dsRNA Inhibiting PROC Gene Expression via Lipid Delivery
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Solution Overview
Problem
Hemophilia patients face challenges due to deficiencies in coagulation cascade factors, and there is a need for effective treatments that can inhibit the expression of the Protein C (PROC) gene to manage bleeding disorders.
Innovation Solution
Development of double-stranded ribonucleic acid (dsRNA) molecules that target the PROC gene, specifically designed to inhibit its expression by hybridizing with the gene's mRNA, using modified nucleotides and conjugates for enhanced stability and delivery, and administered through pharmaceutical compositions including lipid formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If double-stranded RNA molecules are used to inhibit PROC gene expression, then therapeutic efficacy for hemophilia is improved, but delivery stability and resistance to degradation are worsened
Solution Approach 1:
The patent applies parameter changes by chemically modifying the dsRNA structure through 2'-O-methyl modifications on specific nucleotides and incorporating phosphorothioate linkages. These parameter changes in the molecular structure enhance stability against nucleases while maintaining the RNA interference mechanism for PROC gene inhibition, thereby resolving the contradiction between therapeutic efficacy and stability.
Solution Approach 2:
The patent employs composite materials by combining dsRNA with lipid formulations and conjugates to create a composite therapeutic agent. The lipid component provides protection and delivery capabilities, while the dsRNA maintains its gene-silencing function. This composite approach simultaneously improves stability and preserves therapeutic efficacy.
2Reliability
If dsRNA is administered to inhibit PROC gene expression, then coagulation pathway modulation is improved, but delivery to target cells is worsened
Solution Approach 1:
The patent introduces lipid formulations as intermediary carriers that facilitate the delivery of dsRNA to target cells. The lipid component acts as a mediator that protects the dsRNA from degradation in circulation and enables cellular uptake, thereby improving delivery efficiency without compromising the coagulation pathway modulation efficacy.
Solution Approach 2:
The patent modifies the physicochemical parameters of the dsRNA by incorporating 2'-O-methyl modifications and phosphorothioate linkages, which alter the molecular properties to enhance cellular permeability and stability. These parameter changes enable effective delivery to target cells while maintaining the ability to modulate the coagulation pathway.
3Stability of the object's composition
If modified nucleotides are incorporated into dsRNA, then stability and delivery are improved, but manufacturing complexity is worsened
Solution Approach 1:
The patent applies parameter changes by implementing specific chemical modifications (2'-O-methyl and phosphorothioate) at defined positions within the dsRNA sequence. These targeted parameter changes provide the necessary stability improvements while limiting the scope of modification to manageable levels, thereby balancing manufacturing complexity with performance enhancement.
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 dsRNA effectively reduces PROC gene expression by at least 40%, providing a therapeutic approach to treat hemophilia and related bleeding disorders by degrading target mRNA, thereby modulating coagulation pathways.
Implementation Method 1
Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). dsRNA has also been shown to degrade target RNA in other organisms, including plants, Drosophila, and mammals.
Implementation Method 2
specifically designed to inhibit its expression by hybridizing with the gene's mRNA
Data Source
AI summary
The invention relates to double-stranded ribonucleic acid (dsRNA) targeting a PROC gene, and methods of using the dsRNA to inhibit expression of PROC.