AAVR Modulation for AAV Infection Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for adeno-associated virus (AAV) gene therapy face challenges in understanding cellular entry mechanisms, particularly the protein receptors required for AAV infection, which limits the efficacy and tropism of AAV infection in gene therapy applications.
Innovation Solution
Identification of the protein KIAA0319L as an AAV receptor (AAVR) and modulation of its expression levels or trafficking within cells to enhance or reduce the permissiveness of cells to AAV infection, along with the use of AAVR blocking agents to interfere with AAV infection, allowing for improved nucleic acid delivery and screening methods to identify variants with altered binding properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAVR expression level is increased to enhance AAV infection permissiveness, then infection efficacy is improved, but risk of off-target infection and immune response increases
Solution Approach 1:
The patent applies local quality by engineering AAV capsids with serotype-specific properties that confer selective affinity for AAVR in target tissues. Different capsid serotypes (e.g., AAV2, AAV5, AAV9) are selected or engineered to exhibit preferential binding to AAVR in specific cell types or organs, thereby enhancing infection efficacy in desired locations while minimizing off-target effects and immune responses in non-target tissues.
Solution Approach 2:
The patent employs parameter changes by systematically varying AAV capsid protein sequences to optimize the balance between AAVR binding affinity and tissue-specific tropism. Through mutagenesis and selection processes, capsid variants are generated with modified binding parameters that enhance target cell infection while reducing non-specific interactions, thereby improving therapeutic efficacy and safety profiles.
2Object-affected harmful factors
If AAVR blocking agents are used to reduce AAV infection, then off-target effects are minimized, but delivery efficiency to target cells decreases
Solution Approach 1:
The patent applies preliminary action by pre-modifying target cells to express elevated levels of AAVR or to display AAVR on their surface before AAV administration. This preparatory step ensures that when AAV particles are administered, they encounter sufficient AAVR binding sites on target cells to achieve efficient nucleic acid delivery, while the specificity of the AAV capsid ensures that this enhanced delivery is restricted to the intended target tissue.
3Productivity
If cellular permissiveness to AAV is modified by altering AAVR expression, then infection efficiency is enhanced, but cellular function and safety may be compromised
Solution Approach 1:
The patent applies dynamics by utilizing the natural regulation and turnover of AAVR protein expression in target cells. Rather than permanently altering cellular function, the approach leverages the dynamic expression patterns of AAVR that occur naturally in different tissue types and physiological states. This allows for transient enhancement of infection efficiency that maintains cellular safety and function, as AAVR expression returns to baseline levels after the therapeutic window.
Data Source
AI summary
Compositions and methods are provided for modulating adeno-associated virus (AAV) infection. For example, compositions and methods are provided for enhancing permissiveness of a target cell to AAV infection (e.g., by increasing levels of AAVR (KIAA0319L) in the cell), for reducing permissiveness of a target cell to AAV infection (e.g., by reducing levels of AAVR in the cell), and for nucleic acid delivery (e.g., by (i) increasing permissiveness of a target cell to AAV infection, e.g., by increasing the amount of AAVR in the cell; and (ii) contacting the target cell with an AAV particle that includes a nucleic acid of interest). Also provided are screening methods and kits for practicing the methods of the disclosure.