Chemically Modified siNA Molecules for Stable RNAi
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Solution Overview
Problem
Current RNA interference (RNAi) technologies face limitations in effectively modulating gene expression due to instability and delivery issues of native siRNA molecules, which can activate interferon responses and have limited therapeutic applications.
Innovation Solution
Development of chemically modified short interfering nucleic acid (siNA) molecules that retain RNAi activity, enhance stability, and improve cellular uptake, using modifications such as 2'-O-methyl ribonucleotides, 2'-deoxy-2'-fluoro ribonucleotides, and phosphorothioate internucleotide linkages, allowing for efficient modulation of gene expression and reduced immunostimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native siRNA molecules are used for RNA interference, then RNAi activity is achieved, but stability is poor and immunostimulation occurs
Solution Approach 1:
The patent applies chemical modifications to change the physical and chemical parameters of siRNA molecules. Specifically, it modifies the sugar-phosphate backbone and nucleotide structures (e.g., phosphorothioate linkages, 2'-O-methyl modifications, LNA modifications) to alter stability, immunogenicity, and cellular uptake properties while preserving RNAi activity.
Solution Approach 2:
The patent creates composite nucleic acid structures by combining modified and unmodified nucleotides within the same siRNA molecule. It also combines siRNA with delivery vehicles such as liposomes and conjugates with peptides or proteins, forming composite therapeutic compositions that enhance stability and delivery while maintaining RNAi function.
2Stability of the object's composition
If chemically modified siNA molecules are used, then stability and bioavailability are improved, but manufacturing complexity increases
Solution Approach 1:
The patent segments the siRNA molecule into distinct regions with different modification patterns. For example, it applies modifications selectively to specific positions in the sequence rather than uniformly across the entire molecule, allowing optimized stability in certain regions while maintaining RNAi activity in others, thereby reducing overall manufacturing complexity.
Solution Approach 2:
The patent systematically varies chemical modification parameters (type of modification, position, degree of modification) to optimize the balance between stability and manufacturability. By controlling these parameters, the patent achieves enhanced stability without requiring overly complex synthesis procedures.
3Ease of operation
If chemically modified siNA molecules are used, then cellular uptake is improved, but immunostimulation may increase
Solution Approach 1:
The patent applies different chemical modifications to different regions of the siRNA molecule with specific functional intentions. For example, certain modifications enhance cellular uptake in specific cell types, while other modifications are designed to minimize immunostimulation in specific regions, achieving localized optimization of properties.
Solution Approach 2:
The patent converts potentially harmful immunostimulatory effects into beneficial outcomes by carefully selecting modifications that enhance cellular uptake and RNAi activity while using adjuvants or delivery systems that control immune responses. In some cases, controlled immunostimulation is harnessed to enhance therapeutic efficacy.
Data Source
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AI summary
The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of gene expression and/or activity. The present invention is also directed to compounds, compositions, and methods relating to traits, diseases and conditions that respond to the modulation of expression and/or activity of genes involved in gene expression pathways or other cellular processes that mediate the maintenance or development of such traits, diseases and conditions. Specifically, the invention relates to double stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against gene expression, including cocktails of such small nucleic acid molecules and lipid nanoparticle (LNP) formulations of such small nucleic acid molecules. The present invention also relates to small nucleic acid molecules, such as siNA, siRNA, and others that can inhibit the function of endogenous RNA molecules, such as endogenous micro-RNA (miRNA) (e.g, miRNA inhibitors) or endogenous short interfering RNA (siRNA), (e.g., siRNA inhibitors) or that can inhibit the function of RISC (e.g., RISC inhibitors), to modulate gene expression by interfering with the regulatory function of such endogenous RNAs or proteins associated with such endogenous RNAs (e.g., RISC), including cocktails of such small nucleic acid molecules and lipid nanoparticle (LNP) formulations of such small nucleic acid molecules. Such small nucleic acid molecules and are useful, for example, in providing compositions to prevent, inhibit, or reduce diseases, traits and conditions that are associated with gene expression or activity in a subject or organism.