continuous expression of SMN protein. By replacing the missing SMN protein, ZOLGENSMA can stop the progressive loss of motor neurons.1,5

Elements of ZOLGENSMA enable it to address the cause of SMA1

Human SMN geneContinuous promoter AAV9 vector 
Contains the code for the SMN protein patients need1Enables ongoing expression of the SMN gene1,6Crosses the blood-brain barrier and enters motor neuron cells1,7

How ZOLGENSMA works 

  1. The AAV9 vector enters motor neuron cells1 
  2. The AAV9 vector delivers the SMN gene to the cell nucleus1,7
  3. The SMN gene is introduced to target cells as recombinant,
    self-complementary DNA1
  4. The self-complementary ends form a circular episome that can persist in the nucleus of motor neuron cells. These cells are nondividing6,7
  5. This results in rapid activation and continuous expression of the SMN gene1,5
The mechanism of action for ZOLGENSMA showing the AAV9
vector entering the nucleus and releasing the human SMN gene

Watch the process

ZOLGENSMA enables widespread SMN protein expression in the central nervous system (CNS) and in motor neurons6 

SMN protein expression was assessed in 2 patients treated with ZOLGENSMA. Expression was detected in viable motor neurons and detected in cells of the brain, as well as the heart, liver, skeletal muscles, and other evaluated tissues.6

Samples were assessed in autopsy. Neither patient death was considered related to ZOLGENSMA treatment. These images were taken of samples from the motor cortex.6

SMN protein expression in the central nervous system (CNS) and in
motor neurons in patients treated with ZOLGENSMA

Scale bars (left column)=100 μm; Scale bars (right column)=25 μm. 
Reprinted by permission from Springer Nature. Nature Medicine. Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Thomsen G, Burghes AHM, Hsieh C, et al. 2021. 

Dosing and infusion

Preparing and infusing ZOLGENSMA

Dosing and infusion


A Phase 3 clinical trial