MYC Expression Repressor Formulations for Undruggable Target Silencing
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Solution Overview
Problem
The MYC protein is considered 'undruggable' due to the lack of a defined ligand binding site and its essential physiological function, making it challenging to modulate its expression for treating diseases associated with mis-regulation.
Innovation Solution
Development of therapeutic compositions comprising lipid nanoparticles (LNPs) encapsulating expression repressors that include targeting moieties and effector moieties, such as zinc finger domains or CRISPR/Cas molecules, to bind specifically to the MYC gene promoter or super enhancer regions, thereby decreasing MYC expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional drugs are used to target MYC protein, then MYC expression can be modulated, but the approach fails because MYC lacks a defined ligand binding site and has essential physiological functions
Solution Approach 1:
The patent uses RNA as an intermediary molecule to bridge the gap between the drug delivery system and the MYC gene. Specifically, it employs CRISPR RNA (crRNA) or guide RNA that directs the Cas9 enzyme or other effectors to the MYC gene promoter or super enhancer regions, enabling targeted gene expression modulation without directly targeting the undruggable MYC protein
Solution Approach 2:
The patent replaces the conventional small molecule drug mechanism (which requires ligand binding to protein targets) with a nucleic acid-based mechanism. Instead of using chemicals that bind to MYC protein, the invention uses RNA-DNA hybridization and CRISPR-Cas9 enzymatic activity to achieve targeted gene regulation, fundamentally changing the molecular mechanism of action
2Measurement precision
If expression repressors are designed to bind MYC promoter or super enhancer regions, then MYC expression can be specifically decreased, but the complexity of the therapeutic composition increases
Solution Approach 1:
The patent divides the expression repressor into distinct functional modules: a targeting moiety (such as zinc finger domain, TAL effector domain, or CRISPR RNA) that recognizes specific DNA sequences in the MYC promoter or super enhancer regions, and an effector moiety (such as KRAB repressor or DNA methyltransferase) that executes the gene silencing function. This modular design enables precise targeting while allowing independent optimization of each component
Solution Approach 2:
The patent employs universal targeting moieties such as CRISPR RNA that can be programmed to recognize various DNA sequences through simple sequence changes in the guide RNA. This universal platform can target multiple genes and different regulatory regions (promoters, enhancers, super enhancers) using the same effector machinery, reducing overall system complexity despite the specificity requirements
3Productivity
If lipid nanoparticles are used to deliver expression repressors, then delivery efficiency to target cells is improved, but the manufacturing complexity and formulation challenges increase
Solution Approach 1:
The patent optimizes key parameters of the lipid nanoparticle formulation, including the ionizable lipid pKa (adjusted to 6.0-7.5 for optimal endosomal escape), lipid composition ratios, particle size (20-200 nm), and surface charge characteristics. These parameter optimizations enhance delivery efficiency while providing a standardized formulation platform that simplifies manufacturing scale-up
Solution Approach 2:
The patent employs composite lipid nanoparticle formulations containing multiple components: ionizable lipids (for endosomal membrane disruption), PEGylated lipids (for steric stabilization and prolonged circulation), phospholipids (for structural integrity), and cholesterol (for membrane fluidity and particle stability). This composite material approach enables simultaneous optimization of delivery efficiency, stability, and manufacturability
Data Source
AI summary
The present disclosure relates to compositions and methods for reducing expression of MYC gene in a cell. In some embodiments, an expression repressor comprises a targeting moiety that binds a MYC promoter, anchor sequence, or super-enhancer. In some embodiments, the expression repressor comprises an effector moiety that represses transcription or methylates DNA. Systems comprising two expression repressors are also disclosed. The compositions can be used, for example, to treat cancers such as HCC.