Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery.
Animals
Blood-Brain Barrier
/ drug effects
Brain
/ diagnostic imaging
Dependovirus
/ genetics
Genetic Therapy
Genetic Vectors
/ therapeutic use
Green Fluorescent Proteins
/ chemistry
Humans
Injections, Intravenous
Liver
/ diagnostic imaging
Magnetic Resonance Imaging
Mice
Neurons
/ drug effects
Promoter Regions, Genetic
Synapsins
/ chemistry
Tissue Distribution
Transduction, Genetic
Ultrasonography
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 01 2021
21 01 2021
Historique:
received:
29
05
2019
accepted:
20
12
2020
entrez:
22
1
2021
pubmed:
23
1
2021
medline:
24
9
2021
Statut:
epublish
Résumé
Non-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood-brain barrier. Vector and promoter selection can provide neuronal expression in the brain, while limiting biodistribution and expression in peripheral organs. To date, the biodistribution of adeno-associated viruses (AAVs) within peripheral organs had not been quantified following intravenous injection and MRIgFUS delivery to the brain. We evaluated the quantity of viral DNA from the serotypes AAV9, AAV6, and a mosaic AAV1&2, expressing green fluorescent protein (GFP) under the neuron-specific synapsin promoter (syn). AAVs were administered intravenously during MRIgFUS targeting to the striatum and hippocampus in mice. The syn promoter led to undetectable levels of GFP expression in peripheral organs. In the liver, the biodistribution of AAV9 and AAV1&2 was 12.9- and 4.4-fold higher, respectively, compared to AAV6. The percentage of GFP-positive neurons in the FUS-targeted areas of the brain was comparable for AAV6-syn-GFP and AAV1&2-syn-GFP. In summary, MRIgFUS-mediated gene delivery with AAV6-syn-GFP had lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.
Identifiants
pubmed: 33479314
doi: 10.1038/s41598-021-81046-5
pii: 10.1038/s41598-021-81046-5
pmc: PMC7820310
doi:
Substances chimiques
Synapsins
0
Green Fluorescent Proteins
147336-22-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1934Subventions
Organisme : NIBIB NIH HHS
ID : R01 EB003268
Pays : United States
Organisme : Weston Brain Institute
ID : TR130117
Organisme : Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Gé;nie du Canada)
ID : RGPIN-2014-04659
Organisme : Gouvernement du Canada | Instituts de Recherche en Santé; du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)
ID : FRN119312
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé; du Canada)
ID : 137064, 166184
Références
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
Rafii, M. S. et al. Adeno-associated viral vector (serotype 2)–nerve growth factor for patients with alzheimer disease. JAMA Neurol. 75, 834 (2018).
pubmed: 29582053
pmcid: 5885277
doi: 10.1001/jamaneurol.2018.0233
Bartus, R. T. et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 80, 1698–1701 (2013).
pubmed: 23576625
pmcid: 3716474
doi: 10.1212/WNL.0b013e3182904faa
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
Fu, H., Dirosario, J., Killedar, S., Zaraspe, K. & McCarty, D. M. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 19, 1025–1033 (2011).
pubmed: 21386820
pmcid: 3129800
doi: 10.1038/mt.2011.34
Hynynen, K., McDannold, N., Vykhodtseva, N. & Jolesz, F. A. Noninvasive MR Imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220, 640–646 (2001).
pubmed: 11526261
doi: 10.1148/radiol.2202001804
Hsu, P.-H. et al. Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS ONE 8, e57682 (2013).
pubmed: 23460893
pmcid: 3584045
doi: 10.1371/journal.pone.0057682
Thévenot, E. et al. Targeted delivery of self-complementary adeno-associated virus to the brain, using MRI-guided focused ultrasound. Hum. Gene Ther. 23, 1–12 (2012).
doi: 10.1089/hum.2012.013
Weber-Adrian, D. et al. Gene delivery to the spinal cord using MRI-guided focused ultrasound. Gene Ther. 22, 568–577 (2015).
pubmed: 25781651
pmcid: 4490035
doi: 10.1038/gt.2015.25
Xhima, K., Nabbouh, F., Hynynen, K., Aubert, I. & Tandon, A. Noninvasive delivery of an α-synuclein gene silencing vector with magnetic resonance—guided focused ultrasound. Mov. Disord. 33, 1567–1579 (2018).
pubmed: 30264465
pmcid: 6282171
doi: 10.1002/mds.101
Pien, G. C. et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J. Clin. Invest. 119, 1688–1695 (2009).
pubmed: 19436115
pmcid: 2689109
doi: 10.1172/JCI36891
Choi, V. W., McCarty, D. M. & Samulski, R. J. AAV hybrid serotypes: improved vectors for gene delivery. Curr. Gene Ther. 5, 299–310 (2005).
pubmed: 15975007
pmcid: 1462937
doi: 10.2174/1566523054064968
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
Burger, C. et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol. Ther. 10, 302–317 (2004).
pubmed: 15294177
doi: 10.1016/j.ymthe.2004.05.024
Snyder, B. R. et al. Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Hum. Gene Ther. 22, 1129–1135 (2011).
pubmed: 21443428
doi: 10.1089/hum.2011.008
Castle, M. J., Turunen, H. T., Vandenberghe, L. H. & Wolfe, J. H. Controlling AAV tropism in the nervous system with natural and engineered capsids. In Gene Therapy for Neurological Disorders (ed. Manfredsson, F. P.) 133–149 (Springer, New York, 2016).
doi: 10.1007/978-1-4939-3271-9_10
Young, D. Gene therapy-based modeling of neurodegenerative disorders: Huntington’s disease. In Gene Therapy for Neurological Disorders (ed. Manfredsson, F. P.) 383–395 (Springer, New York, 2016).
doi: 10.1007/978-1-4939-3271-9_27
Kügler, S., Hahnewald, R., Garrido, M. & Reiss, J. Long-term rescue of a lethal inherited disease by adeno-associated virus–mediated gene transfer in a mouse model of molybdenum-cofactor deficiency. Am. J. Hum. Genet. 80, 291–297 (2007).
pubmed: 17236133
doi: 10.1086/511281
Arnett, A. L. H. et al. Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction. Gene Ther. 20, 497–503 (2013).
pubmed: 22855092
doi: 10.1038/gt.2012.60
Blits, B. et al. Adeno-associated viral vector (AAV)-mediated gene transfer in the red nucleus of the adult rat brain: comparative analysis of the transduction properties of seven AAV serotypes and lentiviral vectors. J. Neurosci. Methods 185, 257–263 (2010).
pubmed: 19850079
doi: 10.1016/j.jneumeth.2009.10.009
San Sebastian, W. et al. Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. Gene Ther. 20, 1178–1183 (2013).
pubmed: 24067867
doi: 10.1038/gt.2013.48
Huszthy, P. C. et al. Widespread dispersion of adeno-associated virus serotype 1 and adeno-associated virus serotype 6 vectors in the rat central nervous system and in human glioblastoma multiforme xenografts. Hum. Gene Ther. 16, 381–392 (2005).
pubmed: 15812233
doi: 10.1089/hum.2005.16.381
Yang, B. et al. Global CNS transduction of adult mice by intravenously delivered rAAVrh. 8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. Mol. Ther. 22, 1299–1309 (2014).
pubmed: 24781136
pmcid: 4089005
doi: 10.1038/mt.2014.68
Gray, S. J. et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol. Ther. 19, 1058–1069 (2011).
pubmed: 21487395
pmcid: 3129805
doi: 10.1038/mt.2011.72
Wang, S., Olumolade, O. O., Sun, T., Samiotaki, G. & Konofagou, E. E. Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther. 22, 104–110 (2015).
pubmed: 25354683
doi: 10.1038/gt.2014.91
Brettschneider, J., Del Tredici, K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109–120 (2015).
pubmed: 25588378
pmcid: 4312418
doi: 10.1038/nrn3887
Alonso, A. et al. Focal delivery of AAV2/1-transgenes into the rat brain by localized ultrasound-induced BBB opening. Mol. Ther. Nucleic Acids 2, e73 (2013).
pubmed: 23423361
pmcid: 3586801
doi: 10.1038/mtna.2012.64
Casanova, F., Carney, P. R. & Sarntinoranont, M. Effect of needle insertion speed on tissue injury, stress, and backflow distribution for convection-enhanced delivery in the rat brain. PLoS ONE 9(4), e94919 (2014).
pubmed: 24776986
pmcid: 4002424
doi: 10.1371/journal.pone.0094919
Buchanan, I. A. et al. Predictors of surgical site infection after nonemergent craniotomy: a nationwide readmission database analysis. World Neurosurg. 120, e440–e452 (2018).
pubmed: 30149164
pmcid: 6563908
doi: 10.1016/j.wneu.2018.08.102
Liu, H.-L. et al. Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging. Ultrasound Med. Biol. 34, 598–606 (2008).
pubmed: 18313204
doi: 10.1016/j.ultrasmedbio.2008.01.011
Raabe, A., Gerlach, R., Zimmermann, M. & Seifert, V. The risk of haemorrhage associated with early postoperative heparin administration after intracranial surgery. Acta Neurochir. (Wien) 143, 1–7 (2001).
doi: 10.1007/s007010170131
Fan, C. H. et al. Detection of intracerebral hemorrhage and transient blood-supply shortage in focused-ultrasound-induced blood-brain barrier disruption by ultrasound imaging. Ultrasound Med. Biol. 38, 1372–1382 (2012).
pubmed: 22579546
doi: 10.1016/j.ultrasmedbio.2012.03.013
Lipsman, N. et al. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9, 2336 (2018).
pubmed: 30046032
pmcid: 6060168
doi: 10.1038/s41467-018-04529-6
Abrahao, A. et al. First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat. Commun. 10, 1–9 (2019).
doi: 10.1038/s41467-019-12426-9
O’Reilly, M. A., Hough, O. & Hynynen, K. Blood-brain barrier closure time after controlled ultrasound-induced opening is independent of opening volume. J. Ultrasound Med. 36, 475–483 (2017).
pubmed: 28108988
pmcid: 5319892
doi: 10.7863/ultra.16.02005
O’Reilly, M. A. & Hynynen, K. Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263, 96–106 (2012).
pubmed: 22332065
pmcid: 3309801
doi: 10.1148/radiol.11111417
Meng, Y. et al. Safety and efficacy of focused ultrasound induced blood-brain barrier opening, an integrative review of animal and human studies. J. Control. Release 309, 25–36 (2019).
pubmed: 31326464
doi: 10.1016/j.jconrel.2019.07.023
Rezai, A. R. et al. Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc. Natl. Acad. Sci. U.S.A. 117, 9180–9182 (2020).
pubmed: 32284421
pmcid: 7196825
doi: 10.1073/pnas.2002571117
Mainprize, T. et al. Blood–Brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci. Rep. 9, 1–7 (2019).
doi: 10.1038/s41598-018-36340-0
Woodbury, M., Kiyota, T. & Ikezu, T. Gene delivery and gene therapy for Alzheimer’s disease. In Gene Delivery and Therapy for Neurological Disorders Vol. 98 (eds Bo, X. & Verhaagen, J.) 85–119 (Springer, Berlin, 2015).
doi: 10.1007/978-1-4939-2306-9_4
Noroozian, Z. et al. MRI-guided focused ultrasound for targeted delivery of rAAV to the brain. Methods Mol. Biol. 1950, 177–197 (2019).
pubmed: 30783974
pmcid: 6546162
doi: 10.1007/978-1-4939-9139-6_10
Duan, D. Systemic delivery of adeno-associated viral vectors. Curr. Opin. Virol. 21, 16–25 (2016).
pubmed: 27459604
pmcid: 5138077
doi: 10.1016/j.coviro.2016.07.006
Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006).
pubmed: 16474400
doi: 10.1038/nm1358
Grimm, D. et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood 102, 2412–2419 (2003).
pubmed: 12791653
doi: 10.1182/blood-2003-02-0495
Weber-Adrian, D. et al. Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer’s disease. Theranostics 9, 8127–8137 (2019).
pubmed: 31754385
pmcid: 6857057
doi: 10.7150/thno.36718
Kügler, S., Kilic, E. & Bähr, M. Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther. 10, 337–347 (2003).
pubmed: 12595892
doi: 10.1038/sj.gt.3301905
Mason, M. R. et al. Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Mol. Ther. 18, 715–724 (2010).
pubmed: 20179682
pmcid: 2862541
doi: 10.1038/mt.2010.19
Towne, C., Pertin, M., Beggah, A. T., Aebischer, P. & Decosterd, I. Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery. Mol. Pain 5, 52 (2009).
pubmed: 19737386
pmcid: 2747840
doi: 10.1186/1744-8069-5-52
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
Flotte, T. R. & Büning, H. Severe toxicity in nonhuman primates and piglets with systemic high-dose administration of adeno-associated virus serotype 9-like vectors: putting patients first. Hum. Gene Ther. 29, 283–284 (2018).
pubmed: 29378415
doi: 10.1089/hum.2018.021
Hordeaux, J. 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. 10, 79–88 (2018).
pubmed: 30073179
pmcid: 6070681
doi: 10.1016/j.omtm.2018.06.003
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M. & Sah, D. W. Y. Gene therapy for neurological disorders: progress and prospects. Nat. Rev. Drug Discov. 17, 641–659 (2018).
pubmed: 30093643
doi: 10.1038/nrd.2018.110
Hadaczek, P., Mirek, H., Bringas, J., Cunningham, J. & Bankiewicz, K. Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain. Hum. Gene Ther. 15, 469–479 (2004).
pubmed: 15144577
doi: 10.1089/10430340460745793
Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).
pubmed: 15514393
doi: 10.1176/appi.ajp.161.11.1957
Madsen, S. J. & Hirschberg, H. Site-specific opening of the blood-brain barrier. J. Biophotonics 3, 356–367 (2010).
pubmed: 20162563
pmcid: 4116190
doi: 10.1002/jbio.200900095
McDannold, N., Arvanitis, C. D., Vykhodtseva, N. & Livingstone, M. S. Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res. 72, 3652–3663 (2012).
pubmed: 22552291
pmcid: 3533365
doi: 10.1158/0008-5472.CAN-12-0128
Lipsman, N. et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9(1), 1–8 (2018).
doi: 10.1038/s41467-018-04529-6
Aschauer, D. F., Kreuz, S. & Rumpel, S. Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS ONE 8, 1–16 (2013).
doi: 10.1371/journal.pone.0076310
Frisella, W. et al. Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis type VII. Mol. Ther. 3, 351–358 (2001).
pubmed: 11273777
doi: 10.1006/mthe.2001.0274
Bishop, K. M. et al. Therapeutic potential of CERE-110 (AAV2-NGF): targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons. Exp. Neurol. 211, 574–584 (2008).
pubmed: 18439998
pmcid: 2709503
doi: 10.1016/j.expneurol.2008.03.004
Richichi, C. et al. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J. Neurosci. 24, 3051–3059 (2004).
pubmed: 15044544
pmcid: 6729841
doi: 10.1523/JNEUROSCI.4056-03.2004
Niethammer, M. et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI insight 2, e90133 (2017).
pubmed: 28405611
pmcid: 5374069
doi: 10.1172/jci.insight.90133
Scarcelli, T. et al. Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. Brain Stimul. 7, 304–307 (2014).
pubmed: 24629831
pmcid: 4103630
doi: 10.1016/j.brs.2013.12.012
Burgess, A. et al. Alzheimer disease in a mouse model: MR Imaging–guided focused ultrasound targeted to the hippocampus opens the blood–brain barrier and improves pathologic abnormalities and behavior. Radiology 273, 736–745 (2014).
pubmed: 25222068
doi: 10.1148/radiol.14140245
Mooney, S. J. et al. Focused ultrasound-induced neurogenesis requires an increase in blood-brain barrier permeability. PLoS ONE 11, 1–11 (2016).
doi: 10.1371/journal.pone.0159892
Jordão, J. F. et al. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp. Neurol. 248, 16–29 (2013).
pubmed: 23707300
pmcid: 4000699
doi: 10.1016/j.expneurol.2013.05.008
Leinenga, G. & Götz, J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 7, 1–11 (2015).
doi: 10.1126/scitranslmed.aaa2512
Nisbet, R. M. et al. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140, 1220–1230 (2017).
pubmed: 28379300
pmcid: 5405237
doi: 10.1093/brain/awx052
Lentz, T. B., Gray, S. J. & Samulski, R. J. Viral vectors for gene delivery to the central nervous system. Neurobiol. Dis. 48, 179–188 (2012).
pubmed: 22001604
doi: 10.1016/j.nbd.2011.09.014
Taschenberger, G. et al. β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons. Ann. Neurol. 74, 109–118 (2013).
pubmed: 23536356
doi: 10.1002/ana.23905
Kwon, I. & Schaffer, D. V. Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer. Pharm. Res. 25, 489–499 (2008).
pubmed: 17763830
doi: 10.1007/s11095-007-9431-0
Jordão, J. F. et al. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-β plaque load in the TgCRND8 mouse model of alzheimer’s disease. PLoS ONE 5, e10549 (2010).
pubmed: 20485502
pmcid: 2868024
doi: 10.1371/journal.pone.0010549
Treat, L. H. et al. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int. J. Cancer 121, 901–907 (2007).
pubmed: 17437269
doi: 10.1002/ijc.22732
Burgess, A., Shah, K., Hough, O. & Hynynen, K. Focused ultrasound-mediated drug delivery through the blood–brain barrier. Expert Rev. Neurother. 15, 477–491 (2015).
pubmed: 25936845
pmcid: 4702264
doi: 10.1586/14737175.2015.1028369
Coombs, N., Gough, A. & Primrose, J. Optimisation of DNA and RNA extraction from archival formalin-fixed tissue. Nucleic Acids Res. 27, e12 (1999).
pubmed: 10454649
pmcid: 148555
doi: 10.1093/nar/27.16.e12