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Cited by 46Virus-based gene therapy researchRNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders Research

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates

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Mattar, Citra N., Wong, Andrew M. S., Hoefer, Klemens, Alonso-Ferrero, Maria E., Buckley, Suzanne M. K., Howe, Steven J., Cooper, Jonathan D., Waddington, Simon N. +2 more·2015·The FASEB Journal
DOI 10.1096/fj.14-269092PMC PMC4560173
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Abstract

Several acute monogenic diseases affect multiple body systems, causing death in childhood. The development of novel therapies for such conditions is challenging. However, improvements in gene delivery technology mean that gene therapy has the potential to treat such disorders. We evaluated the ability of the AAV9 vector to mediate systemic gene delivery after intravenous administration to perinatal mice and late-gestation non-human primates (NHPs). Titer-matched single-stranded (ss) and self-complementary (sc) AAV9 carrying the green fluorescent protein (GFP) reporter gene were intravenously administered to fetal and neonatal mice, with non-injected age-matched mice used as the control. Extensive GFP expression was observed in organs throughout the body, with the epithelial and muscle cells being particularly well transduced. ssAAV9 carrying the WPRE sequence mediated significantly more gene expression than its sc counterpart, which lacked the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) sequence. To examine a realistic scale-up to larger models or potentially patients for such an approach, AAV9 was intravenously administered to late-gestation NHPs by using a clinically relevant protocol. Widespread systemic gene expression was measured throughout the body, with cellular tropisms similar to those observed in the mouse studies and no observable adverse events. This study confirms that AAV9 can safely mediate systemic gene delivery in small and large animal models and supports its potential use in clinical systemic gene therapy protocols.—Mattar, C. N., Wong, A. M. S., Hoefer, K., Alonso-Ferrero, M. E., Buckley, S. M. K., Howe, S. J., Cooper, J. D., Waddington, S. N., Chan, J. K. Y., Rahim, A. A. Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates. FASEB J. 29, 3876-3888 (2015). www.fasebj.org

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  • Fetal mouse ICV injection has previously been associated with intrauterine mortality due to the technical challenge of this procedure in small animals.

    “However, fetal mouse ICV injection has previously been associated with intrauterine mortality due to the technical challenge of this procedure in small animals (27).”

    From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [27]

    The Methods section describes intravenous injection of fetal mice, not ICV injection. The Discussion mentions in utero intracerebroventricular administration only in connection with AAV9 transduction; it does not discuss intrauterine mortality or technical difficulty. Searches for those terms found no supporting passage in our copy (page numbers unavailable). (LLM, conf=0.77)

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Research works printed but not linked: 25

  1. [1]Goker-Alpan O. (2011) Therapeutic approaches to bone pathology in Gaucher disease: past, present and future. Mol. Genet. Metab. 104, 438– 447 21889384
  2. [2]Cavazzana-Calvo M., Payen E., Negre O., Wang G., Hehir K., Fusil F., Down J., Denaro M., Brady T., Westerman K., Cavallesco R., Gillet-Legrand B., Caccavelli L., Sgarra R., Maouche-Chrétien L., Bernaudin F., Girot R., Dorazio R., Mulder G. J., Polack A., Bank A., Soulier J., Larghero J., Kabbara N., Dalle B., Gourmel B., Socie G., Chrétien S., Cartier N., Aubourg P., Fischer A., Cornetta K., Galacteros F., Beuzard Y., Gluckman E., Bushman F., Hacein-Bey-Abina S., Leboulch P. (2010) Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318– 322 20844535 PMC3355472
  3. [3]Gaspar H. B., Parsley K. L., Howe S., King D., Gilmour K. C., Sinclair J., Brouns G., Schmidt M., Von Kalle C., Barington T., Jakobsen M. A., Christensen H. O., Al Ghonaium A., White H. N., Smith J. L., Levinsky R. J., Ali R. R., Kinnon C., Thrasher A. J. (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181– 2187 15610804
  4. [5]Biffi A., Montini E., Lorioli L., Cesani M., Fumagalli F., Plati T., Baldoli C., Martino S., Calabria A., Canale S., Benedicenti F., Vallanti G., Biasco L., Leo S., Kabbara N., Zanetti G., Rizzo W. B., Mehta N. A., Cicalese M. P., Casiraghi M., Boelens J. J., Del Carro U., Dow D. J., Schmidt M., Assanelli A., Neduva V., Di Serio C., Stupka E., Gardner J., von Kalle C., Bordignon C., Ciceri F., Rovelli A., Roncarolo M. G., Aiuti A., Sessa M., Naldini L. (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 23845948
  5. [6]Nathwani A. C., Tuddenham E. G., Rangarajan S., Rosales C., McIntosh J., Linch D. C., Chowdary P., Riddell A., Pie A. J., Harrington C., O’Beirne J., Smith K., Pasi J., Glader B., Rustagi P., Ng C. Y., Kay M. A., Zhou J., Spence Y., Morton C. L., Allay J., Coleman J., Sleep S., Cunningham J. M., Srivastava D., Basner-Tschakarjan E., Mingozzi F., High K. A., Gray J. T., Reiss U. M., Nienhuis A. W., Davidoff A. M. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365, 2357– 2365 22149959 PMC3265081
  6. [8]Mattar C. N., Waddington S. N., Biswas A., Johana N., Ng X. W., Fisk A. S., Fisk N. M., Tan L. G., Rahim A. A., Buckley S. M., Tan M. H., Lu J., Choolani M., Chan J. K. (2013) Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems. Gene Ther. 20, 69– 83 22278413
  7. [9]Rahim, A. A., Wong, A. M., Hoefer, K., Buckley, S. M., Mattar, C. N., Cheng, S. H., Chan, J. K., Cooper, J. D., Waddington, S. N. (2011) Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system. FASEB J. 25, 3505–3518 21746868
  8. [10]Mattar C. N., Choolani M., Biswas A., Waddington S. N., Chan J. K. (2011) Fetal gene therapy: recent advances and current challenges. Expert Opin. Biol. Ther. 11, 1257– 1271 21623703
  9. [11]Mattar C. N., Nathwani A. C., Waddington S. N., Dighe N., Kaeppel C., Nowrouzi A., Mcintosh J., Johana N. B., Ogden B., Fisk N. M., Davidoff A. M., David A., Peebles D., Valentine M. B., Appelt J. U., von Kalle C., Schmidt M., Biswas A., Choolani M., Chan J. K. (2011) Stable human FIX expression after 0.9G intrauterine gene transfer of self-complementary adeno-associated viral vector 5 and 8 in macaques. Mol. Ther. 19, 1950– 1960 21629224 PMC3222517
  10. [13]Katwal A. B., Konkalmatt P. R., Piras B. A., Hazarika S., Li S. S., John Lye R., Sanders J. M., Ferrante E. A., Yan Z., Annex B. H., French B. A. (2013) Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery. Gene Ther. 20, 930– 938 23535898 PMC3758463
  11. [14]Limberis, M. P., Vandenberghe, L. H., Zhang, L., Pickles, R. J., Wilson, J. M. (2009) Transduction efficiencies of novel AAV vectors in mouse airway epithelium in vivo and human ciliated airway epithelium in vitro. Mol. Ther. 17, 294–301 PMC2835069 19066597
  12. [15]Haddad, M. R., Donsante, A., Zerfas, P., Kaler, S. G. (2013) Fetal brain-directed AAV gene therapy results in rapid, robust, and persistent transduction of mouse choroid plexus epithelia. Mol. Ther. Nucleic Acids 2, e101 PMC3696907 23799375
  13. [16]Di Pasquale G., Chiorini J. A. (2006) AAV transcytosis through barrier epithelia and endothelium. Mol. Ther. 13, 506– 516 16368273
  14. [17]Paterna J. C., Moccetti T., Mura A., Feldon J., Büeler H. (2000) Influence of promoter and WHV post-transcriptional regulatory element on AAV-mediated transgene expression in the rat brain. Gene Ther. 7, 1304– 1311 10918501
  15. [18]Waddington S. N., Buckley S. M., Nivsarkar M., Jezzard S., Schneider H., Dahse T., Kemball-Cook G., Miah M., Tucker N., Dallman M. J., Themis M., Coutelle C. (2003) In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood 101, 1359– 1366 12393743
  16. [19]Chandler R. J., LaFave M. C., Varshney G. K., Trivedi N. S., Carrillo-Carrasco N., Senac J. S., Wu W., Hoffmann V., Elkahloun A. G., Burgess S. M., Venditti C. P. (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J. Clin. Invest. 125, 870– 880 25607839 PMC4319425
  17. [20]Buckley, S. M., Rahim, A. A., Chan, J. K., David, A. L., Peebles, D. M., Coutelle, C., Waddingtont, S. N. (2011) Recent advances in fetal gene therapy. Ther. Deliv. 2, 461–469 22826854
  18. [21]Coutelle C., Waddington S. N. (2012) The concept of prenatal gene therapy. Methods Mol. Biol. 891, 1– 7 22648765
  19. [22]David A. L., Peebles D. (2008) Gene therapy for the fetus: is there a future? Best Pract. Res. Clin. Obstet. Gynaecol. 22, 203– 218 17900991
  20. [23]Mattar C. N., Waddington S. N., Biswas A., Davidoff A. M., Choolani M., Chan J. K., Nathwani A. C. (2012) The case for intrauterine gene therapy. Best Pract. Res. Clin. Obstet. Gynaecol. 26, 697– 709 22819290
  21. [24]Orvisky E., Sidransky E., McKinney C. E., Lamarca M. E., Samimi R., Krasnewich D., Martin B. M., Ginns E. I. (2000) Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediatr. Res. 48, 233– 237 10926300
  22. [26]Boutin S., Monteilhet V., Veron P., Leborgne C., Benveniste O., Montus M. F., Masurier C. (2010) Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum. Gene Ther. 21, 704– 712 20095819
  23. [27]Society for Maternal-Fetal Medicine (SMFM), Berry S. M., Stone J., Norton M. E., Johnson D., Berghella V.; (2013) Fetal blood sampling. Am. J. Obstet. Gynecol. 209, 170– 180 23978246
  24. [28]Bevan, A. K., Duque, S., Foust, K. D., Morales, P. R., Braun, L., Schmelzer, L., Chan, C. M., McCrate, M., Chicoine, L. G., Coley, B. D., Porensky, P. N., Kolb, S. J., Mendell, J. R., Burghes, A. H., Kaspar, B. K. (2011) Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol. Ther. 19, 1971–1980 PMC3222525 21811247
  25. [30]Shen S., Bryant K. D., Brown S. M., Randell S. H., Asokan A. (2011) Terminal N-linked galactose is the primary receptor for adeno-associated virus 9. J. Biol. Chem. 286, 13532– 13540 21330365 PMC3075699

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Authors
Mattar, C. N., Wong, A. M. S., Hoefer, K., Alonso-Ferrero, M. E., Buckley, S. M. K., Howe, S. J., Cooper, J. D., Waddington, S. N., Chan, J. K. Y., & Rahim, A. A.
Affiliations
National University of Singapore (SG)
Corresponding author
Waddington, Simon N.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2015-09
Volume
29
Issue
9
Pages
3876-3888
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.14-269092
PMC
PMC4560173
OpenAlex
W1840644602
Cited by
46
References
4
Citations by year
2026: 5 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 1
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • The FASEB Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Medical Research Council (G1000709)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
AAV9, systemic gene delivery, intravenous administration, fetal mice, neonatal mice, non-human primates, late pregnancy, GFP reporter, cell tropism, gene therapy safety
MeSH terms
Dependovirus, Animals, Haplorhini, Female, Fetus, Genetic Vectors, Pregnancy, Transduction, Genetic, Green Fluorescent Proteins, Mice, Viral Tropism

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