Gene Therapy Approaches in Spinal Muscular Atrophy: Neurological Outcomes and Safety
DOI:
https://doi.org/10.5281/zenodo.22310567Keywords:
Spinal muscular atrophy, Onasemnogene abeparvovec, Nusinersen, Risdiplam, Newborn screeningAbstract
Background: Spinal muscular atrophy (SMA) results from biallelic SMN1 loss, with SMN2 copy number modifying severity.
Three disease-modifying therapies are approved: the gene-replacement therapy onasemnogene abeparvovec, and two SMN2
splicing modifiers, nusinersen and risdiplam.Objective: To review pivotal trial, registry and safety literature on gene-replacement therapy for SMA, contextualised against splicing-modifier data. Methods: Narrative review of phase 1-3 trials, long-term extensions, newborn-screening cohorts, registries and pharmacovigilance reports. Findings: Onasemnogene abeparvovec produced survival and motor-milestone gains far exceeding natural history in symptomatic infants, with presymptomatic dosing yielding near-normal development in most infants. Nusinersen and risdiplam show comparable presymptomatic benefit. Hepatotoxicity and thrombotic microangiopathy are gene-therapy-specific safety signals requiring structured monitoring. Newborn screening consistently improves outcomes by enabling earlier treatment. Conclusions: Treatment timing, more than choice of modality, appears to be the dominant determinant of neurological outcome, supporting newborn screening as central to SMA care.
References
Mendell, J.R., Al-Zaidy, S., Shell, R., Arnold, W.D., Rodino-Klapac, L.R., Prior, T.W., et al. (2017) Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine, 377(18): 1713-1722.
Finkel, R.S., Chiriboga, C.A., Vajsar, J., Day, J.W., Montes, J., De Vivo, D.C., et al. (2016) Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. The Lancet, 388(10063): 3017-3026.
Finkel, R.S., Mercuri, E., Darras, B.T., Connolly, A.M., Kuntz, N.L., Kirschner, J., et al. (2017) Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. New England Journal of Medicine, 377(18): 1723-1732.
Mercuri, E., Darras, B.T., Chiriboga, C.A., Day, J.W., Campbell, C., Connolly, A.M., et al. (2018) Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. New England Journal of Medicine, 378(7): 625-635.
Baranello, G., Darras, B.T., Day, J.W., Deconinck, N., Klein, A., Masson, R., et al. (2021) Risdiplam in Type 1 Spinal Muscular Atrophy. New England Journal of Medicine, 384(10): 915-923.
Darras, B.T., Masson, R., Mazurkiewicz-Bełdzińska, M., Rose, K., Xiong, H., Zanoteli, E., et al. (2021) Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. New England Journal of Medicine, 385(5): 427-435.
Mercuri, E., Deconinck, N., Mazzone, E.S., Nascimento, A., Oskoui, M., Saito, K., et al. (2022) Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. The Lancet Neurology, 21(1): 42-52.
Al-Zaidy, S., Pickard, A.S., Kotha, K., Alfano, L.N., Lowes, L., Paul, G., et al. (2019) Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatric Pulmonology, 54(2): 179-185.
Mendell, J.R., Al-Zaidy, S.A., Lehman, K.J., McColly, M., Lowes, L.P., Alfano, L.N., et al. (2021) Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. JAMA Neurology, 78(7): 834-841.
Day, J.W., Finkel, R.S., Chiriboga, C.A., Connolly, A.M., Crawford, T.O., Darras, B.T., et al. (2021) Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-US): an open-label, single-arm, multicentre, phase 3 trial. The Lancet Neurology, 20(4): 284-293.
Mercuri, E., Muntoni, F., Baranello, G., Masson, R., Boespflug-Tanguy, O., Bruno, C., et al. (2021) Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. The Lancet Neurology, 20(10): 832-841.
Strauss, K.A., Farrar, M.A., Muntoni, F., Saito, K., Mendell, J.R., Servais, L., et al. (2022) Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine, 28(7): 1381-1389.
Strauss, K.A., Muntoni, F., Farrar, M.A., Saito, K., Mendell, J.R., Servais, L., et al. (2022) Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nature Medicine, 28(7): 1390-1397.
De Vivo, D.C., Bertini, E., Swoboda, K.J., Hwu, W.L., Crawford, T.O., Finkel, R.S., et al. (2019) Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscular Disorders, 29(11): 842-856.
Crawford, T.O., Swoboda, K.J., De Vivo, D.C., Bertini, E., Hwu, W.L., Finkel, R.S., et al. (2023) Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle & Nerve, 68(2): 157-170.
Servais, L., Day, J.W., De Vivo, D.C., Kirschner, J., Mercuri, E., Muntoni, F., et al. (2024) Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry. Journal of Neuromuscular Diseases, 11(3): 633-645.
Pechmann, A., König, K., Bernert, G., Schachtrup, K., Schara, U., Schorling, D., et al. (2019) SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet Journal of Rare Diseases, 14(1): 18.
Harada, Y., Rao, V.K., Arya, K., Kuntz, N.L., DiDonato, C.J., Napchan-Pomerantz, G., et al. (2021) Combination molecular therapies for spinal muscular atrophy: How much is enough? Muscle & Nerve, 63(1): 45-52.
Ramdas, S., Servais, L. (2020) New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opinion on Pharmacotherapy, 21(3): 307-315.
Chand, D., Mohr, F., McMillan, H., Tukov, F.F., Montgomery, K., Kleyn, A., et al. (2021) Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. Journal of Hepatology, 74(3): 560-566.
Feldman, A.G., Parsons, J.A., Dutmer, C.M., Veerapandiyan, A., Hafberg, E., Maloney, N., Mack, C.L. (2020) Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1. Journal of Pediatrics, 225: 252-258.
Chand, D.H., Zaidman, C., Arya, K., Millner, R., Farrar, M.A., Mackie, F.E., et al. (2021) Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series. Journal of Pediatrics, 231: 265-268.
Glascock, J., Sampson, J., Haidet-Phillips, A., Connolly, A.M., Darras, B.T., Day, J.W., et al. (2018) Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. Journal of Neuromuscular Diseases, 5(2): 145-158.
Glascock, J., Sampson, J., Connolly, A.M., Darras, B.T., Day, J.W., Finkel, R., et al. (2020) Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. Journal of Neuromuscular Diseases, 7(2): 97-100.
Vill, K., Kölbel, H., Schwartz, O., Blaschek, A., Olgemöller, B., Harms, E., et al. (2021) Newborn screening for spinal muscular atrophy in Germany: clinical results after 2 years. Orphanet Journal of Rare Diseases, 16(1): 153.
Kariyawasam, D.S.T., Russell, J.S., Wiley, V., Alexander, I.E., Farrar, M.A. (2023) Newborn screening for spinal muscular atrophy in Australia: a non-randomised cohort study. The Lancet Child & Adolescent Health, 7(3): 159-170.
Dangouloff, T., Vrščaj, E., Servais, L., Osredkar, D. (2023) Newborn screening for spinal muscular atrophy - what have we learned? Expert Review of Neurotherapeutics, 23(11): 1-13.
