adeno-associated viral vector; disease-modifying treatments; gene therapy; motor milestones; neurodegenerative disorders; newborn screening; onasemnogene abeparvovec; spinal muscular atrophy; survival motor neuron; vector genomes; Clinical Biochemistry; Drug Discovery; Pharmacology
Abstract :
[en] INTRODUCTION: Gene therapy for spinal muscular atrophy (SMA) represents a significant milestone in the treatment of neurologic diseases. SMA is a neurodegenerative disease that results in motor neuron loss because of mutations of the survival motor neuron 1 gene, which directs survival motor neuron (SMN) protein production. Onasemnogene abeparvovec, a one-time gene replacement therapy, delivers a functional transgene to restore SMN protein expression. Onasemnogene abeparvovec has demonstrated improved survival and motor milestone achievements for presymptomatic infants and patients with SMA type 1.
AREAS COVERED: This expert review describes the current state of gene therapy for SMA, reviews the mechanism of and clinical experience with onasemnogene abeparvovec, explains future efforts to expand applications of gene therapy for SMA, and provides context for developing gene therapy for other conditions.
EXPERT OPINION: Onasemnogene abeparvovec has demonstrated efficacy in clinical trials and, because of this, is a valuable treatment option for patients with symptomatic infantile SMA and those identified by newborn screening. Gene therapy is still in its infancy, and challenges and uncertainties associated with transgene delivery must be addressed. With ongoing development of vector technology, more specific tissue tropism, reduced "off-target" effects, and an enhanced safety profile will continue to evolve.
Disciplines :
Neurology Pediatrics
Author, co-author :
McMillan, Hugh J; Departments of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada
Proud, Crystal M; Children's Hospital of The King's Daughters, Norfolk, VA, United States
Farrar, Michelle A; School of Women's and Children's Health, UNSW Medicine, UNSW Sydney ; Sydney Children's Hospital Network, Sydney, Australia
Alexander, Ian E; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia ; Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
Muntoni, Francesco; The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health London, UK ; NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
Language :
English
Title :
Onasemnogene abeparvovec for the treatment of spinal muscular atrophy.
Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80 (1): 155–165.
Wirth B. Spinal muscular atrophy: in the challenge lies a solution. Trends Neurosci. 2021; 44 (4): 306–322.
Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy–a literature review. Orphanet J Rare Dis. 2017; 12 (1): 124.
Lally C, Jones C, Farwell W, et al. Indirect estimation of the prevalence of spinal muscular atrophy type I, II, and III in the United States. Orphanet J Rare Dis. 2017; 12 (1): 175.
Strunk A, Abbes A, Stuitje AR, et al. Validation of a fast, robust, inexpensive, two-tiered neonatal screening test algorithm on dried blood spots for spinal muscular atrophy. Int J Neonatal Screen. 2019; 5 (2): 21.
Burghes AHM, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci. 2009; 10 (8): 597–609.
Calucho M, Bernal S, Alías L, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018; 28 (3): 208–215.
Tiziano FD, Bertini E, Messina S, et al. The Hammersmith functional score correlates with the SMN2 copy number: a multicentric study. Neuromuscul Disord. 2007; 17 (5): 400–403.
Schorling DC, Becker J, Pechmann A, et al. Discrepancy in redetermination of SMN2 copy numbers in children with SMA. Neurology. 2019; 93 (6): 267–269.
Bladen CL, Thompson R, Jackson JM, et al. Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. J Neurol. 2014; 261: 152–163.
Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosc. 2016; 3: 7.
Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018; 28 (3): 197–207.
Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018; 28: 103–115.
Wang CH, Finkel RS, Bertinin ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22 (8): 1027–1049.
Ramdas S, Servais L. New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother. 2020; 21 (3): 307–315.
De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019; 29 (11): 842–856.
Dangouloff T, Servais L. Clinical evidence supporting early treatment of patients with spinal muscular atrophy: current perspectives. Ther Clin Risk Manag. 2019; 15: 1153–1161.
Kirschner J, Butoianu N, Goemans N, et al. European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy. Eur J Paediatr Neurol. 2020; 28: 38–43.
Slayter J, Hodgkinson V, Lounsberry J, et al. A Canadian adult spinal muscular atrophy outcome measures toolkit: results of a national consensus using a modified delphi method. J Neuromuscul Dis. 2021; 8 (4): 579–588.
Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020; 7 (2): 97–100.
Kichula EA, Proud CM, Farrar MA, et al. Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy. Muscle Nerve. 2021; 64 (4): 413–427.
Dangouloff T, Vrscaj E, Servais L, et al. Newborn screening programs for spinal muscular atrophy worldwide: where we stand and where to go. Neuromuscul Disord. 2021; 31 (6): 574–582.
Dangouloff T, Botty C, Beaudart C, et al. Systematic literature review of the economic burden of spinal muscular atrophy and economic evaluations of treatments. Orphanet J Rare Dis. 2021; 16 (1): 47.
Hale K, Ojodu J, Singh S. Landscape of spinal muscular atrophy newborn screening in the United States: 2018–2021. Int J Neonatal Screen. 2021; 7 (3): 33.
Kariyawasam DST, D’Silva AM, Vetsch J, et al. “We needed this”: perspectives of parents and healthcare professionals involved in a pilot newborn screening program for spinal muscular atrophy. EClinicalMedicine. 2021; 33: 100742.
Lopez-Chacon M, Buehner AN, Rao VK. Spinal muscular atrophy diagnosed by newborn screening. Pediatr Neurol Briefs. 2019; 33: 5.
Lowes LP, Alfano LN, Arnold WD, et al. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr Neurol. 2019; 98: 39–45.
Dangouloff T, Burghes A, Tizzano EF, et al. 244th ENMC international workshop: newborn screening in spinal muscular atrophy May 10–12, 2019, Hoofdorp, The Netherlands. Neuromuscul Disord. 2020; 30 (1): 93–103.
Boardman FK, Sadler C, Young PJ. Newborn genetic screening for spinal muscular atrophy in the UK: the views of the general population. Mol Genet Genomic Med. 2018; 6 (1): 99–108.
Novartis Gene Therapies. Novartis Gene Therapies recommits to Global Managed Access Program for 2021. Novartis. 2021 Jan15. Available at: www.novartis.com/news/novartis-gene-therapies-recommits-global-managed-access-program-2021 [Last accessed 2021 Jan15]
Dayton RD, Wang DB, Klein RL. The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin Biol Ther. 2012; 12 (6): 757–766.
Murlidharan G, Sakamoto K, Rao L, et al. CNS-restricted transduction and CRISPR/Cas9-mediated gene deletion with an engineered AAV vector. Mol Ther Nucleic Acids. 2016; 5: e338.
Rashnonejad A, Chermahini GA, Li S, et al. Large-scale production of adeno-associated viral vector serotype-9 carrying the human survival motor neuron gene. Mol Biotechnol. 2016; 58 (1): 30–36.
Marshall E. Gene therapy death prompts review of adenovirus vector. Science. 1999; 286 (5448): 2244–2245.
Thomsen G, Burghes AHM, Hsieh C, et al. Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Nat Med. 2021; 27 (10): 1701–1711.
Dalwadi DA, Calabria A, Tiyaboonchai A, et al. AAV integration in human hepatocytes. Mol Ther. 2021; 29 (10): 2898–2909.
Domenger C, Grimm D. Next-generation AAV vectors—do not judge a virus (only) by its cover. Hum Mol Genet. 2019; 28 (R1): R3–R14.
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019; 18 (5): 358–378
Ronzitti G, Gross D-A, Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors. Front Immunol. 2020; 11: 670.
Chu WS, Ng J. Immunomodulation in administration of rAAV: preclinical and clinical adjuvant pharmacotherapies. Front Immunol. 2021; 12: 658038.
Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol. 2011; 18 (9): 1586–1588.
Day JW, Finkel RS, Mercuri E, et al. Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec. Mol Ther Methods Clin Dev. 2021; 21: 76–82.
Gorovits B, Azadeh M, Buchlis G, et al. Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays. AAPS J. 2021; 23 (6): 108.
Saraiva J, Nobre RJ, Almeida LP. Gene therapy for the CNS using AAVs: the impact of systemic delivery by AAV. J Control Release. 2016; 241: 94–109.
Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther. 2021; 29 (2): 464–488.
Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021; 20 (4): 284–293.
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017; 377: 1713–1722.
Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021; 78 (7): 834–841.
Mercuri E, Muntoni F, Baranello F, 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. 2021; 20: 832–841
Kotulska K, Fattal-Valevski A, Haberlova J. Recombinant adeno-associated virus serotype 9 gene therapy in spinal muscular atrophy. Front Neurol. 2021; 12: 726468.
Chand D, Mohr F, McMillan H, et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol. 2021; 74 (3): 540–566.
Zincarelli C, Soltys S, Rengo G, et al. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008; 16 (6): 1073–1080.
ZOLGENSMA. Prescribing Information. Novartis; October 2021. Available at: www.novartis.us/sites/www.novartis.us/files/zolgensma.pdf [Last accessed 2021 Nov8]
Weiβ C, Ziegler A, Becker LL, et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc Health. 2022; 6 (1): 17–27.
Mercuri E, Lucibello S, Perulli M, et al. Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis. 2020; 15 (1): 84.
Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83 (9): 810–817.
Kolb SJ, Coffey CS, Yankey JW, et al., Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017; 82 (6): 883–891.
Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J Neuromuscul Dis. 2019; 6 (3): 307–317.
Strauss K, Farrar M, Muntoni F, et al. OPR-201 Onasemnogene abeparvovec for presymptomatic infants with spinal muscular atrophy and 2 copies of SMN2: a phase III study. Eur J Neurol. 2021; 28 (Suppl 1): S950–S951.
Strauss KA, Muntoni F, Farrar MA, et al. Onasemnogene abeparvovec gene therapy in presymptomatic spinal muscular atrophy: final results of SPR1NT study for children with three copies of SMN2. Neurology. 2022; In press:Vol. 98.
SPR1NT: an open-label, single-arm clinical trial of presymptomatic patients with SMA. Novartis Gene Therapies, Inc., 2021. Available at: www.zolgensma-hcp.com/clinical-experiences/spr1nt-trial-efficacy. [Last accessed 2021 Nov5]
De Onis M. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006; 450: 76–85.
Finkel RS, Day JW, De Vivo DC, et al. RESTORE: a prospective multinational registry of patients with genetically confirmed spinal muscular atrophy - rationale and study design. J Neuromuscul Dis. 2020; 7 (2): 145–152.
Servais L, De Vivo DC, Kirschner J, et al. Outcomes in US spinal muscular atrophy patients identified by newborn screening or clinical diagnosis: findings from the RESTORE registry. Neurology. 2022; In press:Vol. 98.
Servais L, De Vivo DC, Kirschner J, et al. Effectiveness and safety of onasemnogene abeparvovec in older patients with spinal muscular atrophy: real-world outcomes from the RESTORE registry. Neurology. 2022; In press:Vol. 98.
Registry of patients with a diagnosis of spinal muscular atrophy (SMA). ClinicalTrials.gov identifier: NCT04174157. 2019 Nov22. Available at: clinicaltrials.gov/ct2/show/NCT04174157?term=NCT04174157&draw=2&rank=1 [Last accessed 2021 Nov5]
Wei Y, McCormick A, MacKenzie A, et al. The Canadian Neuromuscular Disease Registry: connecting patients to national and international research opportunities. Paediatr Child Health. 2018; 23 (1): 20–26.
Hodgkinson VL, Oskoui M, Lounsberry J, et al. A national spinal muscular atrophy registry for real-world evidence. Can J Neurol Sci. 2020; 47 (6): 810–815.
Hodgkinson-Brechenmacher V, Oskoui M, Brais B, et al. SMA–OUTCOME MEASURES AND REGISTRIES. EP.262. The Canadian Neuromuscular Disease Registry: a national spinal muscular atrophy (SMA) registry for real-world evidence. Neuromuscul Disord. 2021; 31 (Supplement 1): S129.
Pechmann A, Konig K, Bernert G, et al. SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis. 2019; 14 (1): 18.
Friese J, Geitmann S, Holzwarth D, et al. Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec –a single centre experience. J Neuromuscul Dis. 2021; 8 (2): 209–216.
Waldrop MA, Karingada C, Storey MA, et al. Gene therapy for spinal muscular atrophy: safety and early outcomes. Pediatrics. 2020; 146 (3): e20200729.
Feldman AG, Parsons JA, Dutmer CM, et al. Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1. J Pediatr. 2020; 225: 252–258.
Shieh PB, Bonnemann CG, Muller-Felber W, et al. Re: “Moving forward after two deaths in a gene therapy trial of myotubular myopathy” by Wilson and Flotte. Hum Gene Ther. 2020; 31 (15–16): 787.
Wilson JM, Flotte TR. Moving forward after two deaths in a gene therapy trial of myotubular myopathy. Hum Gene Ther. 2020; 31 (13–14): 695–696.
D‘Amico A, Longo A, Fattori F, et al. Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies. Orphanet J Rare Dis. 2021; 16 (1): 425.
Philippidis A. Fourth boy dies in clinical trial of astellas‘ AT132. Hum Gene Ther. 2021; 32 (19–20): 1008.
Perez BA, Shutterly A, Chan YK, et al. Management of neuroinflammatory responses to AAV-mediated gene therapies for neurodegenerative diseases. Brain Sci. 2020; 10 (2): 119.
Childers MK, Joubert R, Poulard K, et al. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med. 2014; 6 (220): 220ra10.
Morales L, Gambhir Y, Bennett J, et al. Broader implications of progressive liver dysfunction and lethal sepsis in two boys following systemic high-dose AAV. Mol Ther. 2020; 28 (8): 1753–1755.
Chand DH, Zaidman C, Arya K, et al. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series. J Pediatr. 2021; 231: 265–268.
Day JW, Mendell JR, Mercuri E, et al. Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy. Drug Saf. 2021; 44: 1109–1119.
D’Silva AM, Holland S, Kariyawasam D, et al. Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy. Ann Clin Transl Neurol. 2022; 9 (3): 339–350.
Bonnemann CG. AAV related immunological safety and toxicity: preliminary clinical observations in the GAN and MTM1 trials. Presented at: Virtual Workshop on Systemic Immunogenicity Considerations of AAV-Mediated Gene Therapy, NIH, NCATS; 2020. Available at: videocast.nih.gov/watch=38547 [Last accessed 2021 Nov8].
Mueller C, Berry JD, McKenna-Yasek DM, et al. SOD1 Suppression with adeno-associated virus and MicroRNA in familial ALS. N Engl J Med. 2020; 383 (2): 151–158.
Van Alstyne M, Tattoli I, Delestree N, et al. Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit. Nat Neurosci. 2021; 24 (7): 930–940.
Crawford TO, Sumner CJ. Assuring long-term safety of highly effective gene-modulating therapeutics for rare diseases. J Clin Invest. 2021; 131 (15): e152817.
Huang L, Wan J, Wu Y, et al. Challenges in adeno-associated virus-based treatment of central nervous system diseases through systemic injection. Life Sci. 2021; 270: 119142.
Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther. 2018; 26 (10): 2337–2356.
Philippidis A. After patient death, FDA places hold on Pfizer Duchenne muscular dystrophy gene therapy trial. Hum Gene Ther. 2022; 33 (3–4): 111–115.
Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin Immunity in Duchenne’s Muscular Dystrophy. N Engl J Med. 2010; 363 (15): 1429–1437.
A study to evaluate the safety and tolerability of PF-06939926 gene therapy in Duchenne Muscular Dystrophy. ClinicalTrials.gov identifier: NCT03362502. 2021 Oct15. Available at: clinicaltrials.gov/ct2/show/NCT03362502. [Last accessed 2021 Dec13]
Landfeldt E, Pechmann A, McMillan HJ, et al. Costs of illness of spinal muscular atrophy: a systematic review. Appl Health Econ Health Policy. 2021; 19 (4): 501–520.
McMillan HJ, Gerber B, Cowling T, et al. Burden of spinal muscular atrophy (SMA) on patients and caregivers in Canada. J Neuromuscul Dis. 2021; 8 (4): 553–568.
Belter L, Cruz R, Kulas S, et al. Economic burden of spinal muscular atrophy: an analysis of claims data. J Mark Access Health Policy. 2020; 8 (1): 1843277.
Garrison LP, Jiao B, Dabbous O. Gene therapy may not be as expensive as people think: challenges in assessing the value of single and short-term therapies. J Manag Care Spec Pharm. 2021; 27 (5): 674–681
Dean R, Jensen I, Cyr P, et al. An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the institute for clinical and effectiveness review (ICER). J Mark Access Health Policy. 2021; 9: 1889841.
Harris E. Potential solutions to current pricing models for cell and gene therapies. Horsham, PA: Life Science Leader, 2019 Oct1. Available at: www.lifescienceleader.com/doc/potential-solutions-to-current-pricing-models-for-cell-and-gene-therapies-0001 [Last accessed 2021 Nov5]
Seymore B. Payment models for pricey transformative pharmaceuticals. PharmacyTimes.com. Updated 2020 Feb 4. Available at: https://www.pharmacytimes.com/view/payment-models-for-pricey-transformative-pharmaceuticals. [Last accessed 2021 Nov5]
Wong CH, Li D, Wang N, et al. Estimating the financial impact of gene therapy. medRxiv. Available at: www.medrxiv.org/content/10.1101/2020.10.27.20220871v1.full [Last accessed 2021 Nov 8]
Aballéa S, Thokagevistk K, Velikanova R, et al. Health economic evaluation of gene replacement therapies: methodological issues and recommendations. J Mark Access Health Policy. 2020; 8: 1822666.
Broekhoff TF, Sweegers CCG, Krijkamp EM, et al. Early cost-effectiveness of onasemnogene abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) treatment for spinal muscular atrophy I in the Netherlands with relapse scenarios. Value Health. 2021; 24: 759–769.
Jena AB, Lakdawalla DN. Value frameworks for rare diseases: should they be different? Washington, DC: Health Affairs Blog, 2017 Apr12. Available at: www.healthaffairs.org/doi/10.1377/hblog20170412.059563/full/ [Last accessed 2021 Apr12].
Ollendorf DA, Chapman RH, Pearson SD. Evaluating and valuing drugs for rare conditions: no easy answers. Value Health. 2018; 21: 547–552.
Shih STF, Farrar M, Wiley V, et al. Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis. J Neurol Neurosurg Psychiatry. 2021; 92 (12): 1296–1304.
Safety and efficacy of intravenous OAV101 (AVXS-101) in pediatric patients with spinal muscular atrophy (SMA) (SMART). clinicalTrials.gov identifier: NCT04851873. 2021 Apr21. Available at: clinicaltrials.gov/ct2/show/NCT04851873 [Last accessed 2021 Nov5]
Study of intrathecal administration of onasemnogene abeparvovec-xioi for spinal muscular atrophy (STRONG). ClinicalTrials.gov identifier: NCT03381729. 2021 June 9. Available at: https://clinicaltrials.gov/ct2/show/NCT03381729?term=NCT03381729 [Last accessed 2021 Nov18]
Finkel RS, Day JW, Darras BT, et al. One-time administration of AVXS-101 IT for spinal muscular atrophy: phase I/II study (STRONG). Presented online at the 16th International Child Neurology Congress/49th International Child Neurology Society 2020 Virtual Annual Meeting; 2020 Oct12–20.
Efficacy and safety of intrathecal OAV101 (AVXS-101) in pediatric patients with type 2 spinal muscular atrophy (SMA) (STEER). ClinicalTrials.gov identifier: NCT05089656. 2021 Oct 22. Available at: clinicaltrials.gov/ct2/show/NCT05089656. [Last accessed 2021 Nov5]
Harada Y, Rao VK, Arya K, et al. Combination molecular therapies for type 1 spinal muscular atrophy. Muscle Nerve. 2020; 62 (4): 550–554.
Kray KM, McGovern VL, Chugh D, et al. Dual SMN inducing therapies can rescue survival and motor unit function in symptomatic ∆7SMA mice. Neurobiol Dis. 2021; 159: 105488.
Pagliarini V, Guerra M, Di Rosa V, et al. Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in spinal muscular atrophy cells. J Neurochem. 2020; 153: 264–275.
Poletti A, Fischbeck KH. Combinatorial treatment for spinal muscular atrophy: an editorial for ‘Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in spinal muscular atrophy cells‘ on page 264. J Neurochem. 2020; 153 (2): 146–149.
A study of nusinersen among participants with spinal muscular atrophy who received onasemnogene abeparvovec (RESPOND). ClinicalTrials.gov identifier: NCT04488133. 2021 Sept 29. Available at: www.clinicaltrials.gov/ct2/show/NCT04488133 [Last accessed 2021 Oct20]
Masson R, Brusa C, Scoto M, et al. Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review. Dev Med Child Neurol. 2021; 63 (5): 527–536.
Nance ME, Shi R, Hakim CH, et al. AAV9 edits muscle stem cells in normal and dystrophic adult mice. Mol Ther. 2019; 27 (9): 1568–1585.
Fischell JM, Fishman PS. A multifaceted approach to optimizing AAV delivery to the brain for the treatment of neurodegenerative diseases. Front Neurosci. 2021; 15: 747726.
Liu D, Zhu M, Zhang Y, et al. Crossing the blood-brain barrier with AAV vectors. Metab Brain Dis. 2021; 36 (1): 45–52.
Nonnenmacher M, Wang W, Child MA, et al. Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning. Mol Ther. 2021; 20: 366–378.
Marsic D, Mendez-Gomez HR, Zolotukhin S. High-accuracy biodistribution analysis of adeno-associated virus variants by double barcode sequencing. Mol Ther Methods Clin Dev. 2015; 2: 15041.
Weinmann J, Weis S, Sippel J, et al. Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants. Nature. 2020; 11: 5432.
Tabebordbar M, Lagerborg KA, Stanton A, et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell. 2021; 184 (19): 4919–38.e22.
Kariyawasam DST, Russell JS, Wiley V, et al. The implementation of newborn screening for spinal muscular atrophy: the Australian experience. Genet Med. 2020; 22 (3): 557–565.
D‘Silva AM, Kariyawasam DST, Best S, et al. Integrating newborn screening for spinal muscular atrophy into health care systems: an Australian pilot programme. Dev Med Child Neurol. 2022; 64 (5): 625–632.
Hanlon KS, Kleinstiver BP, Garcia SP, et al. High levels of AAV vector integration into CRISPR-induced DNA breaks. Nat Commun. 2019; 10: 4439.
Yu W, Wu Z. Use of AAV vectors for CRISPR-mediated in vivo genome editing in the retina. Methods Mol Biol. 2019; 1950: 123–139.
Li JJ, Lin X, Tang C, et al. Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice. Natl Sci Rev. 2020; 7: 92–101.
Zhou M, Hu Z, Qiu L, et al. Seamless genetic conversion of SMN2 to SMN1 via CRISPR/Cpf1 and single-stranded oligodeoxynucleotides in spinal muscular atrophy patient-specific induced pluripotent stem cells. Hum Gene Ther. 2018; 29: 1252–1263.
Waddington SN, Privolizzi R, Karda R, et al. A broad overview and review of CRISPR-Cas technology and stem cells. Curr Stem Cell Rep. 2016; 2: 9–20.
Xu Y, Li Z. CRISPR-Cas systems: overview, innovations and applications in human disease research and gene therapy. Comput Struct Biotechnol J. 2020; 18: 2401–2415.
Khalaf K, Janowicz K, Dyszkiewicz-Konwinska M, et al. CRISPR/Cas9 in cancer immunotherapy: animal models and human clinical trials. Genes (Basel). 2020; 11: 921.
Hirakawa MP, Krishnakumar R, Timlin JA, et al. Gene editing and CRISPR in the clinic: current and future perspectives. Biosci Rep. 2020; 40 (4): BSR20200127.
U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=crispr&cntry=&state=&city=&dist= [Last accessed 2022 Mar10]
Kariyawasam DST, D’Silva A, Lin C, et al. Biomarkers and the development of a personalized medicine approach in spinal muscular atrophy. Front Neurol. 2019; 10: 898
Servais L, Baranello G, Scoto M, et al. Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities. Expert Opin Investig Drugs. 2021; 30 (5): 519–527.
