Evidence map›Paper›PMID 26186661›Full record

ArticleGene therapy2015

AAV ancestral reconstruction library enables selection of broadly infectious viral variants.

J Santiago-Ortiz, D S Ojala, O Westesson, J R Weinstein, S Y Wong, A Steinsapir, S Kumar, I Holmes, D V Schaffer

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gene therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed.

  1. Article
  2. Review
  3. Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning.Molecular therapy : the journal of the American Society of Gene Therapy · 2025
    Review
  4. Review
  5. Artificial Intelligence-Based Approaches for AAV Vector Engineering.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Review
  6. Molecular Engineering of Virus Tropism.International journal of molecular sciences · 2024
    Review
  7. Review
  8. Review
  9. Review
  10. Review
  11. Review
  12. Article
  13. Review
  14. Review
  15. Review
  16. Article
  17. Developing New Vectors for Retinal Gene Therapy.Cold Spring Harbor perspectives in medicine · 2023
    Article
  18. Review
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

J Santiago-OrtizDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.
D S OjalaDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.
O WestessonDepartment of Bioengineering, University of California, Berkeley, CA, USA.
J R WeinsteinDepartment of Chemistry, University of California, Berkeley, CA, USA.
S Y WongDepartment of Bioengineering, University of California, Berkeley, CA, USA.
A SteinsapirDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.
S KumarDepartment of Bioengineering, University of California, Berkeley, CA, USA.
I HolmesDepartment of Bioengineering, University of California, Berkeley, CA, USA.
D V SchafferDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.

Funding

NDC for the Optical Control of Biological FunctionPN2EY018241 · NEI · UNIVERSITY OF CALIFORNIA BERKELEY · PI ISACOFF, EHUD · 2006 to 2015
$37.5M
Web-based visualization of coronavirus genomes and proteinsR01HG004483 · NHGRI · UNIVERSITY OF CALIFORNIA BERKELEY · PI Ian H Holmes · 2007 to 2026
$9.3M
Directed Evolution of Adeno-Associated Virus for Retinal Gene TherapyR01EY022975 · NEI · UNIVERSITY OF CALIFORNIA BERKELEY · PI FLANNERY, JOHN GERARD, SCHAFFER, DAVID V · 2014 to 2018
$2.1M
NEI NIH HHS PN2 EY018241NEI NIH HHS R01 EY022975NEI NIH HHS R01EY022975NHGRI NIH HHS R01 HG004483
6 · The paper itself

Abstract

Adeno-associated virus (AAV) vectors have achieved clinical efficacy in treating several diseases. However, enhanced vectors are required to extend these landmark successes to other indications and protein engineering approaches may provide the necessary vector improvements to address such unmet medical needs. To generate new capsid variants with potentially enhanced infectious properties and to gain insights into AAV's evolutionary history, we computationally designed and experimentally constructed a putative ancestral AAV library. Combinatorial variations at 32 amino acid sites were introduced to account for uncertainty in their identities. We then analyzed the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to iterative selection on a representative cell line panel. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes and, in general, ancestral libraries were broadly infectious across the cell line panel, indicating that they favored promiscuity over specificity. Interestingly, putative ancestral AAVs were more thermostable than modern serotypes and did not use sialic acids, galactose or heparan sulfate proteoglycans for cellular entry. Finally, variants mediated 19- to 31-fold higher gene expression in the muscle compared with AAV1, a clinically used serotype for muscle delivery, highlighting their promise for gene therapy.

Indexed as

Gene LibraryAnimalsCapsidCell LineCell Line, TumorDependovirusFemaleGenetic TherapyGenetic VectorsHEK293 CellsHumansMiceMice, Inbred BALB CPhylogenySequence Analysis, DNASequence Analysis, Protein

Identifiers

PMID26186661
PMCPMC4509550

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.