CXCL Expression Repressors for Multi-Gene Modulation
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Solution Overview
Problem
There is a need for novel tools and methods to modulate, specifically decrease, the expression of pluralities of associated genes, particularly those involved in diseases such as those in mammals, including humans.
Innovation Solution
The disclosure provides expression repressors or systems comprising expression repressors that can bind to specific cis-acting regulatory elements, such as those within the CXCL locus, to decrease the expression of target genes like CXCL genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional gene expression modulation tools are used, then single gene expression can be controlled, but pluralities of associated genes cannot be effectively modulated simultaneously
Solution Approach 1:
The patent combines multiple targeting moieties (e.g., zinc finger domains, TAL effector domains, or CRISPR guide RNAs) into a single expression repressor protein that can simultaneously bind to multiple cis-acting regulatory elements (enhancers) of different CXCL genes. This merging approach enables simultaneous modulation of pluralities of associated genes (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, and IL-8) through one therapeutic agent, resolving the contradiction between versatility and complexity.
Solution Approach 2:
The expression repressor is designed with multi-functional capabilities to target and repress multiple CXCL gene loci within a single protein molecule. The repressor can bind to various cis-acting regulatory elements across different chromosomal locations (e.g., chr4:74591400-74593000 for CXCL2, chr4:74982639-74983600 for CXCL3) and modulate their expression, providing universal applicability across multiple gene targets without requiring separate therapies for each gene.
2Measurement precision
If multiple separate therapies are used to target different CXCL genes, then each gene can be specifically modulated, but treatment complexity and dosing burden increase
Solution Approach 1:
The patent merges multiple gene-specific targeting capabilities into a single expression repressor therapy. Instead of administering separate therapies for CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, and IL-8, the invention provides one multi-functional repressor that simultaneously targets all these genes through multiple cis-acting regulatory elements, thereby maintaining specificity while dramatically simplifying administration and dosing.
3Productivity
If broad-spectrum gene repressors are used to modulate multiple CXCL genes, then plurality of genes can be modulated simultaneously, but risk of off-target effects increases
Solution Approach 1:
The expression repressor exhibits local quality through its ability to specifically bind to defined cis-acting regulatory elements at precise chromosomal locations (e.g., enhancers at chr4:74591400-74593000 for CXCL2, chr4:74982639-74983600 for CXCL3). Each targeting moiety within the repressor is designed with high specificity for its particular target site, ensuring that the broad-spectrum capability is achieved through multiple specific local interactions rather than non-specific binding, thereby maintaining safety and reducing off-target effects.
Data Source
AI summary
The present disclosure relates to expression repressors decreasing expression of a target plurality of genes in a cell. In some embodiments, the target plurality of genes comprises CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, and IL-8. In some embodiments, the expression repressor targets the E1 cRE of the CXCL locus. In some embodiments, the expression repressor targets the E2 cRE of the CXCL locus.