AAVR-Knockout Humanized Liver Mouse for Accurate AAV Transduction

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing chimeric humanized mouse models are limited in evaluating AAV transduction efficiency due to preferential transduction of mouse hepatocytes over human hepatocytes by AAV serotypes.

Innovation Solution

Development of a chimeric non-human animal model with T-, B-, and NK-cell deficiencies or impairments, combined with AAVR knockouts, allowing for human hepatocyte repopulation and AAVR deficiency, enabling efficient transduction of human hepatocytes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If chimeric humanized mouse models are used to evaluate AAV transduction efficiency, then human hepatocytes are present in the liver, but mouse hepatocytes are preferentially transduced over human hepatocytes

Engineering Contradiction:

Improvehuman hepatocyte presenceVSAvoidtransduction efficiency evaluation

Core Design Contradiction:

Quantity of substanceVSMeasurement precision

Solution Approach 1:

The patent extracts and removes the AAVR gene from the mouse genome to eliminate the preferential transduction of mouse hepatocytes. By knocking out the AAVR receptor in the host animal, the patent eliminates the harmful preference for mouse cells, allowing AAV vectors to transduce human hepatocytes more efficiently and accurately evaluate transduction efficiency for human gene therapy applications

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the genetic parameter of the host animal by introducing AAVR knockout mutations. This genetic modification alters the transduction characteristics of the liver, shifting the preference from mouse to human hepatocytes and enabling accurate evaluation of AAV transduction efficiency in human cells

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If AAVR knockout is introduced to enable accurate transduction evaluation, then transduction efficiency measurement improves, but the model complexity increases

Engineering Contradiction:

Improvetransduction efficiency evaluationVSAvoidchimeric animal model

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent segments the complex chimeric animal model into distinct genetic components: AAVR knockout, Fah−/−, and IL-2Rg−/−/Rag2−/− deficiencies. Each component serves a specific function (eliminating preferential transduction, enabling human hepatocyte engraftment, and preventing immune rejection), allowing systematic construction and evaluation of the model

Inventive Principle:

Principle #1Segmentation

3Quantity of substance

If human hepatocytes are transplanted into immunocompetent animals, then human chimerism is established, but immune rejection occurs

Engineering Contradiction:

Improvehuman hepatocyte engraftmentVSAvoidchimerism stability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent performs preliminary genetic modification of the host animal by introducing IL-2Rg−/−/Rag2−/− deficiencies before human hepatocyte transplantation. This preliminary action eliminates T cells, B cells, and NK cells in the host, preventing immune rejection of human hepatocytes and ensuring long-term stability of human chimerism in the liver

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20260007122A1AAVR knockout mouse in combination with human liver chimerism and methods of use and production of the same

Publication Date: 2026.01.08 AVACHROME INC

AI summary

The present disclosure provides an immunodeficient or immune-impaired chimeric non-human animal with a deletion or impairment of adeno-associated virus receptor (AAVR), comprising human hepatocytes, methods for preparing the chimeric non-human animal comprising human hepatocytes and methods of utilizing the chimeric non-human animal comprising human hepatocytes to evaluate transduction efficiency of adeno-associated viruses (AAV), and determine mechanism of inhibition/modification of AAV transduction in human hepatocytes.