PLG-Targeting dsRNA Compositions for Bleeding Reduction
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Solution Overview
Problem
Current treatments for heavy menstrual bleeding (HMB) and hereditary hemorrhagic telangiectasia (HHT) are inadequate, with existing therapies having side effects and limited efficacy, and there is a need for alternative approaches to inhibit plasminogen (PLG) expression to reduce excessive bleeding.
Innovation Solution
Development of double-stranded ribonucleic acid (dsRNA) agents that target and inhibit PLG gene expression by forming RNA-induced silencing complexes, utilizing modified nucleotides and ligands to enhance specificity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current standard of care therapies (tranexamic acid, OCP, IUDs) are used to treat HMB, then bleeding symptoms can be managed, but side effects, high pill burden and lack of effectiveness lead to discontinuation
Solution Approach 1:
The patent extracts and targets the specific molecular pathway (PLG gene expression) responsible for excessive fibrinolysis in HMB, rather than using broad-spectrum hormonal therapies. By designing iRNA agents that specifically bind to PLG mRNA, the treatment isolates the therapeutic action to the precise molecular target, eliminating the need for systemic hormonal suppression and its associated side effects.
Solution Approach 2:
The patent changes the therapeutic parameter from hormonal modulation to gene expression suppression. By using iRNA agents that reduce PLG mRNA levels and subsequent PLG protein production, the treatment shifts from affecting multiple hormonal pathways to specifically downregulating fibrinolytic activity through targeted gene silencing, thereby improving efficacy while reducing side effects.
2Reliability
If tranexamic acid is used to inhibit fibrinolysis, then bleeding can be reduced, but it is an anti-fibrinolytic inhibitor that may not address underlying PLG overexpression
Solution Approach 1:
The patent applies preliminary action by suppressing PLG gene expression before fibrinolysis occurs. By using iRNA agents to reduce PLG mRNA and protein levels in advance, the treatment prevents the formation of excessive plasminogen, thereby preventing excessive fibrinolysis before it happens, rather than inhibiting the fibrinolytic pathway after activation.
Solution Approach 2:
The patent introduces iRNA agents as an intermediary between the PLG gene and the fibrinolytic pathway. These agents bind to PLG mRNA and prevent its translation into protein, serving as a molecular mediator that blocks the production of plasminogen itself, rather than blocking downstream fibrinolytic enzymes or their inhibitors.
3Reliability
If PLG expression is inhibited to reduce excessive fibrinolysis, then bleeding symptoms improve, but achieving sufficient inhibition without affecting normal physiological function is challenging
Solution Approach 1:
The patent applies local quality by designing iRNA agents with high local concentration and specificity at the target site (PLG mRNA in hepatocytes). The agents are engineered with specific nucleotide sequences that complement only PLG mRNA, ensuring localized and selective inhibition of PLG expression in the liver where it is primarily synthesized, without affecting PLG function in other tissues or normal physiological levels.
Solution Approach 2:
The patent replaces mechanical/pharmacological inhibition with molecular biological suppression. Instead of using small molecule inhibitors that bind to PLG protein or its activators, the treatment uses iRNA agents that act at the nucleic acid level to prevent PLG protein synthesis entirely, providing a more selective and potentially reversible mechanism of inhibition.
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 agents effectively inhibit PLG expression, reducing bleeding symptoms in conditions like HMB and HHT, offering a potential therapeutic option with improved efficacy over existing treatments.
Implementation Method 1
double stranded ribonucleic acid (dsRNA) agents that target and inhibit PLG gene expression by forming RNA-induced silencing complexes
Data Source
AI summary
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the plasminogen (PLG) gene, as well as methods of inhibiting expression of PLG, and methods of treating subjects that would benefit from reduction in expression of PLG, such as subjects having a PLG-associated disease, disorder, or condition, using such dsRNA compositions.