Transgenic Pig Liver Coagulation Factor Modification
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Solution Overview
Problem
Current liver transplantation from pigs to primates faces challenges due to hyperacute rejection and coagulopathy, leading to short survival times, primarily caused by species incompatibility in coagulation factors, despite efforts to overcome immunological rejection.
Innovation Solution
Development of transgenic pigs that express human coagulation factors such as Factor VII, II, and XII, while preventing expression of corresponding porcine coagulation factors, to enhance compatibility and stability of pig-to-primate liver transplants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If pig livers are used for transplantation to primates, then organ availability is improved, but hyperacute rejection and coagulopathy occur leading to short survival times
Solution Approach 1:
The patent applies parameter changes by modifying the genetic composition of the donor pig to express human coagulation factors (Factors II, VII, IX, X, and XII) instead of porcine factors. This biochemical parameter change in the organ tissue resolves the species incompatibility that causes coagulopathy and extends transplant survival from hours to over 9 days in primate models.
2Quantity of substance
If wild type porcine livers are transplanted, then organ supply is increased, but hyperacute rejection occurs within hours
Solution Approach 1:
The patent changes the biochemical parameters of the liver by introducing transgenes for human coagulation factors and knocking out endogenous porcine coagulation factor genes. This genetic modification eliminates the species-specific coagulation factor incompatibility that triggers hyperacute rejection, allowing the organ to be accepted by the primate immune system.
3Duration of action of moving object
If hDAF transgenic porcine livers are used, then some survival is achieved (4-5 days), but thrombocytopenia and coagulopathy develop
Solution Approach 1:
The patent changes the coagulation factor profile from porcine to human by genetic modification. Specifically, it introduces human coagulation factor transgenes (II, VII, IX, X, XII) and knocks out porcine coagulation factor expression. This parameter change resolves the coagulopathy and thrombocytopenia that limited survival to 4-5 days in hDAF transgenic models.
Solution Approach 2:
The patent extracts or removes the harmful porcine coagulation factors from the liver tissue through knockout of the endogenous porcine coagulation factor genes. By eliminating these incompatible porcine factors while retaining human factors, the harmful coagulopathic effects are removed while maintaining coagulation function.
Data Source
AI summary
Transgenic swine that express human coagulation factors, e.g., human coagulation factor VII, and/or one or more of human coagulation factors II, X and XII, and do not express the corresponding porcine coagulation factor or factors, as well as cells, tissues and organs derived therefrom, and their use in transplantation procedures.