Genetically Modified Beta-Like Cells for Immune Killing Resistance
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Solution Overview
Problem
Current methods for protecting beta cells from immune attack in type 1 diabetes, such as beta cell encapsulation, face challenges like packaging density, oxygenation, fibrosis, and delayed insulin secretion, while genetic modifications targeting known immune recognition molecules may be futile due to the immune system's flexibility.
Innovation Solution
Genetic modifications in beta-like cells to inhibit the expression of specific proteins, including menin, HIVEP2, renalase, lengsin, eIF-2-alpha kinase activator GCN1, perilipin-4, mediator of RNA polymerase II transcription subunit 11, zinc finger BED domain-containing protein 3, and metabotropic glutamate receptor 2, using CRISPR/Cas9 or other nucleases, to make the cells resistant to immune killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If beta cells are encapsulated in a physical barrier, then protection from immune attack is achieved, but oxygenation is compromised and fibrosis occurs
Solution Approach 1:
The patent extracts the protective function from the physical encapsulation barrier and transfers it to genetic modifications of the beta cells themselves. By knocking out immune recognition molecules (HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, HLA-DP) and immune response molecules (CD40, CD80, CD86) directly in the beta cells, the protection function is separated from the physical barrier, eliminating the barrier's harmful effects on oxygenation while maintaining immune protection.
Solution Approach 2:
The patent introduces CRISPR/Cas9 genome editing technology as an intermediary mechanism to achieve immune protection. Instead of using a physical barrier, the Cas9 enzyme guided by specific gRNAs mediates the knockout of immune-related genes in beta cells, providing a molecular-level intermediary solution that protects beta cells from immune attack without requiring encapsulation.
2Object-affected harmful factors
If beta cells are encapsulated in a physical barrier, then protection from immune attack is achieved, but insulin secretion is delayed
Solution Approach 1:
The protective function is extracted from the physical encapsulation barrier and transferred to genetic modifications of beta cells. By knocking out immune recognition and response molecules directly in the beta cells, the solution eliminates the time delay caused by diffusion through encapsulation barriers while maintaining protection from immune attack.
3Object-affected harmful factors
If CRISPR/Cas9 is used to knock out immune recognition molecules, then protection from immune killing is achieved, but the immune system's flexibility may render this futile
Solution Approach 1:
The patent segments the immune recognition and response pathways into multiple discrete molecular targets (HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, HLA-DP, CD40, CD80, CD86). By knocking out multiple segments of the immune recognition system simultaneously, the patent reduces the immune system's ability to adapt and find alternative recognition pathways, addressing the flexibility challenge through multi-point disruption.
Solution Approach 2:
The patent fundamentally changes the parameter of immune recognition by eliminating the molecular basis for recognition (HLA molecules) and response (CD40, CD80, CD86). This parameter change at the molecular level makes the beta cells invisible and non-responsive to the adaptive immune system, overcoming the immune system's flexibility by removing the very parameters it uses to identify and attack target cells.
4Object-affected harmful factors
If multiple immune-related genes are knocked out in beta cells, then comprehensive immune protection is achieved, but genetic modification complexity increases
Solution Approach 1:
The patent merges multiple CRISPR/Cas9 targeting strategies into a unified genome editing approach. By designing a coordinated set of gRNAs that target multiple immune-related genes simultaneously, the patent combines multiple protective functions into a single genetic modification protocol, reducing the overall complexity compared to sequential or separate modification approaches.
Data Source
AI summary
Compositions of genetically modified beta-like cells are encompassed. Also encompassed are methods of treatment of type 1 diabetes using these compositions or compositions that inhibit the function of the identified genes.