The efficacy of gene therapy with onasemnogene abeparvovec in spinal muscular atrophy in young patients

Introduction. The advent of pathogenetic therapy has significantly changed the prognosis for spinal muscular atrophy (SMA). However, our knowledge of the pathogenetic methods of treating SMA is mostly based on the results of clinical trials, which are largely limited due to the narrow criteria for selecting patients and the short duration of the following-up.

Objective. To evaluate the efficacy of onasemnogene abeparvovec gene therapy in patients with SMA type I with clinical manifestations of the disease and in children at the presymptomatic stage of the disease in real clinical practice.

Materials and methods. The study included seventy nine SMA children including 42 boys (53.2%). The diagnosis was verified during DNA diagnostics. The children were divided into two subgroups, depending on whether they had symptoms of SMA at the time of inclusion in the study or not. 44 children had SMA type I with the onset of clinical symptoms before the age of 6 months of life. 35 children were at the presymptomatic stage of the disease. All patients received gene therapy with onasemnogene abeparvovec, the average age at themoment of conduction of therapy was 2.90 ± 1.74 months (95% CI: 2.51–3.29 months), min — 1.00 month, max — 7.00 months. A comprehensive assessment of clinical parameters (stages of motor development milestones according to WHO recommendations, HINE-2 and CHOP-INTEND scores) was carried out before the initiation of gene therapy and 6, 12, 18 and 24 months after its implementation.

Results. Children with SMA type I showed favour trend in motor development milestones after gene therapy. By the end of the second year of thefollow-up, 88.6% of patients held their head erect and rolled from back to sides; 60.5% could sit without support, but only 10.3% were able to achieve all motor skills, but none of these children achieved them in accordance with WHO criteria. The HINE-2 score increased from Me of 2.0 (1.00–2.25) points at the initiation of therapy to Me of 20.00 (16.50-24.50) points by the end of the follow-up period. Only two children (4.5%) of this subgroup reached the maximum score of 26 points. The CHOP-INTEND score increased from Me of 30.0 (22.00–37.25) points before starting treatment to Me of 60.0 (58.0-64.0) points by 24 months of follow-up. Only 11.4% of patients with SMA type I reached the maximum score of 64 points. The majority of the presymptomatic patients in our study achieved all motor development milestones according to WHO criteria according to their age on the background of gene therapy. All children from this subgroup who were under sufficient supervision and reached the age of walking alone (23 children) had a maximum HINE-2 score of 26 points by the age of 18 months. All children from this subgroup reached the maximum CHOP-INTEND score of 64 points by the age of 6 months.

Conclusion. The usage of onasemnogene abeparvovec in children with SMA type I both significantly modifies the course of the disease and improves outcomes compared with the natural history of SMA course with early onset, and the usage of gene therapy in most of the presymptomatic patients leads to the achievement of motor development milestones in accordance with WHO criteria.

Compliance with ethical standards. Permission for conducting this study was obtained from the local ethics committee of the National Medical Research Center for Children’s Health, of the Ministry of Health of the Russian Federation (minutes of the local ethics committee meeting No. 10 dated 06.10.2022).

Contribution:
Fisenko D.A. — concept and design of the review, writing the text, editing;
Kurenkov A.L. — concept and design of the review, writing the text, editing;
Kuzenkova L.M. — concept and design of the review, editing;
Chernikov V.V. — statistical data processing;
Uvakina E.V. — concept and design of the review, editing;
Popovich S.G. — editing;
Bursagova B.I. — editing;
Abdullaeva L.M. — editing;
Kurova J.А. — editing;
Adalimova N.S. — editing;
Nikolenko D.S. — editing.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: March 3, 2025
Accepted: April 4, 2025
Published: April 30, 2025

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