Soluble IL7R Splice Modulation with Antisense Oligonucleotides
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Solution Overview
Problem
Current treatments for autoimmune diseases like multiple sclerosis and cancers are limited by adverse side effects due to global immunosuppression, and immunotherapy responses are low in some cancer types, necessitating a targeted approach to address specific etiologies.
Innovation Solution
Development of splice-modulating antisense oligonucleotides (SM-ASOs) that specifically bind to Interleukin-7 receptor (IL7R) pre-mRNA to alter splicing of exon 6, either increasing or decreasing the expression of the soluble isoform (sIL7R) to treat autoimmune diseases or cancers, respectively, using chemically modified oligonucleotides with various backbone and base modifications for enhanced delivery and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If global immunosuppression is used to treat autoimmune diseases, then disease progression is slowed, but severe or lethal adverse side effects occur
Solution Approach 1:
The patent applies local quality by targeting specific molecular mechanisms (IL-7/IL-7R pathway) rather than globally suppressing the immune system. The antisense oligonucleotides specifically modulate IL-7R expression and function, affecting only the pathological autoimmune responses while preserving normal immune functions elsewhere in the system.
Solution Approach 2:
The patent segments the immune system regulation by specifically targeting the IL-7/IL-7R axis. Instead of treating the immune system as a whole, the invention divides the problem into specific molecular targets (IL-7R alpha chain, soluble IL-7R) that can be selectively modulated to treat autoimmune diseases without affecting other immune functions.
2Reliability
If conventional immunotherapy is used to treat cancer, then immune response is enhanced, but response rates remain very low in some cancer types
Solution Approach 1:
The patent applies parameter changes by modifying the expression levels of IL-7R through antisense oligonucleotide treatment. This changes the immunological parameters (receptor density, signaling intensity) to optimize immune cell function and enhance response to immunotherapy, thereby improving response rates in cancer treatments.
Solution Approach 2:
The patent implements feedback mechanisms by using antisense oligonucleotides to modulate IL-7R expression based on the specific cancer type and patient needs. The treatment can be adjusted to achieve optimal IL-7R levels that enhance immune response while avoiding excessive activation, creating a controlled feedback loop for personalized cancer therapy.
Data Source
AI summary
The present invention includes compositions and methods for treating an autoimmune disorder or a cancer in a subject in need thereof, the method comprising: administering an effective amount of a composition comprising an oligonucleotide that specifically binds a complementary sequence of the Interleukin-7 receptor (IL7R) pre-mRNA that influences splicing of exon 6, wherein the SM-ASO increases or decreases inclusion of exon 6 in IL7R pre-mRNAs and respectively decreases or increases expression of the soluble isoform of IL7R (sIL7R). In certain embodiments, the oligonucleotide is an antisense oligonucleotide (ASO), or a splice-modulating antisense oligonucleotide (SM-ASO).