Antisense Oligonucleotides Modulating T Cell Function
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Solution Overview
Problem
Current immunotherapy approaches for cancer and viral infections, such as Hepatitis B-induced Hepatocellular Carcinoma, face challenges in effectively targeting and modulating T-cell functions to enhance antitumor and antiviral responses while minimizing side effects, particularly due to the risk of hepatotoxicity and immunogenicity associated with retro- or lentiviral-transduced cells.
Innovation Solution
The use of antisense oligonucleotides (ASOs) to selectively modulate T-cell functions by inducing exon skipping or intron retention of immune-related genes, such as IFN-γ, Perforin, Granzyme, and PD-1, to enhance T-cell specificity and efficacy against tumor cells or viral-infected cells, thereby reducing cytotoxicity and improving therapeutic outcomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If retro- or lentiviral-transduced cells are used to modulate T-cell functions, then T-cell activity and antitumor response are enhanced, but hepatotoxicity and immunogenicity increase
Solution Approach 1:
The patent extracts the harmful viral transduction mechanism from the system and replaces it with antisense oligonucleotides that directly modulate gene expression without requiring viral vectors. This removes the source of hepatotoxicity and immunogenicity while preserving the ability to enhance T-cell activity through selective gene modulation
Solution Approach 2:
The patent introduces antisense oligonucleotides as an intermediary substance that mediates the modulation of T-cell gene expression. These oligonucleotides bind to specific mRNA sequences to induce exon skipping or intron retention, thereby controlling T-cell function without the need for direct viral integration into the genome, thus avoiding hepatotoxicity
2Reliability
If retro- or lentiviral-transduced cells are used to modulate T-cell functions, then T-cell activity and antitumor response are enhanced, but immunogenicity increases
Solution Approach 1:
The patent removes the immunogenic viral vector component from the system and uses synthetic antisense oligonucleotides instead. These synthetic molecules do not trigger the same immune responses as viral proteins, thereby reducing immunogenicity while maintaining the ability to enhance T-cell antitumor activity
Solution Approach 2:
The patent employs transient antisense oligonucleotide treatment rather than permanent viral integration. The oligonucleotides are non-integrating and provide temporary gene modulation that can be controlled and terminated, reducing the risk of long-term immunogenicity while still achieving enhanced T-cell activity during the treatment period
3Measurement precision
If antisense oligonucleotides are used to modulate T-cell functions, then specificity and efficacy against tumor cells are enhanced, but complexity of the treatment approach increases
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides with sequences specifically complementary to target mRNA sequences in T-cells. This allows precise, localized modulation of specific genes (such as PD-1, CTLA-4, or other immune checkpoint genes) without affecting other cellular functions, thereby achieving high specificity through sequence-targeted action rather than complex multi-component systems
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
This approach allows for transient and specific modulation of T-cell functions, enhancing their ability to target and kill cancer cells or inhibit viral replication with reduced side effects, as demonstrated by increased T-cell activity and antiviral cytokine production, while minimizing liver damage and immunogenicity.
Implementation Method 1
antisense oligonucleotides capable of inducing exon skipping
Data Source
AI summary
The present invention relates to antisense oligonucleotides for modulating the function of a T cell, including antisense oligonucleotides that hybridise to IFN-γ, granzyme, perforin 1, PD-1, PRDM1, PD-L1, CD40LG, NDFIP1, PDCD1 LG2, REL, BTLA, CD80, CD160, CD244, LAG3, TIGIT, ADORA2A & TIM-3 RNAs. In particular, the present invention relates to antisense oligonucleotides capable of inducing exon skipping of RNA. Also claimed is a method for further modifying the specificity of said T-cell by providing for a T cell receptor gene.