Polynucleotide Composition for Cell-Type Specific Expression
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Solution Overview
Problem
Off-target effects limit the utility of drug candidates, particularly in gene editing and mRNA therapeutics, as they can cause unintended alterations in cells, such as myeloid cells or cancer cells, necessitating specific expression in intended cells and microenvironments to enhance safety and efficacy.
Innovation Solution
The use of polynucleotide compositions that encode target molecules with minimal translation ability, which can be selectively turned ON in specific cells or microenvironments through triggers like promoter elements, microRNAs, or environmental changes, utilizing repressor or effector proteins to control translation, and endonucleases to stabilize or destabilize sequences, ensuring targeted expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If therapeutic nucleic acids are expressed in all cell types, then broad therapeutic coverage is achieved, but off-target effects increase reducing safety
Solution Approach 1:
The patent applies local quality by designing nucleic acid therapeutics with cell-type-specific or microenvironment-specific expression properties. Through engineered promoters, RNA elements, and sequence modifications, the therapy expresses its therapeutic effect only in the intended target cells while remaining silent in other cell types, thereby achieving both broad therapeutic coverage and reduced off-target effects.
Solution Approach 2:
The patent utilizes parameter changes by modifying physical and chemical properties of nucleic acids including sequence composition, secondary structure, stability elements, and epigenetic modifications. These parameter changes enable the therapeutic to respond specifically to certain cellular conditions (such as pH, redox state, or presence of specific enzymes) that are characteristic of diseased cells, allowing selective activation only in the target microenvironment.
2Productivity
If gene editing is performed in multiple cell types, then comprehensive disease treatment is achieved, but unintended genetic alterations increase
Solution Approach 1:
The patent applies preliminary action by incorporating safety mechanisms into the gene editing system before delivery. This includes designing self-limiting editing activities, using transient expression of editing components, and incorporating molecular switches that prevent editing until specific cellular conditions are met. These preliminary safeguards ensure that even if the therapy reaches multiple cell types, editing only occurs in the intended target cells.
3Productivity
If mRNA therapeutics are designed for high expression, then therapeutic efficacy is improved, but expression in unintended cells increases causing toxicity
Solution Approach 1:
The patent applies segmentation by dividing the mRNA therapeutic into multiple functional segments: a cell-type-specific promoter region, a coding region with optimized expression elements, and regulatory sequences that control stability and translation. This segmentation allows the mRNA to achieve high expression levels in target cells through optimized coding sequences while the promoter and regulatory elements prevent expression in non-target cells, thereby maintaining both high efficacy and safety.
Data Source
AI summary
The disclosure features compositions or systems and uses thereof, comprising a first polynucleotide encoding a target molecule, optionally a second polynucleotide encoding an effector, repressor, or endonuclease molecule; optionally a recognition or cleavage site in the first or second polynucleotide, and optionally a repressor/effector binding site in the first polynucleotide. The compositions or systems of the present disclosure can increase the level and/or activity of the target molecule in desired cells and/or microenvironments while suppressing the level and/or activity of the target molecule in off-target cells and/or microenvironments.