Binding-Moiety Nucleic Acid Conjugates for Stable Gene Silencing
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Solution Overview
Problem
Nucleic acid therapies face challenges such as poor intracellular uptake, limited blood stability, and non-specific immune stimulation, hindering their effectiveness in treating diseases like cancer.
Innovation Solution
Development of nucleic acid compositions comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer, with specific modifications like 5′-vinylphosphonate nucleotides and endosomolytic moieties, to enhance intracellular delivery and stability, and reduce toxicity and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid therapies are administered directly, then they can potentially silence target genes, but they suffer from poor intracellular uptake and limited blood stability
Solution Approach 1:
The patent applies composite materials by creating a conjugate structure that combines a binding moiety (such as an antibody or ligand) with a polynucleic acid molecule (such as siRNA or antisense oligonucleotide). This composite structure enables the nucleic acid therapy to target specific cells through the binding moiety while maintaining the gene silencing function of the polynucleic acid, thereby improving both intracellular uptake and reliability of gene silencing efficacy
Solution Approach 2:
The binding moiety acts as an intermediary that facilitates the entry of the polynucleic acid molecule into the target cell. By conjugating the binding moiety to the polynucleic acid, the system uses the binding moiety's cell-targeting and cell-entry capabilities as a mediator to overcome the poor intracellular uptake of naked nucleic acid therapies
2Reliability
If nucleic acid therapies are administered directly, then they can potentially silence target genes, but they exhibit limited blood stability
Solution Approach 1:
The conjugate structure combines the polynucleic acid molecule with a binding moiety that provides enhanced stability in blood circulation. The binding moiety protects the polynucleic acid from nucleases and other blood components, thereby improving blood stability while maintaining the gene silencing efficacy of the polynucleic acid payload
3Reliability
If conventional nucleic acid compositions are used, then they can deliver genetic material, but they cause non-specific immune stimulation and toxicity
Solution Approach 1:
The patent applies local quality by modifying the polynucleic acid molecule with specific chemical modifications (such as 2'-O-methyl modifications, phosphorothioate backbones, or locked nucleic acids) at specific positions. These localized modifications reduce immune recognition and toxicity while preserving the gene silencing activity, thereby reducing harmful immune stimulation without compromising efficacy
Solution Approach 2:
The binding moiety serves as an intermediary that enables targeted delivery to specific cell types, reducing non-specific immune stimulation. By directing the nucleic acid therapy to specific target cells through the binding moiety's specificity, the system minimizes off-target effects and non-specific immune activation that occur with conventional non-targeted nucleic acid compositions
Data Source
AI summary
Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a cancer which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer.