Engineered MSCs With Adhesion Ligands for Inflamed Tissue Homing
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Solution Overview
Problem
Existing cell-based therapies, particularly those using mesenchymal stem/stromal cells (MSCs), face challenges in scaling from preclinical success to clinical efficacy due to poor targeting, inconsistent potency, and limited persistence in the body.
Innovation Solution
Genetically engineering MSCs to express specific cell adhesion proteins, immunomodulatory proteins, and therapeutic cargo, such as IL-10, while incorporating a small molecule inducible safety switch and selectable markers, to enhance targeting, potency, and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional MSC therapies are used, then the therapy can be administered, but the cells show poor targeting to inflamed tissues
Solution Approach 1:
The patent modifies cell surface parameters by engineering MSCs to express specific adhesion molecules (P-selectin ligand, E-selectin ligand, L-selectin ligand) that change the cells' physical and chemical properties, enabling them to home to inflamed tissues through enhanced adhesion to endothelial cells at sites of inflammation.
Solution Approach 2:
The patent introduces intermediary adhesion molecules as mediators between the MSCs and the inflamed tissue environment. These engineered surface proteins act as intermediaries that facilitate recognition and binding to the inflammatory milieu, improving targeting without requiring direct cell-to-cell contact mechanisms.
2Reliability
If conventional MSC therapies are used, then the therapy can be administered, but the cells show limited persistence in the body
Solution Approach 1:
The patent changes the immunological parameters of MSCs by engineering them to express immunomodulatory proteins (CTLA-4, PD-L1, CD47) that alter their interaction with the host immune system, thereby enhancing their persistence and survival in the inflammatory environment without rapid clearance.
Solution Approach 2:
The patent performs preliminary genetic engineering of MSCs ex vivo to equip them with enhanced targeting and immunomodulatory capabilities before administration. This preliminary action ensures the cells are pre-programmed with the necessary functions for improved persistence and therapeutic efficacy in the target tissue.
3Reliability
If conventional MSC therapies are used, then the therapy can be administered, but the therapy shows inconsistent potency
Solution Approach 1:
The patent standardizes therapeutic potency by engineering MSCs to express defined levels of therapeutic cargo (such as IL-10) and adhesion molecules, creating a homogeneous cell population with consistent immunomodulatory and targeting functions, thereby reducing variability in therapeutic response.
Solution Approach 2:
The patent incorporates selectable markers and reporters that provide feedback mechanisms during manufacturing to ensure consistent expression of engineered proteins. This allows for quality control and selection of cells that meet specified potency criteria, ensuring batch-to-batch consistency.
4Reliability
If multiple proteins are expressed in the engineered cells, then the therapeutic efficacy is enhanced, but the cell engineering complexity increases
Solution Approach 1:
The patent combines multiple functional proteins (adhesion molecules, immunomodulatory proteins, therapeutic cargo, selectable markers, and reporters) into a single integrated genetic construct or vector system, allowing simultaneous expression of all necessary components in the engineered MSCs through a unified delivery mechanism.
Solution Approach 2:
The patent creates universally applicable MSC engineering platforms where a single genetic construct can deliver multiple functions (targeting, immunomodulation, therapy, selection, and reporting) through multi-functional protein expression, reducing the need for separate engineering steps for each function.
Data Source
AI summary
The present invention is directed to a genetically engineered cell and methods thereof as described herein.