ZOLGENSMA is a gene therapy designed to treat the cause of SMA (deletions of the SMN1 gene) by delivering a copy of a fully functioning human SMN gene1
How ZOLGENSMA works
ZOLGENSMA (onasemnogene abeparvovec-xioi), suspension for intravenous infusion is the first one-time-only gene therapy for the treatment of pediatric patients less than 2 years of age with SMA.
ZOLGENSMA has a Boxed Warning for acute serious liver injury. Please see additional Important Safety Information at the end of this video. Please also see the Full Prescribing Information at zolgensma-hcp.com
SMA is a neurodegenerative disease resulting from the loss of function of the survival motor neuron 1, or SMN1, gene.
SMN1 produces SMN protein, which is critical for neuronal survival.
SMN1 has a backup gene, SMN2, whose splicing variability results in only 10% functional SMN protein.
Without functional SMN1 patients with SMA rely solely on the insufficient levels of protein produced by SMN2
SMN2 copy number is an important modifier for disease severity in SMA. In patients with SMA, there is significant variability in SMN2 copy number. Those with the most severe forms of SMA often have 2 copies of SMN2.
Without sufficient SMN protein production, patients experience irreversible neuronal loss, resulting in progressive physical disability, life-threatening medical emergencies, and premature death.
ZOLGENSMA targets the genetic root cause of SMA, caused by mutations in the SMN1 gene, by inserting a fully functional copy of the human SMN gene. To combat the neurodegenerative nature of the disease, ZOLGENSMA enables continuous SMN protein production, which can halt the progression of disease and preserve motor neurons.
ZOLGENSMA is composed of a fully functioning copy of the human SMN gene, which codes for the SMN protein patients need. ZOLGENSMA is self-complementary and has a promoter that activates the human SMN gene and initiates continuous protein expression. The genetic elements of ZOLGENSMA are packaged in an adeno-associated virus, serotype 9 or AAV9, vector, which enables delivery of the gene into motor neuron cells. The AAV9 vector is nonpathogenic, and the viral genes have been removed to decrease immunogenic potential and eliminate potential viral replication.
ZOLGENSMA is administered as an intravenous infusion. Once in the body, the AAV9 vector is able to cross the blood-brain barrier.
Having crossed the blood-brain barrier, the AAV9 vector can efficiently enter motor neuron cells but is not known to cause disease in humans.
Once inside the cell, the AAV9 vector travels into the cell nucleus. Once inside the cell nucleus, the AAV9 vector releases the human SMN gene.
The ZOLGENSMA SMN gene is designed to replace the function of the defective SMN1 gene without being integrated into the patient’s genome.
The SMN gene is introduced to target cells as recombinant self-complementary DNA.
ZOLGENSMA is also built with a hybrid cytomegalovirus enhancer/chicken-beta-actin promoter that activates expression of the SMN gene.
Together, these critical elements of ZOLGENSMA enable the continuous and sustained production of SMN protein over time.
By targeting motor neurons throughout the CNS, ZOLGENSMA stops the widespread neuronal cell death and subsequent muscle degeneration characteristic of SMA preserving motor neurons and sustaining neuromuscular function.