BCMA CAR Circular RNA for Stable Expression Without Genome Integration
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Solution Overview
Problem
Conventional DNA-based gene therapy methods risk integrating into the host genome, causing mutations, disrupting essential gene function, and triggering immune responses, while viral vectors are costly and difficult to control.
Innovation Solution
The use of circular RNA polynucleotides encoding chimeric antigen receptors (CARs) that specifically bind to BCMA, delivered via nanoparticles, avoiding genomic integration and immune response issues, and utilizing optimized sequences for stable and efficient expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If DNA-based gene therapy is used to deliver genetic information into host cells, then long-lasting action of the introduced genetic material is achieved, but the risk of genomic integration causing mutations and disrupting essential gene function increases
Solution Approach 1:
The patent extracts the harmful integration function from the DNA delivery system by using RNA instead of DNA. The RNA-based therapeutic agent delivers genetic information without the ability to integrate into the host genome, thereby removing the harmful effect while preserving the therapeutic benefit of sustained protein expression.
Solution Approach 2:
The patent changes the fundamental parameter of the genetic material from DNA to RNA. This parameter change transforms the properties of the therapeutic agent: RNA cannot integrate into the genome like DNA, eliminating the mutation risk, while still enabling sustained protein expression through circular RNA stability and repeated translation cycles.
2Productivity
If conventional DNA based gene therapy is used, then effective expression of the desired gene product is achieved, but the requirement for strong promoter sequences leads to undesirable changes in the regulation of normal gene expression
Solution Approach 1:
The patent removes the promoter sequence requirement from the therapeutic construct by using circular RNA. Since circular RNA is transcribed in vitro and then introduced into cells, it does not require viral or cellular promoters that could disrupt normal gene regulation. The circular RNA contains only the essential elements for protein expression: the coding sequence and ribosome binding site.
3Reliability
If DNA based genetic material is introduced into host cells, then gene therapy effect is achieved, but the induction of anti-DNA antibodies triggers possibly fatal immune response
Solution Approach 1:
The patent changes the chemical nature of the therapeutic agent from DNA to RNA. This parameter change fundamentally alters the immune system's recognition and response: RNA does not trigger anti-DNA antibody production, eliminating this specific immune-mediated harm while maintaining therapeutic efficacy through protein expression.
4Ease of manufacture
If viral vectors are used for delivery of genetic material, then targeted delivery is achieved, but the cost and time required for production increases
Solution Approach 1:
The patent replaces expensive, complex viral vectors with a simpler, cheaper in vitro transcribed circular RNA. The circular RNA can be produced using standard transcription machinery without requiring viral vector production facilities, significantly reducing manufacturing cost and time while maintaining sufficient delivery efficiency through nanoparticle or electroporation methods.
5Ease of operation
If viral vectors are used for delivery, then genetic material delivery is achieved, but the targeting control of delivery becomes difficult
Solution Approach 1:
The patent introduces an intermediary delivery system (nanoparticles or electroporation) that provides better control over circular RNA delivery. These intermediary systems allow for more precise targeting and dosing control compared to viral vectors, while avoiding the complexity and unpredictability of viral transduction.
Data Source
AI summary
Circular RNA, along with related compositions and methods are described herein. In some embodiments, the inventive circular RNA comprises group I intron fragments, spacers, an IRES, duplex forming regions, and an expression sequence. In some embodiments, the expression sequence encodes an antigen. In some embodiments, circular RNA of the invention has improved expression, functional stability, immunogenicity, ease of manufacturing, and/or half-life when compared to linear RNA. In some embodiments, inventive methods and constructs result in improved circularization efficiency, splicing efficiency, and/or purity when compared to existing RNA circularization approaches.