ArticleMolecular therapy. Methods & clinical development2022
Structural basis of receptor usage by the engineered capsid AAV-PHP.eB.
Article in Molecular therapy. Methods & clinical development, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Advances in vehicles for in situ delivery: From classical vectors to biologically inspired structures.Synthetic and systems biotechnology · 2026Review
- 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 · 2026Article
- CSNK2B gene replacement rescues autism-related phenotypes and establishes translational EEG biomarkers.Cell reports. Medicine · 2026Article
- Article
- AAV9-Mimetic Peptides and Electroporation Synergistically Enhance Nanoparticle Transport through the Blood-Brain Barrier.ACS biomaterials science & engineering · 2026Article
- Identification of Recombinant Adeno-Associated Virus Serotypes by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry.Analytical chemistry · 2026Article
- The amazing AAV capsids: Into the structure-verse.Molecular therapy. Methods & clinical development · 2025Review
- Article
- AnFrontiers in genetics · 2025Article
- Structural studies of Parvoviridae capsid assembly and evolution: implications for novel AAV vector design.Frontiers in artificial intelligence · 2025Review
- Determining recombinant AAV capsid extracellular and intracellular biodistribution by dual radioisotope labeling.Molecular therapy. Methods & clinical development · 2024Article
- Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder.Nature communications · 2024Article
- Fast, accurate ranking of engineered proteins by target-binding propensity using structure modeling.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Review
- Redirecting AAV vectors to extrahepatic tissues.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Review
- Advances in Recombinant Adeno-Associated Virus Vectors for Neurodegenerative Diseases.Biomedicines · 2023Review
- Vector Affinity and Receptor Distribution Define Tissue-Specific Targeting in an Engineered AAV Capsid.Journal of virology · 2023Article
- Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors.Science advances · 2023Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Adeno-associated virus serotype 9 (AAV9) is a promising gene therapy vector for treating neurodegenerative diseases due to its ability to penetrate the blood-brain barrier. PHP.eB was engineered from AAV9 by insertion of a 7-amino acid peptide and point mutation of neighboring residues, thereby enhancing potency in the central nervous system. Here, we report a 2.24-Å resolution cryo-electron microscopy structure of PHP.eB, revealing conformational differences from other 7-mer insertion capsid variants. In PHP.eB, the 7-mer loop adopts a bent conformation, mediated by an interaction between engineered lysine and aspartate residues. Further, we identify PKD2 as the main AAV receptor (AAVR) domain recognizing both AAV9 and PHP.eB and find that the PHP.eB 7-mer partially destabilizes this interaction. Analysis of previously reported AAV structures together with our pull-down data demonstrate that the 7-mer topology determined by the lysine-aspartate interaction dictates AAVR binding strength. Our results suggest that PHP.eB's altered tropism may arise from both an additional interaction with LY6A and weakening of its AAVR interaction. Changing the insertion length, but not sequence, modifies PKD2 binding affinity, suggesting that a steric clash impedes AAVR binding. This research suggests improved library designs for future AAV selections to identify non-LY6A-dependent vectors and modulate AAVR interaction strength.
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