Hypoimmunogenic Stem Cells Through MHC Knockout and Tolerogenic Editing
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Solution Overview
Problem
Existing cell replacement therapies using human pluripotent stem cells are limited by immune rejection, which current strategies such as HLA-matching and immunosuppressive drugs fail to adequately address.
Innovation Solution
Genome editing tools like TALEN and CRISPR are used to reduce or knock out MHC-I and MHC-II genes in stem cells, and introduce tolerogenic factors into a safe harbor locus to create hypoimmunogenic stem cells that minimize immune rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If human pluripotent stem cells are used for cell replacement therapy, then the potential to treat most degenerative illnesses is achieved, but immune rejection limits the success of such therapies
Solution Approach 1:
The patent extracts and removes the harmful immunogenic components (MHC-I and MHC-II genes) from the stem cells using genome editing tools like TALEN and CRISPR. This extraction of the problematic elements allows the stem cells to maintain their therapeutic potential while eliminating the cause of immune rejection, thereby resolving the contradiction between treatment versatility and therapy success.
Solution Approach 2:
The patent converts the harmful immune recognition properties of stem cells into a benefit by using genome editing to create hypoimmunogenic cells. The same MHC molecules that cause immune rejection are targeted for removal, transforming the stem cells from being immunogenic to hypoimmunogenic, thus converting a therapeutic limitation into an advantage that enables successful transplantation without immune rejection.
2Reliability
If HLA-matching or immunosuppressive drugs are used to overcome immune rejection, then immune acceptance is improved, but the complexity and limitations of current strategies increase
Solution Approach 1:
Instead of adding complex matching protocols or immunosuppressive regimens, the patent extracts the immunogenic MHC-I and MHC-II genes directly from the stem cells. This simplifies the approach by removing the root cause of immune rejection rather than managing it through complex external interventions, thereby improving immune acceptance while reducing strategy complexity.
Solution Approach 2:
Conventional approaches try to make the recipient immune system tolerate the donor cells through matching or suppression. The patent inverts this approach by modifying the donor stem cells to be inherently hypoimmunogenic through genome editing. This reversal of the problem-solving strategy eliminates the need for complex matching or immunosuppression protocols.
3Reliability
If MHC-I and MHC-II genes are knocked out in stem cells, then immune rejection is reduced, but the complexity of genome editing increases
Solution Approach 1:
The patent segments the complex task of creating hypoimmunogenic stem cells into manageable components: (1) designing specific guide RNAs for TALEN or CRISPR systems, (2) delivering the genome editing tools to stem cells, (3) selecting successfully edited clones, and (4) validating MHC knockout. This segmentation makes the complex genome editing process more controllable and reproducible.
Solution Approach 2:
The patent uses guide RNAs as intermediaries to direct the TALEN or CRISPR genome editing tools to specific MHC-I and MHC-II gene loci. These guide RNAs serve as the mediating element that simplifies the targeting process, allowing precise knockout of multiple MHC genes without requiring complex protein-based targeting systems.
Data Source
AI summary
Disclosed herein are universal donor stem cells and related methods of their use and production. The universal donor stem cells disclosed herein are useful for overcoming the immune rejection in cell-based transplantation therapies. In certain embodiments, the universal donor stem cells disclosed herein do not express one or more MHC-I and MHC-II human leukocyte antigens. Similarly, in certain embodiments, the universal donor stem cells disclosed herein do not express one or more human leukocyte antigens (e.g., HLA-A, HLA-B and/or HLA-C) corresponding to MHC-I and MHC-II human leukocyte antigens, thereby rendering such cells hypoimmunogenic.