Chemical Epigenetic Modifiers for Precise Gene Expression Control
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Solution Overview
Problem
There is a need for more precise regulation of gene expression, particularly in gene therapy applications, to achieve optimal levels of gene product expression while minimizing toxicity.
Innovation Solution
The use of chemical epigenetic modifiers (CEMs) that recruit epigenetic modifiers to specific genes, allowing for precise regulation of gene expression through the recruitment of chromatin regulatory proteins such as BRD4 or HDACs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional gene expression regulation methods are used, then gene expression can be controlled, but precision is insufficient and toxicity cannot be minimized
Solution Approach 1:
The patent employs chemical epigenetic modifiers (CEMs) as intermediary molecules that bridge the gap between external control and endogenous chromatin regulatory proteins. These CEMs consist of two functional domains: a recruiting domain that binds to a tether protein delivered to the target gene locus, and a ligand domain that recruits endogenous chromatin regulators (such as HDACs or HATs). This intermediary approach enables precise spatial and temporal control of gene expression by recruiting existing cellular machinery to specific locations, thereby achieving high precision regulation while minimizing toxicity through localized action rather than global effects
2Manufacturing precision
If CRISPR-based chromatin regulatory proteins are used, then locus-specific gene regulation is achieved, but system complexity increases
Solution Approach 1:
The patent extracts and utilizes only the essential chromatin regulatory functions from complex CRISPR systems. Instead of employing entire CRISPR-Cas machinery or large fusion proteins like dCas9-VPR, the invention isolates the key function of recruiting chromatin modifiers to specific loci by using small chemical epigenetic modifiers. These CEMs work in conjunction with simplified tether proteins that can be delivered via standard gene therapy vectors, thereby achieving locus-specific regulation without the substantial complexity of full CRISPR systems
Solution Approach 2:
The patent creates simplified copies or analogs of chromatin regulatory functions through chemical molecules rather than requiring complete protein complexes. The CEMs serve as chemical copies of the recruitment mechanism, using small molecule-ligand interactions to mimic and replicate the function of large protein-protein interactions in CRISPR systems, thereby reducing complexity while maintaining locus-specific regulatory capability
Data Source
AI summary
The invention relates to relates to a chemical epigenetic modifier (CEM) comprising compound 1 (AP1867) or a pharmaceutically acceptable salt thereof, a linker, and a chromatin regulatory protein ligand and compositions thereof. The invention also relates to methods for modulating expression of a gene comprising contacting a polynucleotide with a target gene sequence to a fusion protein comprising a FK506-binding protein (FKBP) polypeptide with a F36V mutation and a gRNA binding polypeptide, a gRNA comprising a gene targeting polynucleotide sequence that binds to a target gene sequence and a polynucleotide sequence recognized by the gRNA binding polypeptide, a CEM, and a protein with a DNA binding domain that binds to the target gene sequence and the gRNA, thereby modulating expression of the gene.