Nucleic Acid Sequences Targeting LPA Gene Expression

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current therapies lack an effective method to specifically reduce Lp(a) levels, which are a significant genetic risk factor for cardiovascular diseases such as coronary heart disease and aortic stenosis, with existing treatments only addressing indirect LDL-lowering measures and not providing a targeted approach for Lp(a) reduction.

Innovation Solution

Development of nucleic acid sequences that interfere with LPA gene expression by forming complementary duplex regions, specifically designed to inhibit LPA gene expression in cells, using modified nucleotides and conjugated ligands for targeted delivery to liver cells to reduce Lp(a) levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If algorithms are used to design nucleic acid silencing triggers, then the design process is simplified, but the accuracy and potency of the iRNAs are reduced due to failure to account for tertiary structure and RNA binding proteins

Engineering Contradiction:

Improvedesign processVSAvoidiRNA potency

Core Design Contradiction:

Ease of operationVSManufacturing precision

Solution Approach 1:

The patent uses computational algorithms to generate multiple candidate iRNA sequences that copy and adapt to the target mRNA structure, then filters these copies through predictive algorithms that account for tertiary structure and RNA binding proteins to identify the most potent sequences

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The patent systematically varies multiple parameters including sequence composition, secondary structure features, and thermodynamic properties to optimize iRNA potency while maintaining specificity, going beyond simple algorithmic generation to explore the design space comprehensively

Inventive Principle:

Principle #35Parameter changes

2Reliability

If highly charged nucleic acid molecules are synthesized for therapeutic use, then gene silencing efficacy is improved, but economic synthesis costs and toxicity limits increase

Engineering Contradiction:

Improvegene silencing efficacyVSAvoidsynthesis cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent divides the nucleic acid molecule into modular components with specific functional regions, allowing for optimized synthesis strategies that reduce overall synthesis cost while maintaining the high charging and efficacy required for effective gene silencing

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent optimizes the charge density and molecular weight parameters of the nucleic acid to achieve effective gene silencing with reduced synthesis complexity and cost, finding the optimal balance between efficacy and manufacturability

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If nucleic acid silencing triggers are designed to be highly specific to LPA gene, then off-target effects are reduced, but the complexity of identifying and validating potent sequences increases

Engineering Contradiction:

Improveoff-target effectsVSAvoididentification process

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent implements iterative feedback loops where predicted off-target effects are fed back into the design algorithm to refine subsequent sequence generations, systematically eliminating sequences with potential off-target activity while maintaining high specificity for the LPA gene

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The patent generates multiple candidate sequences that copy the successful design features from validated sequences, then filters these copies through comprehensive in silico analysis to identify the most specific and potent sequences for LPA targeting

Inventive Principle:

Principle #26Copying

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 nucleic acid sequences effectively downregulate LPA gene expression, providing a targeted approach to lower Lp(a) levels, thereby reducing the risk of cardiovascular diseases like coronary heart disease and aortic stenosis with minimal side effects.

Implementation Method 1

Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression by a mechanism that has been termed RNA interference (RNAi). RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that degrades messenger RNAs homologous to the silencing trigger loaded into the RISC complex.

Methodology Applied

Scientific EffectRNA interference (RNAi):

Implementation Method 2

complementarily bind expressed mRNA... at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the first strand

Methodology Applied

Scientific EffectComplementary base pairing:

Data Source

PatentUS20240327843A1Nucleic acids for inhibiting expression of LPA in a cell

Publication Date: 2024.10.03 SILENCE THERAPEUTICS GMBH

AI summary

The present invention relates to products and compositions and their uses. In particular the invention relates to nucleic acid products that interfere with the LPA gene expression or inhibit its expression for use as treatment, prevention or reduction of risk of suffering cardiovascular disease such as coronary heart disease or aortic stenosis or stroke or any other disorder, pathology or syndrome linked to elevated of Lp(a)-containing particles.