Evidence map›Paper›PMID 41906393›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2026

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

Tyler J Brittain, Seongmin Jang, Gerard M Coughlin, Jonathan D Hoang, Bre'Anna H Barcelona, Izabela Giriat, Fiona Ristic, Nathan Appling, Camille P M A Chossis, Timothy F Shay and 1 more

Abstract read
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In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. AAV-PHP.eB Peripheral Delivery and Central Expression in Cre Mice.The Journal of comparative neurology · 2026
    Article
  2. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Tyler J BrittainDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Seongmin JangDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: sjang@caltech.edu.
Gerard M CoughlinDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Jonathan D HoangDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Bre'Anna H BarcelonaDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Izabela GiriatDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Fiona RisticDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Nathan ApplingDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Camille P M A ChossisDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Timothy F ShayDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Viviana GradinaruDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: viviana@caltech.edu.

Funding

Engineered AAV Identification, Validation, and Dissemination Pipeline for Brain Cell Type-Specific Manipulation Across SpeciesUF1MH128336 · NIMH · CALIFORNIA INSTITUTE OF TECHNOLOGY · PI FOX, ANDREW S, GRADINARU, VIVIANA · 2021 to 2021
$6.1M
Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic VectorsDP1NS111369 · NINDS · CALIFORNIA INSTITUTE OF TECHNOLOGY · PI GRADINARU, VIVIANA · 2018 to 2023
$5.9M
Howard Hughes Medical InstituteNIMH NIH HHS UF1 MH128336NINDS NIH HHS DP1 NS111369
6 · The paper itself

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 cryoelectron microscopy (cryo-EM) structures of CAP-B10 and its complex with the adeno-associated virus 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.

Indexed as

CapsidCapsid ProteinsCentral Nervous SystemDependovirusGenetic VectorsLiverNeuronsAnimalsBrainCryoelectron MicroscopyGene Transfer TechniquesHumansMiceTransduction, GeneticViral TropismCapsid ProteinsAAVAAVRblood-brain barrierbraindirected evolutionliverPKD2

Identifiers

PMID41906393
PMCPMC13267735

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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.