LPA-Targeting Nucleic Acid Duplexes With Local 2′ Fluoro Stabilization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies fail to effectively reduce Lp(a) particle levels, a genetic risk factor for cardiovascular diseases, and there is a need for specific methods to prevent and treat conditions associated with elevated Lp(a) levels such as stroke, atherosclerosis, and coronary heart disease.
Innovation Solution
Development of nucleic acids with specific duplex regions and modified nucleotides that inhibit LPA gene expression, including 2′ fluoro modifications, to reduce LPA gene product levels in cells, thereby lowering Lp(a) particles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If nucleic acid silencing triggers are designed using algorithms, then the design process is simplified, but the potency and specificity of the iRNA are compromised due to inability to account for tertiary structure and RNA binding proteins
Solution Approach 1:
The patent modifies specific parameters of the nucleic acid structure, including introducing 2′ fluoro modifications at positions 2 and 14 from the 5′ end of the first strand, and 2′ fluoro modifications on the second strand at positions corresponding to 11-13 of the first strand. These parameter changes optimize both the design process and the resulting iRNA potency by accounting for structural and binding properties that algorithms alone cannot predict.
2Duration of action of stationary object
If nucleic acids are modified with 2′ fluoro modifications, then the duration of action and stability are enhanced, but the manufacturing complexity increases
Solution Approach 1:
Rather than modifying the entire nucleic acid structure, the patent applies 2′ fluoro modifications at specific local positions: positions 2 and 14 from the 5′ end of the first strand, and positions corresponding to 11-13 of the first strand on the second strand. This local quality approach enhances stability and duration of action while minimizing manufacturing complexity by limiting modifications to critical regions only.
3Measurement precision
If specific nucleic acid sequences are used to target LPA gene, then the specificity and efficacy of Lp(a) reduction is improved, but the risk of off-target effects and toxicity increases
Solution Approach 1:
The patent employs specific parameter changes in the nucleic acid structure, including 2′ fluoro modifications at defined positions and specific sequence selections from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 or 43. These parameter changes enhance target specificity for LPA gene while minimizing off-target effects and toxicity by optimizing the balance between complementarity and structural stability.
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 acids efficiently and specifically inhibit LPA expression, providing a therapeutic approach to prevent and reduce the risk of cardiovascular diseases by stabilizing and enhancing the duration of action with minimal off-target effects.
Implementation Method 1
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, wherein said first strand is at least partially complementary to at least a portion of a RNA transcribed from the LPA gene
Implementation Method 2
the nucleotides at positions 2 and 14 from the 5′ end of the first strand are modified with a 2′ fluoro modification, and the nucleotides on the second strand which correspond to positions 11-13 of the first strand are modified with a 2′ fluoro modification
Data Source
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, preferably 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 levels of Lp(a) particles.