Modulating TLR/NF-kB and p53 Pathways for Interspecies Chimerism

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Solution Overview

Problem

The challenge of achieving interspecies chimerism between evolutionarily distant species, such as humans and mice or pigs, is hindered by a xenogeneic barrier, where human pluripotent stem cells inefficiently contribute to chimera formation due to significant evolutionary distances, preventing the successful generation of human organs in animals for transplantation.

Innovation Solution

The development of chimeric blastocysts comprising a host blastocyst from one mammalian species and donor pluripotent stem cells from another species, with reduced expression or biological activity of proteins in the TLR/NF-kB signaling pathway or the p53 pathway, facilitates interspecies chimerism by enhancing the survival and contribution of donor cells, allowing for the formation of human organs in non-human species.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If human pluripotent stem cells are injected into early post-implantation mouse or pig embryos to form interspecies chimeras, then the potential for generating human organs in animals is achieved, but the xenogeneic barrier causes inefficient contribution of human cells to chimera formation and elimination of human cells during early development

Engineering Contradiction:

Improveinterspecies chimerism capabilityVSAvoiddonor cell survival and contribution efficiency

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies the biological parameters of donor pluripotent stem cells by altering the expression levels or biological activity of specific proteins (TLR4, MYD88, IRAK4, p53, TP53) to enable these cells to survive and contribute efficiently in evolutionarily distant host species, thereby overcoming the xenogeneic barrier while maintaining the adaptability of interspecies chimera formation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces intermediary molecules (small molecule inhibitors or antibodies targeting TLR4, MYD88, IRAK4, or p53 pathways) that mediate between the donor human cells and the host animal immune system, preventing rejection and enabling sustained chimerism between evolutionarily distant species

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If the evolutionary distance between donor and host species is increased to enable organ generation in livestock, then the potential for transplantation is improved, but the xenogeneic barrier becomes more significant and prevents successful chimerism

Engineering Contradiction:

Improveorgan generation potentialVSAvoidxenogeneic barrier strength

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the protein expression parameters in donor cells to compensate for increased evolutionary distance, specifically reducing or modifying TLR4, MYD88, IRAK4, or p53 pathway components to prevent the host immune system from recognizing and eliminating human donor cells, thereby enabling chimerism in livestock species

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the harmful xenogeneic immune response into a beneficial outcome by using the immune recognition pathway itself (TLR4/MYD88/IRAK4 or p53) as the target for modification, where controlling these pathways prevents rejection and enables the very chimerism that would otherwise be blocked by the xenogeneic barrier

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20230073534A1Modulating TLR/NF-KB and p53 signaling pathways to enhance interspecies chimerism between evolutionaryily distant species

Publication Date: 2023.03.09 BOARD OF RGT THE UNIV OF TEXAS SYST

AI summary

Disclosed herein are chimeric blastocysts, such as chimeric blastocysts derived from a host blastocyst from a first mammalian species and having donor pluripotent stem cells from a second mammalian species, wherein the donor pluripotent stem cells have reduced expression or reduced biological activity of one or more proteins in the TLR/NF-kB signaling pathway or the p53 pathway. Methods of preparing chimeric blastocysts and methods of obtaining mammalian organs and tissues are also provided.