AAV-Rh74 Vector Liver Targeting for Hemophilia Gene Transfer

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Solution Overview

Problem

Current gene transfer therapies for hemophilia, particularly using adeno-associated virus (AAV) vectors, face challenges in achieving therapeutic levels of transgene expression in the liver with minimal immune response, and there is a need for AAV serotypes with high liver tropism and low seroprevalence to treat a broader patient population.

Innovation Solution

Development of AAV-Rh74 vector and related serotypes that target hepatocyte cells in the liver, achieving efficient polynucleotide delivery and expression, with lower prevalence of anti-AAV antibodies in humans, allowing for broader clinical application and higher protein expression levels compared to other serotypes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If AAV vectors are used for gene transfer to liver, then transgene expression is achieved, but immune responses are triggered

Engineering Contradiction:

Improvetransgene expressionVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the serotype parameter of AAV vectors from conventional types (AAV2, AAV8) to newly identified serotypes (AAV-Rh74, AAV-Rh44, AAV-Rh39) that exhibit different immunogenicity profiles. This parameter change allows achieving transgene expression while reducing immune responses by selecting serotypes with lower pre-existing antibody prevalence in the human population.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If conventional AAV serotypes (AAV2, AAV8) are used, then liver transduction is achieved, but seroprevalence limits treatment eligibility

Engineering Contradiction:

Improveliver transductionVSAvoidtreatment eligibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent expands the serotype parameter space by identifying and utilizing AAV serotypes AAV-Rh74, AAV-Rh44, and AAV-Rh39, which have distinct serological properties and lower pre-existing antibody prevalence in humans compared to conventional AAV2 and AAV8. This enables treatment of patient populations who would otherwise be ineligible due to pre-existing immunity to conventional serotypes.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If higher vector doses are used to achieve therapeutic expression, then transgene expression levels increase, but immune responses are intensified

Engineering Contradiction:

Improvetransgene expression levelVSAvoidimmune response intensity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the vector serotype parameter to AAV-Rh74, AAV-Rh44, or AAV-Rh39, which have lower pre-existing antibody prevalence in the human population. This allows achieving therapeutic transgene expression levels at lower vector doses compared to conventional AAV2 or AAV8, thereby reducing the intensity of immune responses while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11939590B1AAV vector compositions and methods for gene transfer to cells, organs and tissues

Publication Date: 2024.03.26 THE CHILDRENS HOSPITAL OF PHILADELPHIA

AI summary

The invention relates to adeno-associated virus (AAV) serotype AAV-Rh74 and related AAV vectors, and AAV-Rh74 and related AAV vector mediated gene transfer methods and uses. In particular, AAV-Rh74 targets polynucleotides to cells, tissues or organs for expression (transcription) of genes encoding therapeutic proteins and peptides, and polynucleotides that function as or are transcribed into inhibitory nucleic acid sequences.