Universal Cell Engineering With MHC Knockout and Sialic Acid Overexpression
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Solution Overview
Problem
Current cell-based therapies face challenges due to immune incompatibility and immunological rejection, with existing methods for producing universal allogeneic pluripotent stem cells being costly, inefficient, and prone to severe immunological rejection, while autologous therapies are costly and have uncertain quality.
Innovation Solution
A novel method involving gene editing to knock out MHC-I and MHC-II genes and overexpress sialic acid-related proteins (SLC35A1, GNE, CMAS, ST3Gal5, ST8SIA1, MUC1, APMAP, SMAGP, and CD43) in pluripotent stem cells using a lentiviral vector, creating cells with immune privilege that evade T cell and NK cell attacks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If gene editing is used to knock out MHC-I and MHC-II genes to create universal allogeneic PSCs, then immune compatibility is improved, but susceptibility to NK cell-mediated lysis increases
Solution Approach 1:
The patent converts the harmful effect of MHC-I knockout (NK cell susceptibility) into a benefit by knocking out B2M, which eliminates both MHC-I expression and NK cell recognition. The dual knockout of B2M and CIITA transforms what would be a vulnerability into a protective mechanism against both T cell and NK cell-mediated rejection
Solution Approach 2:
The patent changes the immunogenic parameters of the cells by knocking out specific genes (B2M and CIITA) to alter MHC molecule expression. This genetic parameter modification creates cells with fundamentally different immune recognition properties, enabling universal allogeneic transplantation without immunological rejection
2Object-affected harmful factors
If HLA-matched iPSC banks are established to reduce immunogenicity, then immune compatibility is improved, but construction and maintenance costs increase significantly
Solution Approach 1:
The patent creates universally compatible PSCs through gene knockout that can be transplanted into any patient without HLA matching. This universal cell line serves multiple patients simultaneously, eliminating the need for individualized HLA-matched banks and enabling broad applicability across diverse populations
Solution Approach 2:
The patent extracts the immunogenic elements (MHC-I and MHC-II molecules) from the PSCs through targeted gene knockout. By removing these specific components responsible for immune recognition, the cells become universally compatible without requiring complex HLA matching infrastructure
3Object-affected harmful factors
If autologous cell transplantation is used to circumvent immunological rejection, then immune compatibility is improved, but production cost and preparation time increase
Solution Approach 1:
The patent creates a universal allogeneic PSC line that can serve multiple patients simultaneously, eliminating the need for individualized autologous cell production. This universal cell bank enables rapid off-the-shelf transplantation without the lengthy and costly autologous cell manufacturing process
Data Source
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AI summary
Disclosed are a universal cell and a preparation method therefor. After major histocompatible complex MHC-I and II genes are inactivated in cells, at least one protein of SLC35A1, GNE, CMAS, ST3Gal5, ST8SIA1, MUC1, APMAP, SMAGP, and CD43 is overexpressed, so that the obtained human pluripotent stem cells or human cell lines can further escape the killing of NK cells and macrophages on the basis of escaping the attack of T cells. Meanwhile, the low-immunogenicity pluripotent stem cells retain the stemness and differentiation capacity thereof.