AGT-Targeting Nucleic Acids for Upstream RAAS Suppression
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional methods face difficulties in effectively targeting angiotensinogen (AGT) to inhibit the renin-angiotensin-aldosterone system (RAAS), leading to poor therapeutic outcomes for hypertension and heart failure due to compensatory mechanisms and limited efficacy of existing RAAS inhibitors.
Innovation Solution
Development of AGT-targeting nucleic acids, including sense and antisense strands with specific sequences, and a targeted drug delivery system to deliver these nucleic acids, enhancing their ability to inhibit AGT expression and reduce RAAS activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional RAAS inhibitors (ACE inhibitors, ARBs) are used to treat hypertension, then blood pressure can be reduced, but compensatory pathways are activated causing reactivation of angiotensin and aldosterone escape, leading to poor therapeutic response in refractory hypertension
Solution Approach 1:
The invention extracts and targets the root cause of the problem by directly inhibiting angiotensinogen, the precursor molecule upstream of the compensatory pathways. By using siRNA to specifically degrade AGT mRNA, the therapy removes the source of angiotensin production before compensatory mechanisms can activate, thereby eliminating the harmful reactivation effect while maintaining blood pressure control
Solution Approach 2:
The invention applies preliminary action by targeting angiotensinogen at the very beginning of the RAAS pathway, before any compensatory mechanisms can be triggered. By preventing angiotensin production at its source through AGT gene silencing, the therapy proactively blocks the activation of downstream compensatory pathways that would otherwise lead to therapeutic failure
2Reliability
If ACE inhibitors and angiotensin II receptor blockers are administered, then cardiovascular protection is achieved, but aldosterone escape occurs causing concentrations of Ang II and aldosterone to return to pre-treatment levels or become higher
Solution Approach 1:
The invention extracts and eliminates the root source of aldosterone production by targeting angiotensinogen, the common precursor for all angiotensins including those that lead to aldosterone synthesis. By depleting AGT at the transcriptional level through siRNA, the invention prevents the formation of Ang I and Ang II, thereby blocking the stimulatory signal for aldosterone production and preventing aldosterone escape
Solution Approach 2:
The invention applies preliminary action by intercepting the RAAS pathway at its very origin with angiotensinogen inhibition. This upstream blockade occurs before any angiotensin molecules can be formed that would subsequently stimulate aldosterone release, thereby proactively preventing the aldosterone escape phenomenon that plagues conventional therapies
3Reliability
If conventional methods are used to target angiotensinogen, then therapeutic intervention is attempted, but numerous difficulties are encountered limiting efficacy
Solution Approach 1:
The invention replaces complex mechanical targeting approaches with a molecular biological mechanism. Instead of using complex delivery systems or antibodies that face numerous targeting difficulties, the invention employs siRNA molecules that naturally exploit cellular RNA interference mechanisms to specifically locate and degrade AGT mRNA, thereby simplifying the targeting process while maintaining high efficacy
Solution Approach 2:
The invention applies self-service by designing siRNA molecules that autonomously navigate to their target. The siRNA molecules self-assemble into RNA-induced silencing complexes (RISC), self-localize to the nucleus and cytoplasm, and self-cleave complementary AGT mRNA sequences without requiring complex external delivery mechanisms or additional targeting components
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 AGT-targeting nucleic acids effectively inhibit AGT expression, reducing RAAS activity and providing therapeutic benefits for hypertension and related diseases, overcoming the limitations of current RAAS inhibitor drugs.
Implementation Method 1
RNA interference (RNAi) refers to a highly conserved phenomenon of efficient and specific degradation of homologous mRNA induced by double-stranded small interfering RNA (siRNA) in an evolutionary process.
Data Source
Figure 1~2
Figure 3
AI summary
A nucleic acid targeting angiotensinogen and a use thereof. The nucleic acid can effectively inhibit the expression of AGT, and can effectively reduce the activation degree of RAAS, so that the nucleic acid can be used for treating and/or preventing diseases related to AGT, such as hypertension.