Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.
Autopsy
Biological Products
/ administration & dosage
DNA
/ genetics
Female
Genetic Therapy
/ adverse effects
Genetic Vectors
/ administration & dosage
Humans
Infant
Infant, Newborn
Male
Motor Neurons
/ drug effects
RNA, Messenger
/ genetics
Recombinant Fusion Proteins
/ administration & dosage
Spinal Muscular Atrophies of Childhood
/ genetics
Survival of Motor Neuron 1 Protein
/ genetics
Tissue Distribution
/ drug effects
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
11
11
2020
accepted:
27
07
2021
pubmed:
6
10
2021
medline:
16
11
2021
entrez:
5
10
2021
Statut:
ppublish
Résumé
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.
Identifiants
pubmed: 34608334
doi: 10.1038/s41591-021-01483-7
pii: 10.1038/s41591-021-01483-7
doi:
Substances chimiques
Biological Products
0
RNA, Messenger
0
Recombinant Fusion Proteins
0
SMN1 protein, human
0
Survival of Motor Neuron 1 Protein
0
Zolgensma
0
DNA
9007-49-2
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1701-1711Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 13, 155–165 (1995).
doi: 10.1016/0092-8674(95)90460-3
Burghes, A. H. M. & McGovern, V. L. in Molecular and Cellular Therapies for Motor Neuron Diseases (eds. Boulis, N. M. et al.) 121–139 (Elsevier, 2017).
Kolb, S. J. & Kissel, J. T. Spinal muscular atrophy. Neurol. Clin. 33, 831–846 (2015).
pubmed: 26515624
pmcid: 4628728
doi: 10.1016/j.ncl.2015.07.004
Monani, U. R. et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8, 1177–1183 (1999).
pubmed: 10369862
doi: 10.1093/hmg/8.7.1177
Lorson, C. L., Hahnen, E., Androphy, E. J. & Wirth, B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA 96, 6307–6311 (1999).
pubmed: 10339583
pmcid: 26877
doi: 10.1073/pnas.96.11.6307
Cartegni, L. & Krainer, A. R. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet. 30, 377–384 (2002).
pubmed: 11925564
doi: 10.1038/ng854
Lorson, C. L. et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat. Genet. 19, 63–66 (1998).
pubmed: 9590291
doi: 10.1038/ng0598-63
Burnett, B. G. et al. Regulation of SMN protein stability. Mol. Cell. Biol. 29, 1107–1115 (2009).
pubmed: 19103745
doi: 10.1128/MCB.01262-08
Lefebvre, S. et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16, 265–269 (1997).
pubmed: 9207792
doi: 10.1038/ng0797-265
Coovert, D. D. et al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 6, 1205–1214 (1997).
pubmed: 9259265
doi: 10.1093/hmg/6.8.1205
Feldkötter, M., Schwarzer, V., Wirth, R., Wienker, T. F. & Wirth, B. Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am. J. Hum. Genet. 70, 358–368 (2002).
pubmed: 11791208
doi: 10.1086/338627
Mailman, M. D. et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet. Med. 4, 20–26 (2002).
pubmed: 11839954
doi: 10.1097/00125817-200201000-00004
Roberts, D. F., Chavez, J. & Court, S. D. The genetic component in child mortality. Arch. Dis. Child. 45, 33–38 (1970).
pubmed: 4245389
pmcid: 2020428
doi: 10.1136/adc.45.239.33
D’Amico, A., Mercuri, E., Tiziano, F. D. & Bertini, E. Spinal muscular atrophy. Orphanet J. Rare Dis. 6, 71 (2011).
pubmed: 22047105
pmcid: 3231874
doi: 10.1186/1750-1172-6-71
Finkel, R. S. et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 83, 810–817 (2014).
pubmed: 25080519
pmcid: 4155049
doi: 10.1212/WNL.0000000000000741
Finkel, R. S. Electrophysiological and motor function scale association in a pre-symptomatic infant with spinal muscular atrophy type I. Neuromuscul. Disord. 23, 112–115 (2013).
pubmed: 23146148
doi: 10.1016/j.nmd.2012.09.006
Crawford, T. O. & Pardo, C. A. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 3, 97–110 (1996).
pubmed: 9173917
doi: 10.1006/nbdi.1996.0010
Swoboda, K. J. et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann. Neurol. 57, 704–712 (2005).
pubmed: 15852397
pmcid: 4334582
doi: 10.1002/ana.20473
Lutz, C. M. et al. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J. Clin. Invest. 121, 3029–3041 (2011).
pubmed: 21785219
pmcid: 3148744
doi: 10.1172/JCI57291
Le, T. T. et al. Temporal requirement for high SMN expression in SMA mice. Hum. Mol. Genet. 20, 3578–3591 (2011).
pubmed: 21672919
pmcid: 3159555
doi: 10.1093/hmg/ddr275
Duque, S. I. et al. A large animal model of spinal muscular atrophy and correction of phenotype. Ann. Neurol. 77, 399–414 (2015).
pubmed: 25516063
pmcid: 4453930
doi: 10.1002/ana.24332
Farrar, M. A. et al. Emerging therapies and challenges in spinal muscular atrophy. Ann. Neurol. 81, 355–368 (2017).
pubmed: 28026041
pmcid: 5396275
doi: 10.1002/ana.24864
Wood, M. J. A., Bowerman, M. & Talbot, K. Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Hum. Mol. Genet. 26, R151–R159 (2017).
pubmed: 28977438
doi: 10.1093/hmg/ddx215
Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).
pubmed: 19098898
doi: 10.1038/nbt.1515
Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187–1196 (2009).
pubmed: 19367261
pmcid: 2835208
doi: 10.1038/mt.2009.71
Lykken, E. A., Shyng, C., Edwards, R. J., Rozenberg, A. & Gray, S. J. Recent progress and considerations for AAV gene therapies targeting the central nervous system. J. Neurodev. Disord. 10, 16 (2018).
pubmed: 29776328
pmcid: 5960126
doi: 10.1186/s11689-018-9234-0
Hudry, E. & Vandenberghe, L. H. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron 101, 839–862 (2019).
pubmed: 30844402
doi: 10.1016/j.neuron.2019.02.017
Bevan, A. K. et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol. Ther. 19, 1971–1980 (2011).
pubmed: 21811247
pmcid: 3222525
doi: 10.1038/mt.2011.157
Xu, L. et al. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum. Gene Ther. 12, 563–573 (2001).
pubmed: 11268288
doi: 10.1089/104303401300042500
Wang, Z. et al. Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene. Ther. 10, 2105–2111 (2003).
pubmed: 14625564
doi: 10.1038/sj.gt.3302133
Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).
pubmed: 29378426
pmcid: 5865262
doi: 10.1089/hum.2018.015
Van Alstyne, M. et al. Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit. Nat. Neurosci. https://doi.org/10.1038/s41593-021-00827-3 (2021).
Day, J. W. et al. Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy. Drug Saf. https://doi.org/10.1007/s40264-021-01107-6 (2021).
Al-Zaidy, S. A. et al. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J. Neuromuscul. Dis. 6, 307–317 (2019).
pubmed: 31381526
doi: 10.3233/JND-190403
Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).
pubmed: 29091557
doi: 10.1056/NEJMoa1706198
Mendell, J., et al. Five-year extension results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 78, 834–841 (2021).
pubmed: 33999158
doi: 10.1001/jamaneurol.2021.1272
Day, J. W. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy with two copies of SMN2 (STR1VE): an open-label, single-arm, phase 3 study. Lancet Neurol. 20, 284–293 (2021).
pubmed: 33743238
doi: 10.1016/S1474-4422(21)00001-6
Strauss, K. et al. Onasemnogene abeparvovec gene therapy in presymptomatic spinal muscular atrophy (SMA): SPR1NT study update in children with 2 copies of SMN2. Neurology 96, S15 (2021).
Mercuri, E. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 20, 838–841 (2021).
doi: 10.1016/S1474-4422(21)00251-9
Zincarelli, C., Soltys, S., Rengo, G. & Rabinowitz, J. E. Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 16, 1073–1080 (2008).
pubmed: 18414476
doi: 10.1038/mt.2008.76
Blatnik, A. J. III et al. Conditional deletion of SMN in cell culture identifies functional SMN alleles. Hum. Mol. Genet. 29, 3477–3492 (2020).
pubmed: 33075805
doi: 10.1093/hmg/ddaa229
pmcid: 7946624
Sheng, L., et al. Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model. Nucleic Acids Res. 48, 2853–2865 (2020).
pubmed: 32103257
pmcid: 7102994
doi: 10.1093/nar/gkaa126
Buchlis, G. et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 119, 3038–3041 (2012).
pubmed: 22271447
pmcid: 3321866
doi: 10.1182/blood-2011-09-382317
Bartus, R. T. et al. Post-mortem assessment of the short and long-term effects of the trophic factor neurturin in patients with alpha-synucleinopathies. Neurobiol. Dis. 78, 162–171 (2015).
pubmed: 25841760
doi: 10.1016/j.nbd.2015.03.023
Castle, M. J. et al. Postmortem analysis in a clinical trial of AAV2-NGF gene therapy for Alzheimer’s disease identifies a need for improved vector delivery. Hum. Gene. Ther. 31, 415–422 (2020).
pubmed: 32126838
pmcid: 7194314
doi: 10.1089/hum.2019.367
Meyer, K. et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. Mol. Ther. 23, 477–487 (2015).
pubmed: 25358252
doi: 10.1038/mt.2014.210
Kolb, S. J. et al. Natural history of infantile-onset spinal muscular atrophy. Ann. Neurol. 82, 883–891 (2017).
pubmed: 29149772
pmcid: 5776712
doi: 10.1002/ana.25101
Rindt, H. et al. Astrocytes influence the severity of spinal muscular atrophy. Hum. Mol. Genet. 15, 4094–4102 (2015).
doi: 10.1093/hmg/ddv148
Vukojicic, A. et al. The classical complement pathway mediates microglia-dependent remodeling of spinal motor circuits during development and in SMA. Cell. Rep. 3, 3087–3100 (2019).
doi: 10.1016/j.celrep.2019.11.013
Bevan, A. K. et al. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum. Mol. Genet. 19, 3895–3905 (2010).
pubmed: 20639395
pmcid: 2947399
doi: 10.1093/hmg/ddq300
Shababi, M. et al. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum. Mol. Genet. 19, 4059–4071 (2010).
pubmed: 20696672
doi: 10.1093/hmg/ddq329
Heier, C. R., Satta, R., Lutz, C. & DiDonato, C. J. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum. Mol. Genet. 19, 3906–3918 (2010).
pubmed: 20693262
pmcid: 2947406
doi: 10.1093/hmg/ddq330
Iascone, D. M., Henderson, C. E. & Lee, J. C. Spinal muscular atrophy: from tissue specificity to therapeutic strategies. F1000Prime Rep. 7, 4 (2015).
doi: 10.12703/P7-04
Wijngaarde, C. A. et al. Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet. J. Rare Dis. 12, 67 (2017).
pubmed: 28399889
pmcid: 5387385
doi: 10.1186/s13023-017-0613-5
Prior, T. W. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am. J. Hum. Genet. 85, 408–413 (2009).
pubmed: 19716110
pmcid: 2771537
doi: 10.1016/j.ajhg.2009.08.002
Bernal, S. et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J. Med. Genet. 47, 640–642 (2010).
pubmed: 20577007
doi: 10.1136/jmg.2010.079004
Oskoui, M., Darras, B.T., and De Vivo, D.C. in Spinal Muscular Atrophy (eds. Sumner, C. J. et al.) 3–19 (Academic Press, 2017).
Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2021).
pubmed: 33186633
doi: 10.1016/j.jhep.2020.11.001
Feldman, A. G. et al. Subacute liver failure following gene replacement therapy for spinal muscular atrophy type I. J. Pediatr. 225, 252–258 (2020).
pubmed: 32473148
doi: 10.1016/j.jpeds.2020.05.044