AAV Clade F Capsid for HBB Gene Correction

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Solution Overview

Problem

Current gene therapy approaches for treating sickle cell disease and beta thalassemia, such as those using retroviral vectors, pose safety and efficacy concerns due to the risk of genomic disruption and off-target mutations.

Innovation Solution

The use of replication-defective adeno-associated virus (AAV) compositions, specifically those with an AAV Clade F capsid protein and a correction genome containing an editing element, 5′ homology arm, and 3′ homology arm, to correct mutations in the HBB gene without the need for exogenous nucleases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If retroviral vectors are used for gene therapy, then gene delivery efficiency is improved, but safety is worsened due to risk of genomic disruption and off-target mutations

Engineering Contradiction:

Improvegene delivery efficiencyVSAvoidsafety

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the fundamental parameter of the viral vector system from retroviral to adeno-associated virus (AAV), specifically using AAV Clade F capsid proteins. This parameter change enables the therapy to maintain gene delivery capability while eliminating the safety issues associated with retroviral integration into host genome, as AAV remains episomal and does not integrate into host DNA.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If exogenous nucleases are used for gene editing, then mutation correction precision is improved, but harmful factors are increased due to potential genomic disruption

Engineering Contradiction:

Improvemutation correction precisionVSAvoidgenomic disruption risk

Core Design Contradiction:

Manufacturing precisionVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and eliminates the exogenous nuclease component from the gene editing system. Instead of using CRISPR-Cas9, TALENs, or ZFNs that require nuclease activity, the invention uses AAV-mediated homology-directed repair where the correction genome alone suffices to fix mutations, thereby removing the harmful genomic disruption risks associated with nuclease-based editing.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The correction genome in the AAV vector contains all necessary information for gene correction including the editing element and homology arms. The system is self-sufficient and does not require external nuclease enzymes to facilitate the correction process, allowing the cell's own repair mechanisms to perform the editing safely.

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS12201657B2Adeno-associated virus compositions for restoring HBB gene function and methods of use thereof

Publication Date: 2025.01.21 CITY OF HOPE

AI summary

Provided herein are adeno-associated virus (AAV) compositions for correcting a mutation in a beta globin gene (HBB) gene and methods of using the same to correct an HBB gene mutation in a cell. Also provided are packaging systems for making the adeno-associated virus compositions.