Premature Twins Thrive After Early SMA Gene Therapy

A set of premature twin girls born at sevven months gestation offered researchers a unique opportunity to test how early gene therapy could be administered to infants with spinal muscular atrophy (SMA), potentially preventing symptoms from ever developing.

Katherine Mathews, M.D.

The case study, led by Katherine D. Mathews, M.D., of the University of Iowa Carver College of Medicine and published in Annals of Clinical and Translational Neurology, details how the twins were delivered via emergency C-section when one of the infant’s heat rate had slowed. Newborn screening indicated SMA, and a diagnosis was confirmed. Three weeks later, the girls received Zolgensma (onasemnogene abeparvovec).

Untreated, children with the most common form of SMA typically die or become ventilator dependent by age 2. However, the approval of three disease-modifying therapies since 2016 has greatly improved quality of life and life expectancy for patients with SMA. Still, earlier treatment typically leads to greater results: a previous study showed infants who received one of the SMA drugs a few weeks after birth fared better than those treated only 10 months later.

In this case study, genetic testing initially suggested a dire prognosis, with the twins having zero copies of the SMN1 gene and only one copy of SMN2, which typically predict a severe form of the disease. However, later detailed DNA sequencing revealed a more complex situation: the twins actually had a rare SMN2-SMN1 hybrid gene, which can have a milder effect.

Regardless, two years after treatment, both girls show normal motor function and no signs of SMA symptoms. While the rare hybrid gene played a role, the authors suggested the extremely early treatment was crucial to the twins' excellent motor outcomes.

“These cases illustrate the challenges in predicting phenotype based on standard SMN2 copy number testing and demonstrate that delivery of [Zolgensma] in prematurity can be both safe and highly effective,” the study authors wrote. “The combination of the genetic modifier and early presymptomatic treatment resulted in excellent motor outcome.”