Chimeric aiRNA Design for Multi-Gene Knockdown

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Solution Overview

Problem

Current RNAi-based therapeutics using microRNAs (miRNAs) have limitations such as moderate impact on gene target regulation and limited functionality, while siRNAs can efficiently knockdown one gene at a time, necessitating a need for rationally designed miRNA-based therapeutics that can simultaneously target multiple genes with improved efficiency.

Innovation Solution

Development of chimeric small RNAs (aiRNAs) that incorporate sequences from both miRNAs and siRNAs, allowing for simultaneous disruption of multiple target nucleic acids by sharing the seed sequence with miRNAs and having high sequence homology with siRNAs, thereby enhancing gene knockdown efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If miRNAs are used for gene target regulation, then multiple genes can be targeted simultaneously, but the impact on gene target regulation is moderate and efficiency is limited

Engineering Contradiction:

Improveability to target multiple genesVSAvoidgene knockdown efficiency

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent combines the seed sequence region of miRNA (nucleotides 2-8) with the rest of the siRNA sequence to create a chimeric molecule. This merging allows the chimera to inherit the multi-targeting capability of miRNA through the seed region while gaining the high knockdown efficiency of siRNA through the complementary body region, thus resolving the contradiction between versatility and productivity

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric RNA molecule is designed to perform multiple functions: it can simultaneously target multiple genes through the miRNA-like seed region while maintaining siRNA-like high efficiency knockdown capability. The single chimera molecule thus serves both the multi-targeting function and the efficient knockdown function that were previously separated between different RNA types

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Productivity

If siRNAs are used for gene knockdown, then efficient knockdown of target gene is achieved, but only one gene can be targeted at a time

Engineering Contradiction:

Improvegene knockdown efficiencyVSAvoidability to target multiple genes

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The invention merges the high-efficiency knockdown mechanism of siRNA (maintained in nucleotides 9-22) with the multi-targeting seed sequence of miRNA (nucleotides 2-8). This creates a single chimera molecule that possesses both the efficient knockdown capability of siRNA and the multi-gene targeting capability of miRNA, thereby resolving the contradiction between productivity and adaptability

Inventive Principle:

Principle #5Merging (Combining)

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

The aiRNAs demonstrate improved efficacy in suppressing cancer cell motility and proliferation by targeting multiple genes, offering a more potent tool for RNAi-based therapeutics compared to natural miRNAs or siRNAs alone.

Implementation Method 1

the nucleotide sequence is capable of specifically hybridizing to the at least two target nucleic acids

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS9550989B2Rational design of microRNA-siRNA chimeras for multi-functional target suppression

Publication Date: 2017.01.24 WASHINGTON UNIV IN SAINT LOUIS

AI summary

The present disclosure encompasses methods for rational design of microRNA and small interfering RNA chimeras and compositions and methods of use thereof.