Characterization of a recombinant adeno-associated virus type 2 Reference Standard Material
Open accessAbstract
A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the reference material were carried out by helper virus-free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination, and then distributed for characterization along with standard assay protocols and assay reagents to 16 laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ({X}, 9.18 x 10¹¹ particles/ml; 95% confidence interval [CI], 7.89 x 10¹¹ to 1.05 x 10¹² particles/ml), vector genomes ({X}, 3.28 x 10¹⁰ vector genomes/ml; 95% CI, 2.70 x 10¹⁰ to 4.75 x 10¹⁰ vector genomes/ml), transducing units ({X}, 5.09 x 10⁸ transducing units/ml; 95% CI, 2.00 x 10⁸ to 9.60 x 10⁸ transducing units/ml), and infectious units ({X}, 4.37 x 10⁹ TCID₅₀ IU/ml; 95% CI, 2.06 x 10⁹ to 9.26 x 10⁹ TCID₅₀ IU/ml). Further analysis confirmed the identity of the reference material as AAV2 and the purity relative to nonvector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of interlaboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Type Culture Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards. Anticipated uses of the rAAV2 RSM are discussed.
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qPCR is the standard procedure for genome titration of rAAV reference standard material, but large multi-laboratory studies highlighted its low precision, with repeatability as poor as greater than 30% CV and reproducibility at 70% to 100% CV.
“qPCR is the standard procedure for genome titration of rAAV reference standard material (RSM), but large multi-laboratory studies highlighted its low precision, with repeatability, indicated by the coefficient of variation (CV), as poor as >30% CV and reproducibility at 70%–100% CV.37, 38, 39”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [37]
ELISA is sufficiently robust and specific to be used on samples with moderate matrix effects and free capsid proteins, such as cell lysates.
“The assay is typically performed after a purification step but is sufficiently robust and specific to be used on samples with moderate matrix effects and free capsid proteins, like cell lysates.26,37,61,85”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [37]
Sandwich ELISA was used for characterization of AAV2 and AAV8 reference standard material, demonstrating acceptable precision in the multi-laboratory study, with repeatability of 10% to 15% CV and reproducibility of around 40% CV.
“Sandwich ELISA was used for the characterization of AAV2 and AAV8 RSM, demonstrating acceptable precision in the multi-laboratory study, with repeatability of 10%–15% CV and reproducibility of around 40% CV.37, 38, 39”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [37]
Standardized reference materials are only available for rAAV2 and rAAV8, necessitating development and qualification of in-house reference materials and controls for other serotypes.
“To this extent, the demonstration of the validity of such methods, for which the FDA encourages the use of reference materials,126is also challenging, since standardized reference materials are only available for rAAV2 and rAAV8,37,38 necessitating development and qualification of in-house reference materials and controls for other serotypes.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [37]
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- Authors
- Lock, M., McGorray, S., Auricchio, A., Ayuso, E., Beecham, E. J., Blouin-Tavel, V., Bosch, F., Bose, M., Byrne, B. J., Caton, T., Chiorini, J. A., Chtarto, A., Clark, K. R., Conlon, T., Darmon, C., Doria, M., Douar, A., Flotte, T. R., Francis, J. D., Francois, A., Giacca, M., Korn, M. T., Korytov, I., Leon, X., Leuchs, B., Lux, G., Melas, C., Mizukami, H., Moullier, P., Müller, M., Ozawa, K., Philipsberg, T., Poulard, K., Raupp, C., Rivière, C., Roosendaal, S. D., Samulski, R. J., Soltys, S. M., Surosky, R., Tenenbaum, L., Thomas, D. L., van Montfort, B., Veres, G., Wright, J. F., Xu, Y., Zelenaia, O., Zentilin, L., & Snyder, R. O.
- Affiliations
- University of Pennsylvania (US)
- University of Florida Health (US)
- Federico II University Hospital (IT)
- Universitat Autònoma de Barcelona (ES)
- University of North Carolina at Chapel Hill (US)
- Inserm (FR)
- Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain.
- University of Florida (US)
- National Institutes of Health (US)
- Université Libre de Bruxelles (BE)
- Nationwide Children's Hospital (US)
- Telethon Institute Of Genetics And Medicine (IT)
- Genethon (France) (FR)
- University of Massachusetts Chan Medical School (US)
- INSERM UMR649, Centre Hospitalier Universitaire de Nantes, 44007 Nantes, France.
- International Centre for Genetic Engineering and Biotechnology (IT)
- German Cancer Research Center (DE)
- Pharmazeutische Fabrik Dr. Reckeweg (Germany) (DE)
- Jichi Medical University (JP)
- Amsterdam Molecular Therapeutics, 1100 Amsterdam, The Netherlands.
- Sangamo BioSciences (United States) (US)
- Applied Genetic Technologies (United States) (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Snyder, Richard O.
- ORCID
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2010-10
- Volume
- 21
- Issue
- 10
- Pages
- 1273-1285
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC2957240
- OpenAlex
- W2035671670
- Cited by
- 131
- References
- 22
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 6 · 2019: 13 · 2018: 3 · 2017: 15 · 2016: 7 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 12
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Gene Therapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship@UMassChan (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- UNC Libraries
- Funders
- GlaxoSmithKline
- University of Pennsylvania
- Bayer Corporation
- National Institutes of Health (U42RR11148)
- National Heart, Lung, and Blood Institute (P01HL059412)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK047757)
- National Center for Research Resources (U42RR011148, U42 RR11148)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- recombinant adeno-associated virus type 2, AAV2, infectious titer, inter-laboratory variability, gene delivery vectors, chromatographic purification, TCID50
- MeSH terms
- Dependovirus, Biological Assay, DNA, Viral, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Genetic Vectors, Helper Viruses, Reference Standards, Transduction, Genetic, Virus Replication, Polymerase Chain Reaction, Genome, Viral
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