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Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids.

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Paper

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The authors' code

Jupyter notebook · 39 lines · 799 B · GPL-3.0

  1. # %%
  2. # Import the cellseg package
  3. import cellseg.plot
  5. # Import plotting packages
  6. import bokeh
  7. from bokeh.io import output_file, show
  8. bokeh.io.output_notebook()
  10. # %% [markdown]
  11. # ## Single image validation
  12. # The purpose of this code is to validate individual images using the pipeline.
  13. #
  14. # After setting the round, plate, and well of the desired image, and then images of the brightfield and signal segmentation are produced.
  16. # %%
  17. #Input the path, round, plate, and wells to examine:
  18. path = 'data/images'
  19. round_ = 3
  20. plate = 10
  21. well = 2
  23. # %%
  24. p1, p2 = cellseg.plot.single_image_viewer(path, round_, plate, well)
  26. # %% [markdown]
  27. # First, we can examine the brightfield segmentation:
  29. # %%
  30. bokeh.io.show(p1)
  32. # %% [markdown]
  33. # Then, we can examine the signal image:
  35. # %%
  36. bokeh.io.show(p2)
  38. # %%

analysis_pipeline.ipynb at commit be9be01, under GPL-3.0 · at the source

Overview

Authors: Tyler J Brittain1, Seongmin Jang1, Gerard M Coughlin1, Jonathan D Hoang1, Bre’Anna H Barcelona1, Izabela Giriat1, Fiona Ristic1, Nathan Appling1, Camille PMA Chossis1, Timothy F Shay1, Viviana Gradinaru1,2
ORCID iDs: Seongmin Jang, Viviana Gradinaru
  1. Division of Biology & Biological Engineering, California Institute of Technology, Pasadena CA 91125, USA
  2. Howard Hughes Medical Institute, Caltech, Pasadena, CA 91125, USA
Institutions: California Institute of Technology (United States); Howard Hughes Medical Institute (United States)
Journal: Molecular therapy : the journal of the American Society of Gene Therapy, volume 34, issue 7, pages 3820-3837
Dates: published online 28 March 2026; in print 1 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.ymthe.2026.03.030 · PMID 41906393 · PMCID PMC13267735 · OpenAlex W7142323317
Open access: hybrid, a free copy (OpenAlex)
Status: code verified (how the code is found and verified)
Categories: histology / microscopy (modality), human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: AAV, AAVR, PKD2, blood-brain barrier, directed evolution, brain, liver
MeSH: Capsid*, Capsid Proteins*, Central Nervous System*, Dependovirus*, Genetic Vectors*, Liver*, Neurons*, Animals, Brain, Cryoelectron Microscopy, Gene Transfer Techniques, Humans, Mice, Transduction, Genetic, Viral Tropism (* major topic)
Topic: Nerve injury and regeneration (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: NINDS NIH HHS (DP1 NS111369); NIMH NIH HHS (UF1 MH128336); Howard Hughes Medical Institute; National Institute of Mental Health and Neurosciences; National Institutes of Health (UF1MH128336); Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign; National Institute of Neurological Disorders and Stroke (PIONEER DP1NS111369)
Citations: not cited yet (Europe PMC); 76 references in the paper

Abstract

Developing effective vectors for gene therapy requires accurate on-target coverage while minimizing off-target transduction that can lead to adverse events. In mice, the engineered capsid PHP.eB shows enhanced brain transduction, while the further engineered CAP-B10 is also de-targeted from astrocytes and liver. Here, we solved cryo-EM structures of CAP-B10 and its complex with AAV receptor (AAVR) domain PKD2, at 2.22 and 2.20 Å resolutions, respectively. These structures reveal a motif that hinders AAVR binding, which we confirmed by measuring affinities. We showed that this motif is transferable to other capsids by solving cryo-EM structures of AAV9-X1, at 3.09 Å, and AAV9-X1.1 without and with PKD2, at 2.51 and 2.18 Å, respectively. Using this structural information, we designed and validated novel AAV variants with reduced liver and altered brain cell tropism in vivo. Overall, we provide a framework for using structural information to guide rational engineering of gene delivery vectors to achieve safe and effective delivery.

Reproduced under the paper's license (CC BY), from the paper cited above.

Repository

Its files are read in the Code ↔ Paper reader above.

GradinaruLab/in-vitro-transduction-assay

License: GPL-3.0
State: the link answers, verified on 4 November 2026
Evidence: files inventoried
Commit: be9be01a33ec84588401cb8709572b0e734419d9, 3 March 2023
Languages: Python (4), Jupyter (3)
Size: 9 files, 7 scripts
Software Heritage: not archived
Found in: the text, “Cell infectivity assay”
Holds: README, license file, environment (setup.py), 3 notebooks
Not found: CITATION.cff, tests, continuous integration, documentation
Tools: NumPy (4 files), pandas (3 files), scikit-image (2 files), SciPy (1 file)
Availability: 2 checks, the latest on 4 November 2026: the link answers
  • 4 November 2026: the link answers
  • 30 September 2026: the link answers
9 files
At the source: github.com/GradinaruLab/in-vitro-transduction-assay

The paper's code and data availability statement is in the Data section.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
  • 7 scripts, each with its path and the digest of its content;
  • no match between paragraphs and code yet;
  • neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data availability

Cryo-EM maps and atomic models have been deposited with the accession codes EMDB:71273 and PDB:9P4L (CAP-B10), EMDB:71278 and PDB:9P4Q (CAP-B10 - PKD2), EMDB:71277 and PDB:9P4P (AAV9-X1), EMDB:71279 and PDB:9P4R (AAV9-X1.1), EMDB:71275 and PDB:9P4N (AAV9-X1.1 - PKD2), EMDB:71274 and PDB:9P4M (AAV9-B10), and EMDB:71276 and PDB:9P4O (eB.24).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 keywords, 15 MeSH terms, 7 funders, 75 references.

Cite

This paper

Brittain, T. J., Jang, S., Coughlin, G. M., Hoang, J. D., Barcelona, B. H., Giriat, I., Ristic, F., Appling, N., Chossis, C. P., Shay, T. F., & Gradinaru, V. (2026). Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids. Molecular therapy : the journal of the American Society of Gene Therapy, 34(7), 3820-3837. https://doi.org/10.1016/j.ymthe.2026.03.030

BibTeX

@article{brittain2026structural,
author = {Brittain, Tyler J and Jang, Seongmin and Coughlin, Gerard M and Hoang, Jonathan D and Barcelona, Bre’Anna H and Giriat, Izabela and Ristic, Fiona and Appling, Nathan and Chossis, Camille PMA and Shay, Timothy F and Gradinaru, Viviana},
title = {{Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids}},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
year = {2026},
month = mar,
volume = {34},
number = {7},
pages = {3820--3837},
publisher = {American Society of Gene \& Cell Therapy},
issn = {1525-0016},
doi = {10.1016/j.ymthe.2026.03.030},
url = {https://doi.org/10.1016/j.ymthe.2026.03.030},
pmid = {41906393},
pmcid = {PMC13267735}
}

RIS

TY - JOUR
AU - Brittain, Tyler J
AU - Jang, Seongmin
AU - Coughlin, Gerard M
AU - Hoang, Jonathan D
AU - Barcelona, Bre’Anna H
AU - Giriat, Izabela
AU - Ristic, Fiona
AU - Appling, Nathan
AU - Chossis, Camille PMA
AU - Shay, Timothy F
AU - Gradinaru, Viviana
TI - Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids
T2 - Molecular therapy : the journal of the American Society of Gene Therapy
J2 - Mol Ther
PY - 2026
DA - 2026/03/28
VL - 34
IS - 7
SP - 3820
EP - 3837
SN - 1525-0016
PB - American Society of Gene & Cell Therapy
DO - 10.1016/j.ymthe.2026.03.030
UR - https://doi.org/10.1016/j.ymthe.2026.03.030
LA - en
ER -

CSL-JSON

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