CRISPR-GNDM System Suppresses MYD88 Expression for Inflammatory Disease Treatment
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Solution Overview
Problem
Current therapeutic agents are ineffective in targeting the MYD88 gene, which plays a central role in inflammatory signaling pathways and is associated with diseases like NASH, inflammatory diseases, and hematological malignancies, due to its lack of catalytic activity and difficulty in homodimerization.
Innovation Solution
A CRISPR-Guide Nucleotide Directed Modulation (GNDM) system is used to suppress MYD88 expression by targeting specific expression regulatory regions of the MYD88 gene using dCas9 or dCpf1 proteins, which recruit transcription repressors to inhibit gene expression without affecting adjacent genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule approaches are used to interfere MYD88 homodimerization, then therapeutic treatment is attempted, but the approach is ineffective due to MYD88's lack of catalytic activity and difficulty in homodimerization
Solution Approach 1:
The patent uses CRISPR-GNDM system as an intermediary mechanism to suppress MYD88 expression. Instead of directly targeting MYD88 protein with small molecules, the invention employs guide nucleotides to direct dCas9 or dCpf1 proteins to specific expression regulatory regions of the MYD88 gene, using transcription repressors to block gene expression at the DNA level, thereby overcoming the limitations of small molecule approaches
Solution Approach 2:
The patent replaces the mechanical/small molecule approach with a biological molecular system. Instead of using small molecules that physically interact with protein surfaces, the invention uses programmable nucleic acid-guided protein complexes that can specifically recognize and bind to DNA sequences, providing a more reliable mechanism for targeting MYD88
2Reliability
If CRISPR-GNDM system is used to suppress MYD88 expression by targeting expression regulatory regions, then selective suppression of MYD88 is achieved, but the complexity of the system increases
Solution Approach 1:
The patent employs a universal CRISPR-GNDM platform that can target any gene with a known sequence by simply changing the guide nucleotide sequence. The core components (dCas9/dCpf1, transcription repressors, delivery mechanisms) remain the same across different applications, providing multi-functionality that justifies the initial system complexity through broad applicability
Solution Approach 2:
The patent uses guide nucleotides as information carriers that copy the target sequence information from the MYD88 gene regulatory region. This copying mechanism allows the system to precisely identify and suppress the correct gene without requiring complex recognition mechanisms, as the guide nucleotide sequence itself encodes the targeting information
3Object-affected harmful factors
If MYD88 expression is suppressed using CRISPR-GNDM system, then chronic pro-inflammatory signaling and tumor cell propagation are reduced, but the need for precise targeting of regulatory regions increases difficulty
Solution Approach 1:
The patent applies local quality by specifically targeting only the expression regulatory regions (promoters, enhancers, silencers) of the MYD88 gene while leaving the coding regions and adjacent genes unaffected. By using guide nucleotides that match only specific regulatory sequences and employing localized transcription repression, the system achieves precise spatial control of gene suppression, reducing harmful effects without requiring genome-wide targeting
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 effectively reduces chronic pro-inflammatory signaling and tumor cell propagation, providing a novel therapeutic strategy for treating MYD88-associated diseases by selectively suppressing MYD88 gene expression.
Implementation Method 1
a CRISPR-Guide Nucleotide Guided Modulation (GNDM) system for targeting MYD88 gene and suppressing its expression
Implementation Method 2
recruit transcription repressors to inhibit gene expression without affecting adjacent genes
Data Source
AI summary
The present invention provides a method of treating a disease associated with activated MYD88 signaling in a subject, including suppressing MYD88 expression in a subject by targeting an expression regulatory region of MYD88 gene by using a CRISPR-Guide Nucleotide Directed Modulation (GNDM), without affecting the expression of an adjacent ACAA1 gene. Also, provided is a CRISPR-GNDM system for suppressing MYD88, including expression comprising (a) a protein selected from the group consisting of dCas9 or dCpf1, a fusion protein of dCas9 or dCpf1 and Kruppel associated box (KRAB) and (b) a guide RNA (gRNA) targeting an expression regulatory region of MYD88 gene.