Antisense Oligonucleotide Exon Skipping for B Cell Disease Treatment
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Solution Overview
Problem
Current treatments for multiple myeloma and other B cell-related diseases are limited in their ability to specifically target and eliminate cancerous plasma cells while sparing healthy B cells, leading to side effects and resistance issues with existing therapies.
Innovation Solution
The use of antisense oligonucleotides (AONs) that induce exon skipping in the variable or constant regions of immunoglobulin chains, resulting in the production of truncated immunoglobulins, which cause apoptosis in cancerous plasma cells, allowing for targeted therapy through personalized or generic approaches.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy agents are used to treat multiple myeloma, then tumor mass is reduced, but healthy B cells are also affected causing side effects and resistance
Solution Approach 1:
The invention targets specific exons (such as exon 1 or exon 2 of immunoglobulin heavy chain) for skipping, thereby selectively affecting plasma cells that express abnormal immunoglobulin while sparing healthy B cells. This segmental targeting approach allows differentiation between diseased and healthy cells based on their immunoglobulin expression patterns.
Solution Approach 2:
The AONs are designed to bind to specific local regions (exons) of the immunoglobulin gene transcript, inducing skipping only in those regions. This local modification creates truncated immunoglobulins that are toxic to plasma cells but does not affect the normal function of healthy B cells,从而实现选择性治疗
2Reliability
If AONs induce exon skipping to produce truncated immunoglobulins, then plasma cells are eliminated through apoptosis, but the mechanism requires precise targeting to avoid affecting healthy B cells
Solution Approach 1:
The AONs act as intermediary molecules that bind to specific sequences in the immunoglobulin gene transcript, recruiting splicing machinery to skip target exons. This intermediary mechanism translates the sequence-specific binding into exon skipping and subsequent plasma cell death, providing a bridge between genetic targeting and cellular elimination.
Solution Approach 2:
The invention utilizes the cell's own splicing machinery and immunoglobulin expression system against the plasma cells. By inducing exon skipping, the cell produces truncated immunoglobulins that interfere with its own function and trigger apoptosis, making the therapeutic effect self-generated within the target cell.
3Measurement precision
If personalized AON therapy is developed based on V(D)J rearrangement analysis, then treatment specificity is improved, but diagnostic and treatment complexity increases
Solution Approach 1:
The invention requires preliminary analysis of the patient's V(D)J rearrangement pattern to identify the specific immunoglobulin variant expressed by the plasma cells. This preliminary characterization informs the design of customized AONs that target the specific exon sequences, ensuring treatment specificity before therapy initiation.
Solution Approach 2:
The personalized approach involves changing the nucleotide sequence parameters of the AONs to match the patient's specific V(D)J rearrangement. By adjusting the AON sequence parameters based on individual genetic variations, the therapy achieves high specificity while maintaining a standardized mechanism of action.
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 enables precise elimination of tumor clones, reducing side effects and modulating efficacy, while also being applicable to a broad spectrum of B cell-related diseases, including multiple myeloma, by inducing cell stress and apoptosis in cancerous plasma cells.
Implementation Method 1
contacting the immunoglobulin heavy or light chain mRNA with an antisense oligonucleotide
Data Source
AI summary
The present invention concerns a treatment of diseases involving B cells, B lymphocytes or plasmocytes. In particular, it concerns an antisense oligonucleotide or a mixture of antisense oligonucleotides capable of inducing exon skipping at the RNA of the immunoglobulin heavy or light chains, for the use of same in the treatment of diseases involving B cells.