siRNA CAR-T Vector for CRS Management
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Solution Overview
Problem
Current treatments for Cytokine Release Syndrome (CRS) associated with CAR-T cell therapy, such as Tocilizumab, are expensive and can lead to increased infection risk due to immunosuppression.
Innovation Solution
Development of a siRNA of human IL-6 and a recombinant expression CAR-T vector that uses a lentiviral vector to deliver siRNA targeting IL-6, thereby reducing IL-6 levels and mitigating CRS symptoms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If Tocilizumab is used to treat CRS, then IL-6 inhibition is achieved, but infection risk increases due to immunosuppression
Solution Approach 1:
The patent segments the treatment approach by using siRNA to specifically target and silence the IL-6 gene at the molecular level, rather than using broad-spectrum immunosuppressive antibodies. This targeted gene silencing approach selectively inhibits pathogenic IL-6 while preserving other immune functions, thus reducing infection risk compared to Tocilizumab's broad immunosuppression
Solution Approach 2:
The patent replaces the mechanical/chemical approach of antibody-drug conjugates (Tocilizumab) with a biological molecular mechanism (siRNA-mediated RNA interference). The siRNA enters cells and directs the RISC complex to cleave IL-6 mRNA, providing targeted gene silencing that avoids the off-target immunosuppressive effects of antibody therapy
2Object-affected harmful factors
If antihistamine or corticosteroid is injected to inhibit inflammatory reaction, then CRS symptoms are relieved, but CAR-T cell killing effect on tumor is inhibited
Solution Approach 1:
The patent applies local quality by using siRNA to specifically target the IL-6 gene in a localized molecular manner, rather than using systemic anti-inflammatory drugs that affect all immune cells. The siRNA-mediated silencing is selective for IL-6 mRNA, allowing other immune functions including CAR-T cell cytotoxicity to remain intact
Solution Approach 2:
The patent converts the harmful overexpression of IL-6 (which causes CRS) into a benefit by using the siRNA mechanism to specifically silence only the pathogenic IL-6 transcripts. This selective silencing removes the harmful inflammatory effect while preserving the beneficial anti-tumor activity of CAR-T cells
3Object-affected harmful factors
If siRNA is used to knock down IL-6, then CRS symptoms are alleviated, but treatment cost and complexity increase
Solution Approach 1:
The patent merges the CAR-T cell therapy with IL-6 gene silencing by integrating siRNA expression cassettes into the same viral vector used for CAR expression. This combined approach delivers both the CAR transgene and the siRNA sequence simultaneously to T cells, creating a unified therapeutic product that addresses both tumor targeting and CRS prevention in one treatment
Solution Approach 2:
The patent creates a multi-functional viral vector that serves dual purposes: expressing the CAR protein for tumor recognition and expressing siRNA for IL-6 gene silencing. This universal vector platform handles both therapeutic functions, simplifying the overall treatment architecture compared to separate therapies
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The siRNA effectively decreases IL-6 expression levels, alleviating CRS symptoms and maintaining the anti-tumor efficacy of CAR-T cells without the adverse effects of existing treatments.
Implementation Method 1
after entering plant and invertebrate cells, dsRNA is broken down by Type III endonuclease Dicer into siRNA... After the integration with corresponding target mRNA, one or more endonuclease(s) in RISC cleave(s) target mRNA, giving rise to mRNA silencing
Implementation Method 2
a recombinant expression CAR-T vector (especially a CAR-T transgene vector used for the remission of CRS by knocking down IL-6)... uses a lentiviral vector to deliver siRNA targeting IL-6
Data Source
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Figure 3A~3B
AI summary
Provided are a siRNA of the human interleukin 6, a recombinant expression CAR-T vector, and a construction method and a use thereof. The siRNA can be used in the treatment of acute B-cell lymphocytic leukemia with CAR19-T for eliminating or alleviating the symptoms of cytokine release syndrome (CRS), and can also be used for alleviating the CRS symptoms caused by treating tumours with CAR-T and even can also be used for alleviating CRS caused by other types of treatment.