Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I

Abstract

Background: Spinal muscular atrophy (SMA) is a neuromuscular progressive disease, characterized by decreased amounts of survival motor neuron (SMN) protein, due to an autosomal recessive genetic defect. Despite recent research, there is still no cure. Nusinersen, an antisense oligonucleotide acting on the SMN2 gene, is intrathecally administered all life long, while onasemnogene abeparvovec-xioi, a gene therapy, is administered intravenously only once. Both therapies have proven efficacy, with best outcomes obtained when administered presymptomatically. In recent years, disease-modifying therapies such as nusinersen and onasemnogene abeparvovec-xioi have changed the natural history of SMA. Methods: We observed seven SMA type I patients, who received both therapies. We compared their motor function trajectories, ventilation hours and cough assist sessions to a control group of patients who received one therapy, in order to investigate whether combination therapy may be more effective than a single intervention alone. Results: Patients who received both therapies, compared to the monotherapy cohort, had the same motor function trajectory. Moreover, it was observed that the evolution of motor function was better in the 6 months following the first therapy than in the first 6 months after adding the second treatment. Conclusions: Our results suggest that early treatment is more important than combined therapy.

Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

“…Nevertheless, a combination of therapies directly acting to increase SMN protein through splicing or gene replacement mechanisms with other SMN-independent approaches might allow their synergistic action and enhance the overall clinical outcome of the disease. Combined Nusinersen and Zolgensma therapy (both SMN-dependent) in 5q SMA type I patients seems to offer no additional benefits in motor function progression or ventilation over monotherapy with either of these treatments, emphasizing that early treatment is more important than the combined strategy [ 141 ]. However, NMJ transmission defects are still reported after 14 months of treatment with nusinersen [ 142 ], illustrating the heterogeneity of this disease among patients who could benefit from SMN-independent therapies tackling other mechanisms underlying the disease.…”

“…However, NMJ transmission defects are still reported after 14 months of treatment with nusinersen [ 142 ], illustrating the heterogeneity of this disease among patients who could benefit from SMN-independent therapies tackling other mechanisms underlying the disease. Though encouraging results have been observed with regards to muscle mass, motor neuron function, and physical performance in the preclinical stage [ 139 , 143 ], clinical trials have been limited to a small number of participants, therefore leaving the benefits of dual therapy over monotherapy unclear [ 141 , 144 ].…”

Clinical and Electrophysiological Changes in Pediatric Spinal Muscular Atrophy after 2 Years of Nusinersen Treatment

“…Nusinersen treatment has changed the paradigm of this disease evolution; early forms with neonatal onset or in the first months of life, with severe bulbar dysfunction, are no longer fatal, and in late forms have significantly improved motor performance and quality of life. We found a clinically significant improvement in patients who started treatment as soon as possible [ 35 ] at the time of the first signs of the disease (motor regression), both in the early and late forms.…”

Neuromuszkuláris betegségek • Neuromuscular Diseases

“…Az ALS kezelésére alkalmazott riluzol vagy edaravon hatása nem drámai, a betegséget nem tudják megállítani. SMA-ban napjainkban áttörést hozott a mielőbb, már enyhe tüneteknél elkezdendő, s a gerincvíztérbe adandó nusinersen vagy a szájon át alkalmazható risdiplam, illetve az intravénásan egy alkalommal adandó onasemnogeme abeparovec-xioi (Mirea et al, 2021). Ezek a kezelések már a génterápia körébe tartoznak, s a survival motor neuron gén egyik típusának átírását módosítva vagy a megfelelő gén sejtekbe juttatásával érik el hatásukat.…”