miR155 Locus CAR Integration to Prevent Graft-versus-Host Disease
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for hematologic malignancies using allo-hematopoietic stem cell transplants are hindered by the high incidence of acute graft-versus-host disease (aGVHD), which poses significant morbidity and mortality risks.
Innovation Solution
Genetically modifying T cells by deleting miR155 before transplantation and targeting the miR155 locus as an insertion site for a chimeric antigen receptor (CAR) to reduce the risk of aGVHD while enabling targeted cancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allo-hematopoietic stem cell transplant is used to treat hematologic malignancies, then cancer treatment efficacy is improved, but the incidence of acute graft-versus-host disease increases
Solution Approach 1:
The patent extracts and removes the harmful miR155 component from the donor T cells before transplantation. By specifically deleting the miR155 gene using CRISPR/Cas9 technology, the patent eliminates the source of aGVHD while preserving the therapeutic anti-tumor activity of the T cells, thus resolving the contradiction between treatment efficacy and safety
Solution Approach 2:
The patent converts the harmful effect of miR155 (which causes aGVHD) into a beneficial therapeutic strategy. By targeting and deleting miR155, the patent transforms what was previously a harmful factor into a precise genetic modification that prevents aGVHD while maintaining or enhancing the anti-tumor efficacy of the adoptive T cell therapy
2Object-affected harmful factors
If miR155 is deleted in T cells before transplant, then the risk of acute graft-versus-host disease is reduced, but the ability to treat cancer may be compromised
Solution Approach 1:
The patent applies local quality modification by specifically targeting only the miR155 gene for deletion while leaving the rest of the T cell genome and functional characteristics intact. This precise genetic modification ensures that only the harmful aspect (miR155-mediated aGVHD) is removed, while the beneficial anti-tumor functions of T cells are preserved
Solution Approach 2:
The patent changes the genetic parameter of the T cells by deleting the miR155 gene sequence. This parameter change (genetic modification) fundamentally alters the behavior of the T cells regarding host tissue interaction, reducing aGVHD risk while maintaining their ability to recognize and attack tumor cells through other molecular mechanisms
3Adaptability or versatility
If CAR is inserted into random genomic locations, then targeted cancer therapy is enabled, but genomic stability and safety are compromised
Solution Approach 1:
The patent uses the miR155 locus as an intermediary target site for CAR insertion. By directing CAR integration to this specific genomic location through CRISPR/Cas9-mediated homology-directed repair, the patent achieves precise, controlled insertion that maintains genomic stability while enabling the desired targeted therapy function
Solution Approach 2:
The patent creates a multi-functional approach by using the miR155 deletion strategy to simultaneously achieve two goals: (1) prevent aGVHD by removing miR155, and (2) provide a defined integration site for CAR insertion. This dual-purpose strategy consolidates multiple therapeutic benefits into a single genetic modification approach
Data Source
AI summary
The present disclosure relates to CAR-T cells and uses thereof. Disclosed herein is a genetically modified T cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR) polypeptide comprising a single-chain variable fragment (scFV) that specifically binds to a target molecule, wherein the nucleic acid sequence encoding the CAR polypeptide is integrated into an integration site located at a miR-155 host gene.