Results of a two-year comprehensive follow-up in patients with spinal muscular atrophy who received gene therapy with onasemnogen abeparvovec at the presymptomatic stage of the disease

Introduction. The use of gene therapy in patients with spinal muscular atrophy (SMA) has led to a significant improvement in the prognosis of motor development. The inclusion of SMA in the expanded neonatal screening in the Russian Federation allowed not only identifying patients as early as possible, but also gene therapy at the presymptomatic stage of the disease became available for some of them.Objective. To evaluate the effectiveness of gene therapy in real clinical practice during 2 years of follow-up of SMA patients treated with onasemnogen abeparvovec at the presymptomatic stage of the disease.Materials and methods. The study included thirty five SMA children, with a genetically verified diagnosis of SMA without developing symptoms of the disease. The diagnosis of SMA was established during the pilot project of the extended neonatal screening or from 01/01/2023 as part of the extended neonatal screening. The diagnosis was verified during DNA diagnostics. Deletion of exons 7 and/or 8 of the SMN1 gene in the homozygous state was detected in all children. All patients received gene therapy with onasemnogen abeparvovec, the average age at the time of therapy was 2.00 ± 0.94 months (95% CI 1.68–2.32), min — 1.00, max — 5.00. A comprehensive assessment was conducted of clinical (the motor development milestones according to WHO, HINE-2 and CHOP-INTEND scores), electroneuromyographic (latency, amplitude and area of the negative peak of the compound muscle action potential during electrical stimulation of the ulnar nerve on the wrist; the motor nerve conduction velocity of the ulnar nerve on the forearm) and biochemical parameters (levels of light and heavy chains of neurofilaments (NF) in blood serum in SMA patients at the presymptomatic stage before initiation of gene therapy and after 6, 12, 18, and 24 months after its implementation.Results. In our study, SMA patients at the presymptomatic stage, both before and after gene therapy, had motor development in accordance with age norms and did not significantly differ from children without neurological pathology. A comparative analysis of the electroneuromyographic parameters in SMA children and a group of healthy children revealed no statistically significant differences in patients at the presymptomatic stage of SMA on the background of gene therapy. A comparative analysis of the levels of light and heavy NF chains in the blood serum in SMA patients at the presymptomatic stage before gene therapy and 76 neurologically healthy children obtained in a recent study showed the level of light NF chains in SMA to be significantly higher (p < 0.001) — Me — 6.00, Q1; Q3 = 6.00; 31.43 pg/ml and Me — 4.00, Q1; Q3 = 2.50; 9.57 pg/ml, respectively. At the same time, the level of heavy NF chains did not significantly differ when comparing SMA patients at the presymptomatic stage before gene therapy with healthy peers. The use of onasemnogen abeparvovec in SMA patients at the presymptomatic stage led to a statistically significant decrease in the level of light chains NF in the blood serum. The maximum decrease in NF was observed 3–6 months after the gene therapy.Conclusion. Carrying out gene therapy using the onasemnogen abeparvovek in SMA patients at the presymptomatic stage made it possible to prevent the development of symptoms of the disease and achieve the main stages of motor development milestones according to WHO criteria.Compliance with ethical standards. Permission to conduct this study was obtained from the local ethics committee of the National Medical Research Center for Children’s Health (Minutes of the Local ethics committee, meeting No. 10 dated 10/06/2022).Contribution:Kuzenkova L.M., Kurenkov A.L., Uvakina E.V., Fisenko D.A. — concept and design of research, writing, editing;Chernikov V.V. — statistical data processing, editing.All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.Funding. The study had no sponsorship.Conflict of interest. The authors declare no conflict of interest.Received: November 6, 2024Accepted: December 1, 2024Published: January 31, 2025