Onasemnogene Abeparvovec: First Global Approval

Hoy, Sheridan M.

doi:10.1007/s40265-019-01162-5

Cited by 337Neurogenetic and Muscular Disorders ResearchVirus-based gene therapy researchLysosomal Storage Disorders Research

Onasemnogene Abeparvovec: First Global Approval

Hoy, Sheridan M.·2019·Drugs

DOI 10.1007/s40265-019-01162-5

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Abstract

Onasemnogene abeparvovec (onasemnogene abeparvovec-xioi; formerly AVXS-101; ZOLGENSMA ® ) is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the human survival motor neuron (SMN) gene to the motor neuron cells of patients with spinal muscular atrophy (SMA). It has been developed by AveXis, a Novartis company, and was approved in May 2019 in the USA for the treatment of paediatric patients aged 14 vector genomes per kg of bodyweight, administered as a single intravenous infusion over 60 min. Regulatory assessments for this formulation of onasemnogene abeparvovec are underway in the EU and Japan; an intrathecal formulation is currently undergoing clinical development in the USA. This article summarizes the milestones in the development of onasemnogene abeparvovec leading to this first approval for the treatment of paediatric patients aged < 2 years with SMA and bi-allelic mutations in SMN1.

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Onasemnogene Abeparvovec (Zolgensma) was commercialized in 2019 to treat children with Spinal Muscular Atrophy (SMA).
“In 2019, Onasemnogene Abeparvovec was commercialized under the brand name of Zolgensma to treat children with the lethal motor neuron disease Spinal Muscular Atrophy (SMA) [89].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [89]

1 retracted

RETRACTED ARTICLE: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN
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Retracted
Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy
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“In parallel, rare disease and (tailored) genetic therapies are gaining mainstream attention with the Food and Drug Administration (FDA) approval of the antisense oligonucleotide (Nusinersen) as well as the gene therapy (onasemnogene abeparvovec) for Spinal muscular atrophy (SMA) [34, 35] and the first personalized ant…”
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“Molec This is an open access article under the CC BY-NC-N has approved a therapeutic approach based on the stable replacement of SMN1 using viral vectors, called onasemnogene abeparvovec (Zolgensma).(9,10)”
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“This is the case of onasemnogene abeparvovec (Zolgensma®), which, if administered early in life seems to cure spinal muscular atrophy (Hoy, 2019).”
Background
Advanced Therapies and Regulatory Framework in Different Areas of the Globe: Past, Present, and Future
Bosio, C. G. P., Bettiol, V. L., Alencar‐Silva, T., Franco, O. L., Pogue, R. E., Carvalho, J. L., & Felipe, M. S. S. (2021) · Clinical Therapeutics · doi:10.1016/j.clinthera.2021.02.006 · Cited by 39 · see citing works
The Platform Vector Gene Therapies Project: Increasing the Efficiency of Adeno-Associated Virus Gene Therapy Clinical Trial Startup
Brooks, P., Ottinger, E., Portero, D., Lomash, R. M., Alimardanov, A., Terse, P., Xu, X., Chandler, R., Hauserman, J., Esposito, E., et al. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.259 · Cited by 33 · see citing works
“Food and Drug Administration (FDA) has now approved gene therapy products for treating an RPE65 mutation-associated retinal disease, Leber congenital amaurosis,(3) and a neurodegenerative disease, spinal muscular atrophy.(4)”
Background
Intellectual abilities, language comprehension, speech, and motor function in children with spinal muscular atrophy type 1
Zappa, G., Lomauro, A., Baranello, G., Cavallo, E., Corti, P., Mastella, C., & Costantino, M. A. (2021) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-021-09355-4 · Cited by 32
Adeno-Associated Virus (AAV-DJ)—Cryo-EM Structure at 1.56 Å Resolution
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“Three decades of development have culminated in the use of recombinant forms as vectors for the first FDA-approved in vivo gene therapies of genetic diseases, most notably in 2019 for a treatment of spinal muscular atrophy (SMA) [17,18].”
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Updated review of therapeutic strategies for Charcot-Marie-Tooth disease and related neuropathies
Pisciotta, C., Saveri, P., & Pareyson, D. (2021) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2021.1935242 · Cited by 29
“This is also true for repeat gene silencing approaches, like those with ASOs and siRNAs, as for ATTRv and SMA, which however are lethal diseases as compared to most CMT forms which do not shorten the life span.”
BackgroundInfluential
Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta‐analysis
Pascual-Morena, C., Martínez-Vizcaíno, V., Cavero-Redondo, I., Martínez-García, I., Moreno-Herráiz, N., Álvarez-Bueno, C., & Saz-Lara, A. (2023) · Pharmacotherapy · doi:10.1002/phar.2866 · Cited by 28
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Kok, C. Y., Tsurusaki, S., Cabanes-Creus, M., Igoor, S., Rao, R., Skelton, R., Liao, S. H., Ginn, S., Knight, M., Scott, S., et al. (2023) · Molecular Therapy: Methods & Clinical Development · doi:10.1016/j.omtm.2023.08.010 · Cited by 28 · see citing works
Genome Editing for CNS Disorders
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“, 2017), and spinal muscular atrophy (SMA) with Zolgensma (a rAAV9 encoding the survival motor neuron 1 protein; Hoy, 2019) provide examples of approved products.”
Background
Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations
Aartsma-Rus, A. M., van Roon‐Mom, W., Lauffer, M. C., Siezen, C. L. E., Duijndam, B., Roo, T. C.-D., Schüle, R., Synofzik, M., & Graeßner, H. (2023) · RNA · doi:10.1261/rna.079540.122 · Cited by 32 · see citing works
Gene Transfer Therapy for Neurodevelopmental Disorders
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Vaiserman, A. M., FALCO, E. D., Koliada, A. K., Maslova, O., & Balistreri, C. R. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100977 · Cited by 30 · see citing works
Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?
Harkins, A. L., Ambegaokar, P. P., & Keeler, A. M. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00435 · Cited by 32 · see citing works
Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches
Mijanović, O., Branković, A., Borovjagin, A. V., Butnaru, D. V., Bezrukov, E. A., Sukhanov, R. B., Shpichka, A. I., Timashev, P. S., & Ulasov, I. V. (2020) · Viruses · doi:10.3390/v12040460 · Cited by 32 · see citing works
“In contrast to the majority of viral vectors utilized for gene therapy interventions, AAV-based vectors exhibit the highest potential and success rate in the treatment of several monogenic diseases, as demonstrated by clinical trials [64,65].”
Background
AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy
Villalón, E., Kline, R., Smith, C. E., Lorson, Z. C., Osman, E. Y., O’Day, S., Murray, L. M., & Lorson, C. L. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz188 · Cited by 29 · see citing works
“The most recent FDA approved therapeutic, Zolgensma, in contrast, employs a gene replacement approach in order to restore SMN expression (9).”
Background
Considerations for Systemic Use of Gene Therapy
Byrne, B. J., Corti, M., & Muntoni, F. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.01.016 · Cited by 23 · see citing works
Tetramer-Based Enrichment of Preexisting Anti-AAV8 CD8+ T Cells in Human Donors Allows the Detection of a TEMRA Subpopulation
Vandamme, C., Xicluna, R., Hesnard, L., Devaux, M., Jaulin, N., Guilbaud, M., Le Duff, J., Couzinié, C., Moullier, P., Saulquin, X., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03110 · Cited by 23 · see citing works
Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges
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“Two other patients had asymptomatic AST and ALT elevations that resolved without intervention [81,82].”
BackgroundInfluential
Current non-invasive strategies for brain drug delivery: overcoming blood–brain barrier transport
Zheng, X., Yang, J., Hou, Y., Fang, Y., Wu, K., Song, Y., Liu, K., & Zhu, J. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08968-3 · Cited by 25 · see citing works
“The first successful AAV-based gene therapy for a CNS disorder (NCT03955679) is onasemnogene abe-parvovec (Zolgensma) approved for the treatment of paediatric patients aged 2 years with spinal muscular atrophy (SMA) by FDA [54].”
Assessment of Health-Related Quality of Life in Adult Spinal Muscular Atrophy Under Nusinersen Treatment—A Pilot Study
Thimm, A., Brakemeier, S., Kizina, K., Munoz-Rosales, J., Stolte, B., Totzeck, A., Deuschl, C., Kleinschnitz, C., & Hagenacker, T. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.812063 · Cited by 23 · see citing works
Adeno-associated virus therapies: Pioneering solutions for human genetic diseases
Liu, D., Tian, L., Liu, L., Che, X., Li, X., Liu, C., & Wu, G. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.09.003 · Cited by 27 · see citing works
Hidden regulators: the emerging roles of lncRNAs in brain development and disease
Alammari, F., Al-Hujaily, E. M., Alshareeda, A. T., Albarakati, N., & Al-Sowayan, B. S. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1392688 · Cited by 22 · see citing works
“Moreover, another AAV-based therapy targeting SMN gene, called Onasemnogene abeparvovec, is the first gene therapy for SMA approved in the United States and proves that AAV methods are effective in treating neurological diseases (Hoy, 2019).”
Background
Gene therapy in pediatrics – Clinical studies and approved drugs (as of 2023)
Gol, T. M., Zahedipour, F., Trosien, P., Ureña-Bailén, G., Kim, M., Antony, J. S., & Mezger, M. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122685 · Cited by 30 · see citing works
Safety and efficacy of gene therapy with onasemnogene abeparvovec in the treatment of spinal muscular atrophy: A systematic review and meta‐analysis
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Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders
Limia, C. E. G., Baird, M., Schwartz, M., Saxena, S., Meyer, K., & Wein, N. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12121979 · Cited by 23 · see citing works
“Survival has also been extended well beyond the two-year life expectancy [166].”
Background
Drug Discovery of Spinal Muscular Atrophy (SMA) from the Computational Perspective: A Comprehensive Review
Chong, L. C., Gandhi, G., Lee, J. M., Yeo, W. W. Y., & Choi, S. B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168962 · Cited by 21 · see citing works
“Given its effectiveness in resolving the SMA molecular defect, it adversely affects the liver by increasing the level of serum aminotransferase, a liver enzyme [7,101,102].”
Background
Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
Biferi, M. G., Cohen-Tannoudji, M., García-Silva, A., Souto-Rodríguez, O., Viéitez, I., Millán, B. S., Fernández‐Carrera, A., Pérez-Márquez, T., Teijeira, S., Barrera, S., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.10.016 · Cited by 26 · see citing works
An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission
Suriano, C. M., Kumar, N., Verpeut, J. L., Ma, J., Jung, C., Dunn, C. E., Carvajal, B. V., Nguyen, A. V., & Boulanger, L. M. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.036 · Cited by 21 · see citing works
“…clinically to restore endogenous protein function in the nervous system to treat Leber ’ s congenital amaurosis 2 2,3 and spinal muscular atrophy, 4,5 and AAV-based clinical trials are under way to treat numerous other disorders of the nervous system, including Alzheimer ’ s disease, Canavan ’ s…”
Targeted-Deletion of a Tiny Sequence via Prime Editing to Restore SMN Expression
Zhou, M., Tang, S., Duan, N., Xie, M., Li, Z., Feng, M., Wu, L., Hu, Z., & Liang, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147941 · Cited by 28 · see citing works
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Background
The impact of long-term ventilator-use on health-related quality of life and the mental health of children with neuromuscular diseases and their families: need for a revised perspective?
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Early Development of Spinal Deformities in Children Severely Affected with Spinal Muscular Atrophy after Gene Therapy with Onasemnogene Abeparvovec—Preliminary Results
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Flexible endoscopic evaluation of swallowing in children with type 1 spinal muscular atrophy
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Cell-penetrating peptides enhance the transduction of adeno-associated virus serotype 9 in the central nervous system
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Authors: Hoy, S. M.
Affiliations: Springer Nature (New Zealand) (NZ)
Corresponding author: Hoy, Sheridan M.
Venue: Drugs
Publisher: Springer Science and Business Media LLC
Published: 2019-07
Volume: 79
Issue: 11
Pages: 1255-1262
ISSN: 0012-6667 (ISSN-L)
1179-1950
DOI: 10.1007/s40265-019-01162-5
OpenAlex: W2955699452
Cited by: 337
References: 0
Citations by year: 2026: 31 · 2025: 36 · 2024: 54 · 2023: 42 · 2022: 38 · 2021: 68 · 2020: 58 · 2019: 9 · 2018: 1
FWCI: 23.71
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Drugs (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords: onasemnogene abeparvovec, Zolgensma, spinal muscular atrophy, gene therapy, adeno-associated virus vectors, SMN1, survival motor neuron protein, pediatric patients, regulatory approval, drug development milestones
MeSH terms: Dependovirus, Genetic Vectors, Humans, Infant, Infant, Newborn, Infusions, Intravenous, Motor Neurons, Muscular Atrophy, Spinal, Mutation, United States, United States Food and Drug Administration, Genetic Therapy, Drug Approval, SMN Complex Proteins

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Onasemnogene Abeparvovec: First Global Approval

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