Adeno-associated virus vectors and neurotoxicity—lessons from preclinical and human studies

Colon-Thillet R, Jerome KR, Stone D. Optimization of AAV vectors to target persistent viral reservoirs. Virol J. 2021;18:85.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18:358–78.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hudry E, Vandenberghe LH. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron. 2019;101:839–62.

Article  CAS  PubMed  Google Scholar 

Morris JA, Boshoff CH, Schor NF, Wong LM, Gao G, Davidson BL. Next-generation strategies for gene-targeted therapies of central nervous system disorders: a workshop summary. Mol Ther. 2021;29:3332–44.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schuster DJ, Dykstra JA, Riedl MS, Kitto KF, Belur LR, McIvor RS, et al. Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse. Front Neuroanat. 2014;8:42.

Article  PubMed  PubMed Central  Google Scholar 

Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, 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. 2018;29:285–98.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hordeaux J, Buza EL, Dyer C, Goode T, Mitchell TW, Richman L, et al. Adeno-associated virus-induced dorsal root ganglion pathology. Hum Gene Ther. 2020;31:808–18.

Article  CAS  PubMed  Google Scholar 

Hordeaux J, Buza EL, Jeffrey B, Song C, Jahan T, Yuan Y, et al. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Sci Transl Med. 2020;12:eaba9188.

Article  CAS  PubMed  Google Scholar 

Hordeaux J, Hinderer C, Buza EL, Louboutin JP, Jahan T, Bell P, et al. Safe and sustained expression of human iduronidase after intrathecal administration of adeno-associated virus serotype 9 in infant Rhesus monkeys. Hum Gene Ther. 2019;30:957–66.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hordeaux J, Hinderer C, Goode T, Buza EL, Bell P, Calcedo R, et al. Toxicology study of intra-cisterna magna adeno-associated virus 9 expressing iduronate-2-sulfatase in Rhesus macaques. Mol Ther Methods Clin Dev. 2018;10:68–78.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hordeaux J, Hinderer C, Goode T, Katz N, Buza EL, Bell P, et al. Toxicology study of intra-cisterna magna adeno-associated virus 9 expressing human alpha-L-iduronidase in Rhesus macaques. Mol Ther Methods Clin Dev. 2018;10:79–88.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hordeaux J, Wang Q, Katz N, Buza EL, Bell P, Wilson JM. The neurotropic properties of AAV-PHP.B are limited to C57BL/6J mice. Mol Ther. 2018;26:664–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bolt MW, Brady JT, Whiteley LO, Khan KN. Development challenges associated with rAAV-based gene therapies. J Toxicol Sci. 2021;46:57–68.

Article  CAS  PubMed  Google Scholar 

EMA. Zolgensma assessment report. https://www.ema.europa.eu/en/documents/assessment-report/zolgensma-epar-public-assessment-report_en.pdf, 2020.

Palazzi X, Pardo ID, Sirivelu MP, Newman L, Kumpf SW, Qian J, et al. Biodistribution and tolerability of AAV-PHP.B-CBh-SMN1 in wistar han rats and cynomolgus macaques reveal different toxicologic profiles. Hum Gene Ther. 2022;33:175–87.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hinderer C, Bell P, Louboutin JP, Katz N, Zhu Y, Lin G, et al. Neonatal tolerance induction enables accurate evaluation of gene therapy for MPS I in a canine model. Mol Genet Metab. 2016;119:124–30.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Marco S, Haurigot V, Jaen ML, Ribera A, Sanchez V, Molas M, et al. Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal. Mol Ther Methods Clin Dev. 2021;23:370–89.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hordeaux J, Jeffrey BA, Jian J, Choudhury GR, Michalson K, Mitchell TW, et al. Efficacy and safety of a krabbe disease gene therapy. Hum Gene Ther. 2022.

Buss N, Lanigan L, Zeller J, Cissell D, Metea M, Adams E, et al. Characterization of AAV-mediated dorsal root ganglionopathy. Mol Ther Methods Clin Dev. 2022;24:342–54.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fader KA, Pardo ID, Kovi RC, Somps CJ, Wang HH, Vaidya VS, et al. Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species. Mol Ther Methods Clin Dev. 2022;25:264–77.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Johnston S, Parylak SL, Kim S, Mac N, Lim C, Gallina I, et al. AAV ablates neurogenesis in the adult murine hippocampus. Elife. 2021;10:e59291.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ciesielska A, Hadaczek P, Mittermeyer G, Zhou S, Wright JF, Bankiewicz KS, et al. Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell-mediated immune responses. Mol Ther. 2013;21:158–66.

Article  CAS  PubMed  Google Scholar 

Klein RL, Dayton RD, Leidenheimer NJ, Jansen K, Golde TE, Zweig RM. Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins. Mol Ther. 2006;13:517–27.

Article  CAS  PubMed  Google Scholar 

Samaranch L, Sebastian WS, Kells AP, Salegio EA, Heller G, Bringas JR, et al. AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction. Mol Ther. 2014;22:329–37.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zerah M, Piguet F, Colle MA, Raoul S, Deschamps JY, Deniaud J, et al. Intracerebral gene therapy using AAVrh.10-hARSA recombinant vector to treat patients with early-onset forms of metachromatic leukodystrophy: preclinical feasibility and safety assessments in nonhuman primates. Hum Gene Ther Clin Dev. 2015;26:113–24.

Article  CAS  PubMed  Google Scholar 

Crystal R. Clinical and nonclinical consequences of direct CNS parenchymal administration of AAV vectors: https://www.fda.gov/media/151998/download, 2021.

Rosenberg JB, Chen A, De BP, Dyke JP, Ballon DJ, Monette S, et al. Safety of direct intraparenchymal AAVrh.10-mediated central nervous system gene therapy for metachromatic leukodystrophy. Hum Gene Ther. 2021;32:563–80.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Golebiowski D, van der Bom IMJ, Kwon CS, Miller AD, Petrosky K, Bradbury AM, et al. Direct intracranial injection of AAVrh8 encoding monkey beta-N-acetylhexosaminidase causes neurotoxicity in the primate brain. Hum Gene Ther. 2017;28:510–22.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Keiser MS, Ranum PT, Yrigollen CM, Carrell EM, Smith GR, Muehlmatt AL, et al. Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain. Nat Med. 2021;27:1982–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Davidson MK, Lindsey JR, Davis JK. Requirements and selection of an animal model. Isr J Med Sci. 1987;23:551–5.

CAS  PubMed  Google Scholar 

Eaton SL, Wishart TM. Bridging the gap: large animal models in neurodegenerative research. Mamm Genome. 2017;28:324–37.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

Article  CAS  PubMed  Google Scholar 

Kuzmin DA, Shutova MV, Johnston NR, Smith OP, Fedorin VV, Kukushkin YS, et al. The clinical landscape for AAV gene therapies. Nat Rev Drug Discov. 2021;20:173–4.

Article  CAS  PubMed  Google Scholar 

Chand DH, Zaidman C, Arya K, Millner R, Farrar MA, Mackie FE, et al. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series. J Pediatr. 2021;231:265–8.

Article  CAS  PubMed  Google Scholar 

Feldman AG, Parsons JA, Dutmer CM, Veerapandiyan A, Hafberg E, Maloney N, et al. Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1. J Pediatr. 2020;225:252–8 e1.

Article  CAS  PubMed  PubMed Central  Google Scholar 

High-dose AAV gene therapy deaths. Nat Biotechnol. 2020; 38:910. https://doi.org/10.1038/s41587-020-0642-9

留言 (0)

沒有登入
gif