Genetically Modified Donor Organs for Reduced Xenograft Rejection
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Solution Overview
Problem
There is a shortage of organs, tissues, or cells available for transplantation, and unmodified wild-type non-human animal tissues are often rejected by the immune system of recipients due to antibody binding and cell-mediated immunity.
Innovation Solution
Genetically modify non-human animals, such as those in the Laurasiatheria superorder or non-human primates, to reduce the expression of specific genes associated with immune rejection, and introduce exogenous polynucleotides encoding proteins that suppress immune response, thereby reducing the likelihood of graft rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If unmodified wild-type non-human animal tissues are used for transplantation, then the supply of transplantable organs and tissues is increased, but the tissues are rejected by the recipient's immune system due to antibody binding and cell-mediated immunity
Solution Approach 1:
The patent applies parameter changes by genetically modifying the donor animal's cells to alter the expression levels of specific genes (upregulation of HLA-G, downregulation of NLRC5, TAP1, C3, and other immune-related genes). These genetic parameter modifications change the immunogenicity profile of the transplanted tissues, reducing antibody binding and cell-mediated immune responses while maintaining tissue functionality, thereby improving graft survival rates without compromising the supply of transplantable organs.
2Reliability
If genetically modified animals are used to reduce immune rejection, then graft survival rate is improved, but the complexity of the transplantation process increases due to genetic modification requirements
Solution Approach 1:
The patent implements preliminary action by performing genetic modifications on the donor animal's cells before transplantation. The cells are pre-modified to express appropriate levels of HLA-G and suppressed expression of immunogenic genes (NLRC5, TAP1, C3, etc.), creating immunologically optimized cell lines or tissues in advance. This preliminary genetic engineering allows the transplanted tissues to be inherently resistant to rejection, reducing the need for complex post-transplantation immunosuppression protocols and simplifying the overall transplantation process.
3Object-affected harmful factors
If genes associated with immune rejection are reduced in expression, then antibody binding and cell-mediated immunity are decreased, but the ability to maintain immune surveillance may be compromised
Solution Approach 1:
The patent applies local quality by implementing gene expression modifications specifically in the transplanted cells and tissues rather than systemically throughout the entire organism. The genetic modifications (upregulation of HLA-G, downregulation of NLRC5, TAP1, C3) are localized to the donor cells, creating a local immunological environment that is tolerant to the graft. This localized approach allows the recipient's overall immune surveillance system to remain functional and responsive to other antigens, while the transplanted tissues specifically exhibit reduced immunogenicity and resistance to rejection.
Data Source
AI summary
Genetically modified cells, tissues, and organs for treating or preventing diseases are disclosed. Also disclosed are methods of making the genetically modified cells and non-human animals.