Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design
Open accessAbstract
The fitness landscape of AAV: Adeno-associated virus (AAV) is an important gene therapy vector. Using tools from synthetic biology, Ogden et al. provide a comprehensive view of how sequence changes in capsid proteins affect AAV properties. After saturation mutagenesis of the AAV2 capsid gene, the resulting library was subjected to multiplexed phenotypic analyses, including virus production, immunity, thermostability, and biodistribution. The mutant distribution to major organs in mice revealed dominant trends affecting in vivo delivery. Moreover, the findings uncovered a viral accessory protein with a role in viral production. Finally, a model built from the capsid fitness landscape enabled machine-guided design of useful variants with much higher efficiency than random mutagenesis. Science , this issue p. 1139
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AAV is a 26nm, non-enveloped virus of Parvoviridae family.
“Adeno-associated virus (AAV) is a 26nm, non-enveloped virus of Parvoviridae family.”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [1]
AAV has a 4.7kb single-stranded DNA genome containing 4 open reading frames (rep, cap, aap, and MAAP) flanked by inverted terminal repeats (ITRs).
“It is 4.7kb single-stranded DNA genome containing 4 open reading frames (ORFs) (rep, cap, aap, and MAAP) flanked by inverted terminal repeats (ITRs) (1, 2).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [1]
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Self-citation
- Authors
- Ogden, P. J., Kelsic, E. D., Sinai, S., & Church, G. M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Ogden, Pierce J.
- Kelsic, Eric D.
- Church, George M.
- Venue
- Science
- Published
- 2019-11-29
- Volume
- 366
- Issue
- 6469
- Pages
- 1139-1143
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7197022
- OpenAlex
- W2991022372
- Cited by
- 356
- References
- 21
- Citations by year
- 2026: 41 · 2025: 50 · 2024: 72 · 2023: 52 · 2022: 46 · 2021: 66 · 2020: 28
- FWCI
- 21.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH Office of the Director (HG005550, HG008525)
- 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 › CRISPR and Genetic Engineering
- Keywords
- adeno-associated virus, accessory proteins, competitive exclusion, viral gene expression, tissue distribution, gene therapy vectors
- MeSH terms
- Dependovirus, Capsid, Genes, Viral, Humans, Transfection, Protein Engineering, Genetic Therapy, Mutagenesis, Insertional, Sequence Deletion, Capsid Proteins, HEK293 Cells
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