Plasminogen siRNA Lipid Nanoparticles for Stable Bleeding Prophylaxis
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Solution Overview
Problem
Current treatments for bleeding disorders, such as hemophilia, are limited by frequent injections, thrombosis risks, and ineffective long-term management, with existing therapies like factor replacement and antifibrinolytic drugs having significant drawbacks.
Innovation Solution
The use of duplex or single-stranded siRNA molecules targeting plasminogen mRNA, delivered via lipid nanoparticles, to inhibit plasminogen expression, thereby modulating coagulation and reducing fibrinolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If factor replacement therapy is used to treat severe hemophilia, then bleeding symptoms are controlled, but thrombosis risk increases and patient compliance becomes difficult
Solution Approach 1:
The patent extracts and targets the specific molecular mechanism of fibrinolysis by using siRNA to silence plasminogen expression. This selective approach removes only the harmful fibrinolytic activity without affecting the entire coagulation cascade, thereby controlling bleeding while avoiding the thrombosis risk associated with broad coagulation factor replacement therapy.
Solution Approach 2:
The patent changes the molecular parameter of plasminogen expression levels through siRNA-mediated gene silencing. By reducing plasminogen mRNA and protein levels, the therapy shifts the balance of the fibrinolytic system to favor clot stability without requiring systemic coagulation factor supplementation that would increase thrombosis risk.
2Reliability
If bypassing agents are used to treat active bleeding episodes, then bleeding is controlled, but thrombosis risk increases and long-term prophylaxis is not suitable
Solution Approach 1:
The patent employs siRNA therapy that acts preliminarily by silencing plasminogen expression before bleeding episodes occur. This preventive gene silencing approach establishes long-term clot stability and reduces fibrinolytic capacity in advance, eliminating the need for acute bypassing agent administration and enabling sustained prophylactic protection.
Solution Approach 2:
The patent achieves continuous therapeutic action through siRNA-mediated sustained gene silencing. The therapeutic effect persists for extended periods following a single administration, providing continuous reduction in fibrinolytic activity and clot instability, thereby replacing the intermittent dosing required by bypassing agents with continuous protective action.
3Reliability
If antifibrinolytic drugs like tranexamic acid are used for short-term prophylaxis, then bleeding is controlled, but long-term use is limited by short activity life and adverse events
Solution Approach 1:
The patent replaces the mechanical/pharmacological approach of antifibrinolytic drugs with a molecular biological approach using siRNA gene silencing. Instead of administering drugs that temporarily inhibit plasminogen activators, the therapy uses RNA interference to directly reduce plasminogen expression at the genetic level, providing prolonged duration of action without the metabolic clearance limitations of small molecule drugs.
Solution Approach 2:
The patent applies partial action by selectively silencing only plasminogen expression rather than broadly inhibiting all fibrinolytic pathways with antifibrinolytic drugs. This targeted gene silencing achieves sufficient reduction in fibrinolytic capacity to control bleeding while avoiding the excessive suppression that leads to thrombosis and adverse events with conventional drug therapy.
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
This approach effectively reduces plasminogen expression, enhancing clot stability and reducing bleeding episodes, with potential for long-term prophylaxis without thrombosis risks, as demonstrated in various animal models.
Implementation Method 1
The use of duplex or single-stranded siRNA molecules targeting plasminogen mRNA, delivered via lipid nanoparticles, to inhibit plasminogen expression
Implementation Method 2
delivered via lipid nanoparticles
Data Source
AI summary
The present disclosure provides a duplex or single-stranded siRNA molecule against plasminogen, the siRNA molecule containing modified or unmodified nucleotides and wherein at least one strand of the duplex or the single-stranded siRNA has a sequence that has at least 80% sequence identity to any one of SEQ NOs: 1 to 28. Further provided is a duplex or single-stranded siRNA molecule against plasminogen, the siRNA molecule containing modified or unmodified nucleotides and is between 25 and 35 nucleotides in length. The siRNA molecule may be formulated in a lipid nanoparticle as described herein.