Circular RNA CAR Constructs for In Vivo Cancer Cell Targeting
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Solution Overview
Problem
Existing CAR-T therapies for cancer treatment suffer from toxic side effects, complex procedures, and the need for lymphodepletion, which can cause neutropenia, anemia, thrombocytopenia, and immunosuppression, while traditional CAR therapies require specialized equipment and high costs.
Innovation Solution
The use of circular RNA constructs encoding chimeric antigen receptors (CARs) paired with lipid transfer vehicles, such as LNPs, to deliver and express CARs in immune cells, thereby avoiding lymphodepletion and reducing side effects by programming immune cells to recognize and attack cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional CAR-T therapy is used, then cancer treatment efficacy is improved, but toxic side effects and complex procedures increase
Solution Approach 1:
The patent extracts the essential therapeutic function (CAR expression) from the complex CAR-T cell therapy process, delivering only the necessary circular RNA encoding the CAR to immune cells present in the patient's body, thereby eliminating the need for complex ex vivo cell manipulation and reducing toxic side effects associated with traditional CAR-T therapy
Solution Approach 2:
The patent uses circular RNA as an intermediary carrier to transfer the CAR genetic information directly to immune cells in vivo, avoiding the need for direct cell modification and complex procedures while maintaining treatment efficacy
2Reliability
If lymphodepletion is performed to enhance CAR-T cell expansion, then treatment efficacy is improved, but patient toxicity increases
Solution Approach 1:
The patent removes the lymphodepletion step from the treatment protocol entirely, delivering circular RNA directly to the patient's existing immune cells without requiring prior immunosuppressive conditioning, thereby eliminating associated toxicities while preserving treatment efficacy
Solution Approach 2:
The patent allows the patient's own immune system to naturally process and respond to the circular RNA without requiring external intervention through lymphodepletion, enabling the immune cells to self-select and expand appropriately in response to the therapeutic stimulus
3Device complexity
If circular RNA constructs are used to encode CARs, then procedure complexity is reduced, but delivery efficiency must be maintained
Solution Approach 1:
The patent employs lipid nanoparticle formulations as composite delivery vehicles to encapsulate and protect the circular RNA constructs, enabling efficient cellular uptake and intracellular delivery while maintaining the simplicity of the in vivo approach
Solution Approach 2:
The patent optimizes the physical and chemical parameters of the circular RNA constructs and their lipid nanoparticle formulations to enhance stability, cellular uptake, and translational efficiency, ensuring reliable delivery without complicating the overall procedure
Data Source
AI summary
Provided herein are circular RNA constructs comprising an IRES, and at least one expression sequence encoding binding molecule, compositions thereof, and methods of treatment, including for cancer and autoimmune disease. In particular, circular RNA comprising an IRES and a CD19 binder, a HER2 binder, or a BCMA binder are provided, optionally formulated with a delivery vehicle. Precursor polynucleotides comprising an IRES, and at least one expression sequence encoding a CAR construct are also described herein.