Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial

Allay, James A.; Sleep, Susan; Long, Scott; Tillman, David M.; Clark, Rob; Carney, Gael; Fagone, Paolo; McIntosh, Jenny H.; Nienhuis, Arthur W.; Davidoff, Andrew M.; Nathwani, Amit C.; Gray, John T.

doi:10.1089/hum.2010.202

Cited by 152Virus-based gene therapy researchHemophilia Treatment and ResearchViral Infectious Diseases and Gene Expression in Insects

Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial

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Allay, James A., Sleep, Susan, Long, Scott, Tillman, David M., Clark, Rob, Carney, Gael, Fagone, Paolo, McIntosh, Jenny H. +4 more·2011·Human Gene Therapy

DOI 10.1089/hum.2010.202PMC PMC3081439

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Abstract

To generate sufficient clinical-grade vector to support a phase I/II clinical trial of adeno-associated virus serotype 8 (AAV8)-mediated factor IX (FIX) gene transfer for hemophilia B, we have developed a large-scale, good manufacturing practice (GMP)-compatible method for vector production and purification. We used a 293T-based two-plasmid transient transfection system coupled with a three-column chromatography purification process to produce high-quality self-complementary AAV2/8 FIX clinical-grade vector. Two consecutive production campaigns using a total of 432 independent 10-stack culture chambers produced a total of ∼2 × 10(15) vector genomes (VG) by dot-blot hybridization. Benzonase-treated microfluidized lysates generated from pellets of transfected cells were purified by group separation on Sepharose beads followed by anion-exchange chromatography. The virus-containing fractions were further processed by gel filtration and ultrafiltration, using a 100-kDa membrane. The vector was formulated in phosphate-buffered saline plus 0.25% human serum albumin. Spectrophotometric analysis suggested ∼20% full particles, with only low quantities of nonviral proteins were visible on silver-stained sodium dodecyl sulfate-polyacrylamide gels. A sensitive assay for the detection of replication-competent AAV was developed, which did reveal trace quantities of such contaminants in the final product. Additional studies have confirmed the long-term stability of the vector at -80°C for at least 24 months and for at least 24 hr formulated in the clinical diluent and stored at room temperature within intravenous bags. This material has been approved for use in clinical trials in the United States and the United Kingdom.

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Genome titer represents capsids containing the vector genome, estimates the potency of a sample, and is primarily used for clinical dosing of rAAV.
“The genome titer represents capsids containing the vector genome (i.e., virions), estimates the potency of a sample, and is primarily used for clinical dosing of rAAV.25,35”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [25]
When an oversized transgene in AAV is truncated from the terminals, neither qPCR nor ddPCR, using a selected amplicon toward the end of the transgene, can accurately determine the titer of complete genomes, because the PCR replication cycle only considers the presence of the amplicon itself.
“When an oversized transgene in AAV is truncated from the terminals, neither qPCR nor ddPCR, using a selected amplicon toward the end of the transgene, can accurately determine the titer of complete genomes, as the PCR replication cycle only considers the presence of the amplicon itself, i.e., the DNA flanked by the primer sequences.25,83”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [25]
For accuracy, qPCR and ddPCR require chemical or enzymatic treatment of the sample to digest non-encapsidated DNA and denature capsid proteins to expose the encapsidated DNA.
“For accuracy, these methods require chemical or enzymatic treatment of the sample to digest non-encapsidated DNA and denature capsid proteins to expose the encapsidated DNA.18,25,35”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [25]
TEM results are often unreliable and show poor agreement with orthogonal methods such as AUC.
“However, unreliable results are common, and poor agreement with orthogonal methods, such as analytical ultracentrifugation (AUC), has been reported.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [25]
Results between orthogonal methods are often not in agreement, and especially the accuracy of negative-staining TEM is often questioned.
“First, results between orthogonal methods are often not in agreement, and especially, the accuracy of negative-staining TEM is often questioned.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [25]

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Preclinical Evaluation Supporting an Ongoing Adeno-Associated Virus Clinical Trial
(2016)

Authors: Allay, J. A., Sleep, S., Long, S., Tillman, D. M., Clark, R., Carney, G., Fagone, P., McIntosh, J. H., Nienhuis, A. W., Davidoff, A. M., Nathwani, A. C., & Gray, J. T.
Affiliations: Children's GMP, Memphis, TN 38105.
St. Jude Children's Research Hospital (US)
University College London (GB)
ORCID: Fagone, Paolo
McIntosh, Jenny H.
Davidoff, Andrew M.
Nathwani, Amit C.
Gray, John T.
Venue: Human Gene Therapy
Publisher: SAGE Publications
Published: 2011-05
Volume: 22
Issue: 5
Pages: 595-604
ISSN: 1043-0342 (ISSN-L)
1557-7422
DOI: 10.1089/hum.2010.202
PMC: PMC3081439
OpenAlex: W2048842430
Cited by: 152
References: 54
Citations by year: 2026: 6 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 17 · 2015: 13 · 2014: 12 · 2013: 10 · 2012: 12
FWCI: 8.18
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations: Human Gene Therapy (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: Assisi Foundation of Memphis
American Lebanese Syrian Associated Charities
National Institute for Health and Care Research
University College London Hospitals NHS Foundation Trust
Medical Research Council
National Heart, Lung, and Blood Institute (HL073838, R01HL073838)
National Cancer Institute (CA027165)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095169)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords: AAV8, self-complementary AAV, hemophilia B, good manufacturing practices, HEK293T cells, anion exchange chromatography, vector stability
MeSH terms: Dependovirus, Biotechnology, Cell Line, Hemophilia B, Chromatography, Gel, Chromatography, Ion Exchange, Clinical Trials as Topic, Genetic Vectors, Humans, Spectrophotometry, Immunoblotting, Genetic Therapy

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Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial

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