Results of a Two-Year Comprehensive Follow-Up of Patients with Spinal Muscular Atrophy Type I Who Received Gene Therapy with Onasemnogen Abeparvovek

Introduction . Spinal muscular atrophy (SMA) is among the most severe inherited neuromuscular diseases. The development of pathogenetic treatment methods, including gene therapy, and their widespread clinical adoption has ushered in a new era in SMA treatment, making it possible not only to halt the progression of the disease but also to improve patients’ functional capabilities. Aim : to evaluate the efficacy of gene therapy in a real-world clinical practice with a 2-year follow-up study of patients with SMA type I who received treatment with onasemnogene abeparvovec. Materials and methods . The study included 73 patients with SMA type I. The disease was confirmed by molecular genetic testing.The diagnosis of SMA type I in 22 patients (30.1%) was established due to the development of the clinical picture of the disease and after confirmatory DNA diagnostics. In 51 patients (69.9%), initially identified as part of expanded neonatal screening, the diagnosis was established immediately after the onset of the first SMA symptoms. The mean age at the time of gene therapy was 2.78±1.87 months (95% CI 2.35–3.22), min 1.00, max 7.00. A comprehensive assessment of treatment effectiveness included clinical (the main the motor development milestones according to WHO, HINE-2 and CHOP-INTEND scores) and electroneuromyographic (latency, amplitude and area of the negative peak of the distal compound muscle action potential during electrical stimulation of the ulnar nerve at the wrist, the motor nerve conduction velocity of the ulnar nerve on the forearm) parameters before the initiation of gene therapy and 6, 12, 18 and 24 months after its implementation. Results . Following gene therapy, a large number of patients with SMA type I were able to achieve basic motor skills: 42.5% had good head control in the prone position; 78.1% rolled over from a supine to prone position; 47.2% sitting without support; 31.9% standing with assistance; 23.2% hands-&-knees crawling; 20.0% walking with assistance; 13.2% standing alone; 5.7% walking alone. However, most patients reached motor development milestones later than the WHO standards. By the end of the observation period, the HINE-2 score in patients with SMA type I significantly increased and amounted to Me 18.50 (16.00–24.00) points, with three children achieving the maximum score. The CHOP-INTEND scale score also increased significantly and amounted to Me 60.00 (58.00–64.00) points by the end of the 2-year observation period, with 17 children (23.3%) achieving the maximum score. Before gene therapy, patients with type I SMA had low values of the amplitude [Me 0.32 mV (0.15–0.81)] and area [Me 0.80 ms×mV (0.36–1.70)] of the compound muscle action potential. 24 months after gene therapy, the values of the amplitude and area significantly increased [Me 0.80 mV (0.60–1.20) and Me 1.40 ms×mV (1.00–2.10), respectively]. However, they did not reach the electroneuromyographic values of children without neurological pathology. During clinical and electroneuromyographic assessment in the dynamics of 2-year follow-up, it was not possible to establish statistically significant differences in patients with SMA type I depending on the onset of expanded neonatal screening. Conclusion . Gene therapy in patients with SMA type I results in significant improvements in motor development. Despite persistent delays in motor skill development, a large number of patients achieved key milestones in early motor development, as demonstrated by significant increases in HINE-2 and CHOP-INTEND scores and improved electroneuromyographic parameters.