Cfh Knockout Rats for Rapid C3G Pathology Modeling

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Solution Overview

Problem

Current models for C3 glomerulopathy (C3G), such as complement factor H deficient mice, take several months to develop end-stage renal disease (ESRD), necessitating long preclinical studies for therapeutic assessment, and there is a lack of effective treatments for C3G.

Innovation Solution

Genetically modified rats with an inactivated complement factor H (Cfh) locus, which exhibit rapid development of C3G symptoms and ESRD, allowing for shorter preclinical studies and potential therapeutic efficacy assessment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If complement factor H deficient mice are used as a model for C3 glomerulopathy, then the model accurately represents human C3G pathology, but the development of end-stage renal disease takes several months, necessitating long preclinical studies

Engineering Contradiction:

Improveaccuracy of C3G pathology representationVSAvoidduration of preclinical studies

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent changes the species parameter from mouse to rat, utilizing the naturally faster development rate of renal disease in rats compared to mice. This parameter change allows the model to maintain accuracy in representing human C3G pathology while significantly reducing the study duration, as rat Cfh knockout models develop ESRD within weeks rather than months.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If complement factor H deficient mice are used as a model for C3 glomerulopathy, then the model accurately represents human C3G pathology, but there is a lack of effective treatments for C3G

Engineering Contradiction:

Improveaccuracy of C3G pathology representationVSAvoidtherapeutic development efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the model organism from mouse to rat, creating a Cfh knockout rat model that develops C3G and ESRD more rapidly. This parameter change enhances therapeutic development efficiency by allowing faster assessment of potential treatments, while the model maintains reliability in representing human C3G pathology through its genetic and phenotypic characteristics.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If the Cfh locus is inactivated in rats, then rapid development of C3G symptoms and ESRD is achieved, enabling faster evaluation of therapeutic agents

Engineering Contradiction:

Improvespeed of C3G developmentVSAvoidduration of preclinical studies

Core Design Contradiction:

ProductivityVSLoss of time

Solution Approach 1:

The patent applies preliminary action by inactivating the Cfh locus in the rat model before the development of C3G symptoms. The Cfh knockout is established in the model organism beforehand, which then rapidly progresses to C3G and ESRD. This preliminary genetic modification enables the disease to develop at an accelerated rate, allowing faster evaluation of therapeutic agents without requiring extended study periods.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentEP3849304B1Complement factor h gene knockout rat as a model of c3 glomerulopathy

Publication Date: 2024.01.10 REGENERON PHARMACEUTICALS INC

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AI summary

Rat cells and rats comprising an inactivated Cƒh locus and methods of making and using such rat cells and rats are provided. The rats comprising an inactivated Cƒh locus model C3 glomerulopathy (C3G). Methods are provided for using such rats comprising an inactivated Cƒh locus to assess in vivo efficacy of putative C3G therapeutic agents.