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Updated: Jul 30, 2025

Production, Purification, and Quality Control for Adeno-associated Virus-based Vectors

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Published on: January 29, 2019

Vector Affinity and Receptor Distribution Define Tissue-Specific Targeting in an Engineered AAV Capsid.

R Alexander Martino¹, Qiang Wang¹, Hao Xu¹

¹Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Journal of Virology

|May 18, 2023

Summary

Engineered adeno-associated virus (AAV) capsids can improve gene therapy delivery. This study reveals how capsid-receptor affinity impacts AAV vector performance for central nervous system targeting.

Keywords:

Adeno-associated virus Blood-brain barrier Capsid engineering

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Published on: April 2, 2012

Area of Science:

* Gene therapy
* Virology
* Neuroscience

Background:

* Engineered adeno-associated virus (AAV) capsids show promise for overcoming gene therapy delivery challenges, including blood-brain barrier (BBB) penetration.
* Understanding capsid-receptor interactions is crucial for precision engineering and translating preclinical findings to human trials.
* The adeno-associated virus (AAV)-PHP.B-Ly6a model provides a defined system to study capsid-receptor affinity and *in vivo* activity.

Purpose of the Study:

* To investigate the relationship between capsid-receptor affinity and the *in vivo* performance of engineered AAV vectors.
* To develop and utilize a high-throughput method for quantifying capsid-receptor affinity.
* To determine how target receptor expression levels and affinity influence central nervous system (CNS) transduction and off-target effects.

Main Methods:

* Employed the AAV-PHP.B-Ly6a model system with a defined capsid-receptor pair.
* Developed a high-throughput method to quantify capsid-receptor binding affinity.
* Assessed *in vivo* vector performance, including CNS transduction, off-target tissue transduction, and endothelial barrier penetration.

Main Results:

* High-throughput binding assays successfully categorized AAV vectors by their affinity to the target receptor.
* Efficient CNS transduction requires high target receptor expression at the BBB, but not exclusively in the target tissue.
* Increased receptor affinity reduced off-target transduction but could impair on-target transduction and barrier penetration.

Conclusions:

* Capsid-receptor affinity is a critical parameter influencing AAV vector performance for CNS targeting.
* Receptor affinity analysis aids in selecting vectors with optimized properties for gene therapy.
* This work provides tools and insights for improving AAV vector design and translation from preclinical models to humans.