Gene Therapy for Spinal Muscular Atrophy Safe, Improves Motor Function

By Reuters Staff

August 26, 2020

NEW YORK (Reuters Health) - For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec-xioi (Zolgensma) is safe and provides improvements in motor function, report clinicians from Ohio.

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons. Zolgensma replaces the defective or missing SMN1 gene to halt disease progression.

The gene therapy was approved in the United States in May 2019 for all children younger than age 2 years with SMA without end-stage weakness. However, Zolgensma has only been studied in children aged 8 months and younger.

"Thus, the safety and important features of drug administration in older (and likely heavier) individuals has not been well studied or reported," Dr. Megan Waldrop with the Center for Gene Therapy, Nationwide Children's Hospital, in Columbus, and colleagues write in Pediatrics.

They describe safety and early outcome data from the first 21 children with SMA who received Zolgensma at four children's hospitals in Ohio. The children ranged in age 1 to 23 months.

In young children aged 6 months and younger, Zolgensma was well tolerated, with only "modest" elevations in aspartate aminotransferase (AS) and alanine aminotransferase (ALT), with no elevation in gamma glutamyl transpeptidase (GGT).

Initial prednisolone administration was in line with that given in the clinical trials of Zolgensma. In older and heavier children, elevations in all three liver enzymes were more common and required a higher dose of prednisolone, but all were without clinical symptoms.

Eight (67%) of the 12 children aged 8 months or older, had elevations at least two times the upper limit of normal in AST and/or ALT; six of these children also had elevations in GGT more than one times normal.

Of the 12 children who weighed 8 kg or more, 10 (83%) had elevations of at least two times the upper limit of normal in AST and/or ALT, and four of these children also had GGT elevations greater than one times normal. "However, all patients remained clinically well and had no abnormalities indicative of symptomatic liver dysfunction," Dr. Waldrop and colleagues report.

Regardless of age or weight, the majority of children (19 of 21, 90%) experienced a drop in platelet count in the first week after treatment; none were symptomatic, all recovered without treatment.

Of the 19 children with repeated outcome assessments, two (11%) experienced stabilization and 17 (89%) saw improvement in their motor function.

Summing up, Dr. Waldrop and colleagues say their experience "suggests that when a thorough screening process is completed, social isolation is implemented to minimize the risk of illness after gene transfer, and patients are monitored closely in the weeks to months after gene transfer, adverse events are few."

The study had no external funding. Dr. Waldrop and several of his colleagues report ties to Avexis Inc, which sells Zolgensma.

Dr. Waldrop did not respond to a request for comment by press time.

SOURCE: Pediatrics, online August 25, 2020.