Gene therapy: Zolgensma to treat spinal muscular atrophy

Gene therapy: Zolgensma to treat spinal muscular atrophy

Last Updated on May 30, 2019 by Joseph Gut – thasso

May 29, 2019 – Spinal muscular atrophy (SMA) is a group of neuromuscular disorders that result in the loss of motor neurons and progressive muscle wastingThe severity of symptoms and age of onset varies by the type. Some types are apparent at or before birth while others are not apparent until adulthood. All result in worsening muscle weakness associated with muscle twitching with arm, leg and respiratory muscles affected first. Associated problems may include congenital heart disease, scoliosis, and joint contractures. SMA is a leading genetic cause of death in babies.

Spinal muscular atrophy is due to a genetic defect (mutation)  in the survival motor neuron 1 (SMN1) gene which is inherited from a person’s parents in an autosomal recessive manner. The SMN1 gene encodes SMN, a protein necessary for survival of motor neurons. Loss of these neurons prevents the sending of signals between the brain and skeletal muscles. Diagnosis is suspected based on symptoms and confirmed by genetic testing.

The American Food and Drug Administration (FDA) just approved Onasemnogene Abeparvovec-xioi (Zolgensma), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality. SMA caused by mutations in the SMN1 gene is generally classified into several subtypes, based on the age of onset and severity; infantile-onset SMA is the most severe and most common subtype. Children with this condition have problems holding their head up, swallowing and breathing. These symptoms may be present at birth or may present by the age of 6 months.

Most children with this disease do not survive past early childhood due to respiratory failure. These children now have a exciting treatment option to minimize the progression of SMA and improve survival. Overall, Onasemnogene Abeparvovec-xioi (Zolgensma) is indicated for the treatment of children less than two years of age with SMA. The product is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of Onasemnogene Abeparvovec-xioi (Zolgensma) results in expression of the SMN protein in a child’s motor neurons, which improves muscle movement and function, and survival. Dosing is determined based on the weight of the patient.

The safety and effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) is based on an ongoing clinical trial and a completed clinical trial involving a total of 36 pediatric patients with infantile-onset SMA between the ages of approximately 2 weeks and 8 months at study entry. The primary evidence of effectiveness is based on results from the 21 patients treated with Onasemnogene Abeparvovec-xioi (Zolgensma) in the ongoing clinical trial. In this trial, there are 19 remaining patients, who range in age from 9.4 to 18.5 months; 13 of these 19 patients are at least 14 months of age. Compared to the natural history of patients with infantile-onset SMA, patients treated with Onasemnogene Abeparvovec-xioi (Zolgensma) also demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support).

The most common side effects of Onasemnogene Abeparvovec-xioi (Zolgensma) are elevated liver enzymes and vomiting. Onasemnogene Abeparvovec-xioi (Zolgensma) has a boxed warning that acute serious liver injury can occur. Patients with pre existing liver impairment may be at higher risk of experiencing serious liver injury. Clinical examination and laboratory tests to assess liver function should be completed prior to treatment with Onasemnogene Abeparvovec-xioi (Zolgensma), and patients’ liver function should be monitored for at least three months after Onasemnogene Abeparvovec-xioi (Zolgensma) administration. Moreover, certain vaccines are contraindicated for patients on a substantially immunosuppressive steroid dose. Therefore, caregivers should consult with their healthcare professional to determine if adjustments to the patient’s vaccination schedule are necessary to accommodate concomitant corticosteroid administration.

Noteworthy, the FDA granted this application Fast Track, Breakthrough Therapy, and Priority Review designations. Onasemnogene Abeparvovec-xioi (Zolgensma) also received Orphan Drug designation, which provides incentives to encourage the development of drugs for rare diseases. Furthermore, the FDA also awarded the manufacturer a rare pediatric disease priority review voucher, under a program intended to encourage the development of new drugs and biological products for the prevention and treatment of certain rare pediatric diseases. See also here a pivotal published study on gene replacement in the treatment of spinal muscular atrophy,


Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.