Neutralisation of adeno-associated virus transduction by human vitreous humour
Open accessAbstract
Neutralising antibodies (NAbs), caused by past adeno-associated virus (AAV) infection, represent a critical challenge for AAV-mediated gene therapy, with even low NAb titres capable of inhibiting gene transfer, however in protein-rich environments such as the vitreous it is expected that other constituents could also interact with the transduction process. Inhibition of AAV2/2, AAV2/5, AAV2/6 and AAV2/8 transduction by human vitreous humour (VH) obtained from 80 post-mortem eye cups was investigated in this report, with clinically relevant vitreous dilutions as low as 1:2. Unexpectedly, the highest prevalence of inhibition of transduction was observed against AAV2/6, with 66% of tested samples displaying neutralisation at a 1:2 VH dilution. Only two samples showed inhibition of AAV2/8, indicating this serotype is an attractive vector for use in non-vitrectomised eyes of unscreened individuals. Levels of anti-AAV NAbs observed in the VH were much lower than previously observed in serum of a similar Australian population. Among ten tested eye cup pairs, we observed only small variation in anti-AAV NAbs levels between the left and right eye cups. Interaction with 1:2 diluted VH had an augmentation effect on AAV2/8 transduction (p = 0.004), a phenomenon which was not due to albumin or transferrin and which, if developed, might benefit the use of AAV2/8 in clinical settings.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
It is unclear at what level vitreous fluid antibodies become clinically impactful, though even low levels might exert functional consequences.
“It is unclear at what level vitreous fluid antibodies become clinically impactful, though even low levels might exert functional consequences39.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [39]
Cites
Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration
Brown, D. M., Kaiser, P. K., Michels, M., Soubrane, G., Heier, J. S., Kim, R. Y., Sy, J. P., & Schneider, S. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa062655 · Cited by 3,522 · see citing works
Adeno-Associated Virus (AAV) as a Vector for Gene Therapy
Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362 · see citing works
Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M. F., & Masurier, C. (2010) · Human Gene Therapy · doi:10.1089/hum.2009.182 · Cited by 970 · see citing works
Emerging issues in AAV-mediated in vivo gene therapy
Colella, P., Ronzitti, G., & Mingozzi, F. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2017.11.007 · Cited by 881 · see citing works
Regillo, C. D., Brown, D. M., Abraham, P., Yue, H., Ianchulev, T., Schneider, S., & Shams, N. (2008) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2007.10.004 · Cited by 858 · see citing works
Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses
Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J., & Wilson, J. M. (2009) · The Journal of Infectious Diseases · doi:10.1086/595830 · Cited by 808 · see citing works
Early breakdown of the blood-retinal barrier in diabetes.
Cunha-Vaz, J. G., de Abreu, J. R. F., & de Campos, A. J. A. (1975) · British Journal of Ophthalmology · doi:10.1136/bjo.59.11.649 · Cited by 564 · see citing works
Adult vitreous structure and postnatal changes
Goff, M., & Bishop, P. N. (2008) · Eye · doi:10.1038/eye.2008.21 · Cited by 366 · see citing works
Inner limiting membrane barriers to aav-mediated retinal transduction from the vitreous
Dalkara, D., Kolstad, K. D., Caporale, N., Visel, M., Klimczak, R. R., Schaffer, D. V., & Flannery, J. G. (2009) · Molecular Therapy · doi:10.1038/mt.2009.181 · Cited by 357 · see citing works
Mordenti, J. J., Cuthbertson, R. A., Ferrara, N., Thomsen, K., Berleau, L. T., Ličko, V., Allen, P. C., Valverde, C. R., Meng, Y. G., Fei, D. T. W., et al. (1999) · Toxicologic Pathology · doi:10.1177/019262339902700507 · Cited by 350 · see citing works
The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens
Díaz-Alvarez, L., & Ortega, E. (2017) · Mediators of Inflammation · doi:10.1155/2017/9247574 · Cited by 262 · see citing works
Penetration of Bevacizumab through the Retina after Intravitreal Injection in the Monkey
Heiduschka, P., Fietz, H., Hofmeister, S., Schultheiss, S., Mack, A. F., Peters, S., Ziemssen, F., Niggemann, B., Julien, S., Bartz‐Schmidt, K. U., et al. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-1171 · Cited by 253 · see citing works
Halbert, C. L., Miller, A. D., McNamara, S., Emerson, J., Gibson, R. L., Ramsey, B. W., & Aitken, M. L. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.440 · Cited by 227 · see citing works
Li, C., Narkbunnam, N., Samulski, R. J., Asokan, A., Hu, G., Jacobson, L. J., Manco-Johnson, M. J., Monahan, P. E., & The Joint Outcome Study Investigators (2012) · Gene Therapy · doi:10.1038/gt.2011.90 · Cited by 225 · see citing works
Pharmaceutical development of AAV-based gene therapy products for the eye
Rodrigues, G. A., Shalaev, E., Karami, T. K., Cunningham, J., Slater, N. K. H., & Rivers, H. M. (2019) · Pharmaceutical Research · doi:10.1007/s11095-018-2554-7 · Cited by 213 · see citing works
Intravitreal injection of AAV2 transduces macaque inner retina
Yin, L., Greenberg, K., Hunter, J. J., Dalkara, D., Kolstad, K. D., Masella, B. D., Wolfe, R., Visel, M., Stone, D., Libby, R. T., et al. (2011) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-6250 · Cited by 212 · see citing works
Dengue virus antibodies enhance Zika virus infection
Paul, L. M., Carlin, E., Jenkins, M. M., Tan, A. L., Barcellona, C. M., Nicholson, C. O., Trautmann, L., Michael, S. F., & Isern, S. (2016) · Clinical & Translational Immunology · doi:10.1038/cti.2016.72 · Cited by 211 · see citing works
Complement Is an Essential Component of the Immune Response to Adeno-Associated Virus Vectors
Zaiss, A. K., Cotter, M. J., White, L. R., Clark, S. A., Wong, N. C. W., Holers, V. M., Bartlett, J. S., & Muruve, D. A. (2008) · Journal of Virology · doi:10.1128/jvi.01990-07 · Cited by 177 · see citing works
Neutralizing antibodies against AAV serotypes 1, 2, 6, and 9 in sera of commonly used animal models
Rapti, K., Louis-Jeune, V., Kohlbrenner, E., Ishikawa, K., Ladage, D., Zolotukhin, S., Hajjar, R. J., & Weber, T. (2012) · Molecular Therapy · doi:10.1038/mt.2011.177 · Cited by 170 · see citing works
Preclinical safety evaluation of AAV2-sFLT01— a gene therapy for age-related macular degeneration
MacLachlan, T. K., Lukason, M., Collins, M., Munger, R., Isenberger, E., Rogers, C., Malatos, S., DuFresne, E., Morris, J., Calcedo, R., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2010.258 · Cited by 166 · see citing works
Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils
Karlsson, A., Christenson, K., Matlak, M., Björstad, Å., Brown, K. L., Telemo, E., Salomonsson, E., Leffler, H., & Bylund, J. (2008) · Glycobiology · doi:10.1093/glycob/cwn104 · Cited by 163 · see citing works
Ocular Manifestations Associated with Chikungunya
Mahendradas, P., Ranganna, S. K., Shetty, R., Balu, R., Narayana, K. M., Babu, R. B., & Shetty, B. (2007) · Ophthalmology · doi:10.1016/j.ophtha.2007.03.085 · Cited by 159 · see citing works
Proteomic analysis of human vitreous humor
Murthy, K. R., Goel, R., Subbannayya, Y., Jacob, H. K., Murthy, P. R., Manda, S. S., Patil, A. H., Sharma, R., Sahasrabuddhe, N. A., Parashar, A., et al. (2014) · Clinical Proteomics · doi:10.1186/1559-0275-11-29 · Cited by 145 · see citing works
Vitreous humor analysis for the detection of xenobiotics in forensic toxicology: a review
Bévalot, F., Cartiser, N., Bottinelli, C., Fanton, L., & Guitton, J. (2015) · Forensic Toxicology · doi:10.1007/s11419-015-0294-5 · Cited by 141 · see citing works
Herpes simplex virus type 2 as a cause of acute retinal necrosis syndrome in young patients
Gelder, R. N. V., Willig, J. L., Holland, G. N., et al. (2001) · Ophthalmology · doi:10.1016/s0161-6420(01)00556-5 · Cited by 138 · see citing works
The chemical morphology of the vitreous
Scott, J. E. (1992) · Eye · doi:10.1038/eye.1992.120 · Cited by 134 · see citing works
Chikungunya and the eye: a review
Mahendradas, P., Avadhani, K., & Shetty, R. R. (2013) · Journal of Ophthalmic Inflammation and Infection · doi:10.1186/1869-5760-3-35 · Cited by 133 · see citing works
First AAV gene therapy poised for landmark approval
Smalley, E. (2017) · Nature Biotechnology · doi:10.1038/nbt1117-998 · Cited by 121 · see citing works
Aging and Age-Related Diseases of the Ocular Lens and Vitreous Body
Petrash, J. M. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12940 · Cited by 120 · see citing works
Detection of Intraocular Antibody Production to Herpesviruses in Acute Retinal Necrosis Syndrome
de Boer, J. H., Luyendijk, L., Rothová, A., et al. (1994) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(14)73077-6 · Cited by 113 · see citing works
Meyer, C. H., Krohne, T. U., & Holz, F. G. (2011) · Retina · doi:10.1097/iae.0b013e318217373c · Cited by 112 · see citing works
Proteome Analysis of Human Vitreous Proteins
Yamane, K., Minamoto, A., Yamashita, H., Takamura, H., Miyamoto-Myoken, Y., Yoshizato, K., Nabetani, T., Tsugita, A., & Mishima, H. K. (2003) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m300038-mcp200 · Cited by 110 · see citing works
Current Evidence for the Prevention of Endophthalmitis in Anti-VEGF Intravitreal Injections
Lau, P. E., Jenkins, K. S., & Layton, C. J. (2018) · Journal of Ophthalmology · doi:10.1155/2018/8567912 · Cited by 95 · see citing works
Self-citationProteomic Analyses of the Vitreous Humour
Angi, M., Kalirai, H., Coupland, S. E., Damato, B. E., Semeraro, F., & Romano, M. R. (2012) · Mediators of Inflammation · doi:10.1155/2012/148039 · Cited by 87 · see citing works
Human Galectin 3 Binding Protein Interacts with Recombinant Adeno-Associated Virus Type 6
Denard, J., Beley, C., Kotin, R. M., Lai–Kuen, R., Blot, S., Leh, H., Asokan, A., Samulski, R. J., Moullier, P., Voït, T., et al. (2012) · Journal of Virology · doi:10.1128/jvi.00297-12 · Cited by 64 · see citing works
Niu, N., Zhang, J., Sun, Y., et al. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0572-7 · Cited by 59 · see citing works
Ramlogan‐Steel, C. A., Murali, A., Andrzejewski, S., Dhungel, B. P., Steel, J. C., & Layton, C. J. (2018) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.13416 · Cited by 59 · see citing works
Self-citationHüser, D., Khalid, D., Lutter, T., Hammer, E.-M., Weger, S., Heßler, M., Kalus, U. J., Tauchmann, Y., Hensel-Wiegel, K., Laßner, D., et al. (2016) · Journal of Virology · doi:10.1128/jvi.02137-16 · Cited by 58 · see citing works
Tan, L. E., Orilla, W. C., Hughes, P. M., Tsai, S., Burke, J. A., & WILSON, C. G. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5813 · Cited by 55 · see citing works
Harbison, C. E., Weichert, W. S., Gurda, B. L., Chiorini, J. A., Agbandje-McKenna, M., & Parrish, C. R. (2012) · Journal of General Virology · doi:10.1099/vir.0.035113-0 · Cited by 54 · see citing works
Dengue Virus Antibodies Enhance Zika Virus InfectionPreprint
Paul, L. M., Carlin, E., Jenkins, M. M., et al. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/050112 · Cited by 53 · see citing works
Wang, M., Sun, J., Crosby, A. J., Woodard, K., Hirsch, M. L., Samulski, R. J., & Li, C. (2016) · Gene Therapy · doi:10.1038/gt.2016.75 · Cited by 50 · see citing works
Obermann, J., Priglinger, C., Merl‐Pham, J., Geerlof, A., Priglinger, S., Götz, M., & Hauck, S. M. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m116.066381 · Cited by 44 · see citing works
AAV-8 and AAV-9 Vectors Cooperate with Serum Proteins Differently Than AAV-1 and AAV-6
Denard, J., Rouillon, J., Léger, T., Garcia, C., Lambert, M. P., Griffith, G., Jenny, C., Camadro, J., Garcı́a, L., & Svinartchouk, F. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.08.001 · Cited by 44 · see citing works
de Moraes, G., & Layton, C. J. (2016) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.12795 · Cited by 41 · see citing works
Self-citationEvaluation of Functional Filtering Bleb Using Optical Coherence Tomography Angiography
Seo, J. H., Kim, Y. A., Park, K., & Lee, Y. (2019) · Translational Vision Science & Technology · doi:10.1167/tvst.8.3.14 · Cited by 37 · see citing works
Nogueira, M. L., Siqueira, R. C., Freitas, N., et al. (2001) · Journal of Clinical Pathology · doi:10.1136/jcp.54.2.103 · Cited by 36 · see citing works
Laboratory support in the diagnosis of uveitis
Biswas, J., Majumder, P. D., & Sudharshan, S. (2013) · Indian Journal of Ophthalmology · doi:10.4103/0301-4738.114095 · Cited by 28 · see citing works
Lee, S., Kang, I. K., Kim, J. H., Jung, B. K., Park, K., Chang, H., Lee, J. Y., & Lee, H. (2019) · Translational Vision Science & Technology · doi:10.1167/tvst.8.2.14 · Cited by 27 · see citing works
Proteomic Analysis of Vitreous Humor in Retinal Vein Occlusion
Reich, M., Dacheva, I., Nobl, M., Siwy, J., Schanstra, J. P., Mullen, W., Koch, F., Kopitz, J., Kretz, F. T. A., Auffarth, G. U., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158001 · Cited by 25 · see citing works
Stability of Human Immunodeficiency Virus (HIV) Antibodies in Postmortem Samples
Karhunen, P. J., Brummer‐Korvenkontio, H., Leinikki, P., et al. (1994) · Journal of Forensic Sciences · doi:10.1520/jfs13578j · Cited by 24 · see citing works
AAV8 virions hijack serum proteins to increase hepatocyte binding for transduction enhancement
Pei, X., He, T., Hall, N. E., Gerber, D. A., Samulski, R. J., & Li, C. (2018) · Virology · doi:10.1016/j.virol.2018.02.007 · Cited by 23 · see citing works
Comparative anatomy of the vitreous body in rhesus monkeys and man
Worst, J. G. F., & Los, L. I. (1992) · Documenta Ophthalmologica · doi:10.1007/bf00157007 · Cited by 20 · see citing works
Immunological analysis of the aqueous humour in candida endophthalmitis. II: Clinical study.
Mathis, A., Malecaze, F., Bessières, M.-H., et al. (1988) · British Journal of Ophthalmology · doi:10.1136/bjo.72.4.313 · Cited by 8 · see citing works
Adeno-associated virus neutralising antibodies in type 1 diabetes mellitus
Andrzejewski, S., Murali, A., Ramlogan‐Steel, C. A., Edwards, K. P., Efron, N., Steel, J. C., & Layton, C. J. (2019) · Gene Therapy · doi:10.1038/s41434-019-0076-5 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Investigation of Cas9 Antibodies in the Human Eye
Toral, M. A., Charlesworth, C. T., Ng, B., Chemudupati, T., Homma, S., Nakauchi, H., Bassuk, A. G., Porteus, M. H., & Mahajan, V. B. (2022) · Nature Communications · doi:10.1038/s41467-022-28674-1 · Cited by 28 · see citing works
- Authors
- Andrzejewski, S., Moyle, P. M., Stringer, B. W., Steel, J. C., & Layton, C. J.
- Affiliations
- Translational Research Institute (AU)
- The University of Queensland (AU)
- Central Queensland University (AU)
- Corresponding author
- Layton, Christopher J.
- Venue
- Gene Therapy
- Published
- 2020-06-15
- Volume
- 28
- Issue
- 5
- Pages
- 242-255
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W3035160354
- Cited by
- 10
- References
- 55
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2
- FWCI
- 1.02
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Layton Vision Foundation
- CQUniversity
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- adeno-associated virus, AAV2/8, AAV serotypes, vitreous humor, neutralizing antibodies, ocular gene therapy, vitrectomy, albumin, transferrin
- MeSH terms
- Dependovirus, Australia, Genetic Vectors, Humans, Transduction, Genetic, Vitreous Body, Genetic Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
