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Cited by 85Virus-based gene therapy researchRNA Interference and Gene DeliveryCRISPR and Genetic Engineering

Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing

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Gonzalez, Trevor J., Simon, Katherine E., Blondel, Leo O., Fanous, Marco M., Roger, Angela L., Maysonet, Maribel Santiago, Devlin, Garth W., Smith, Timothy J. +7 more·2022·Nature Communications
DOI 10.1038/s41467-022-33745-4PMC PMC9548504
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Abstract

Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies.

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  • Bioengineering of novel AAV variants for BBB-crossing and CNS targeting has achieved some successes, yielding AAV.CPP.16, AAV.CAP-B10, and AAV.cc47 with variable enhancements over AAV9 from mice to NHPs.

    “The bioengineering of novel AAV variants in terms of BBB-crossing and CNS targeting has achieved some successes in recent years, yielding AAV.CPP.16 [57], AAV.CAP-B10 [68] and AAV.cc47 [111] with variable enhancements over AAV9 from mice to NHPs.”

    From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [111]

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References 44 · Cited by 85

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Authors
Gonzalez, T. J., Simon, K. E., Blondel, L. O., Fanous, M. M., Roger, A. L., Maysonet, M. S., Devlin, G. W., Smith, T. J., Oh, D. K., Havlik, L. P., Castellanos Rivera, R. M., Piedrahita, J. A., ElMallah, M. K., Gersbach, C. A., & Asokan, A.
Affiliations
  • Duke University (US)
  • North Carolina State University (US)
Corresponding author
Asokan, Aravind
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-10-10
Volume
13
Issue
1
Pages
5947-5947
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-33745-4
PMC
PMC9548504
OpenAlex
W4303982751
Cited by
85
References
44
Citations by year
2026: 20 · 2025: 31 · 2024: 17 · 2023: 17
FWCI
9.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (UH3AR075336)
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, therapeutic gene transfer, CRISPR gene editing, Cre recombination, transduction efficiency, clinical translation, gene therapy vectors, pigs, macaque, mice
MeSH terms
Gene Editing, Dependovirus, Animals, Genetic Vectors, Humans, Macaca, Swine, Transduction, Genetic, Genetic Therapy, Mice

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