Mendell JR, et al. - Here, the researchers aimed to investigate functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in spinal muscular atrophy type 1 (SMA1). Compared to historical cohorts, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function in patients with SMA1. To confirm the safety and efficacy of this gene therapy, further studies were required.

Methods

• The researchers administered a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein to 15 patients with SMA1.
• Among them, 3 patients received a low dose (6.7×10¹³vg per kilogram of body weight), and 12 received a high dose (2.0×10¹⁴ vg per kilogram).
• Safety was the primary outcome.
• The time until death or the need for permanent ventilatory assistance was the secondary outcome.
• They compared scores on the CHOP INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the 2 cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts) in exploratory analyses.

Results

• As compared with a rate of survival of 8% in a historical cohort, all 15 patients were alive and event-free at 20 months of age as of the data cutoff on August 7, 2017.
• In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort.
• 11 patients sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently, among 12 patients who had received the high dose.
• The researchers found elevated serum aminotransferase levels in 4 patients and were attenuated by prednisolone.