HFpEF Treatment Through Biomarker-Guided NO-cGMP-PKG Stratification
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Solution Overview
Problem
Current pharmacological treatments for heart failure with preserved ejection fraction (HFpEF) are ineffective due to the assumption of a uniformly impaired NO-cGMP-PKG signaling axis, which does not account for pathway heterogeneity among patients, leading to failed clinical trials and an unmet medical need.
Innovation Solution
Targeting distinct nodes in the NO-cGMP-PKG signaling axis with a combination of soluble guanylate cyclase (sGC) modulators and Nitric Oxide Synthase (NOS) recouplers and substrates to treat a specific subgroup of HFpEF patients with impaired signaling, identified through biomarkers such as NADPH oxidase Type 5 (Nox5) and nitrotyrosine levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If a uniform treatment strategy targeting the NO-cGMP-PKG signaling axis is applied to all HFpEF patients, then the treatment approach is simple and easy to implement, but the treatment effectiveness is poor due to pathway heterogeneity among patients
Solution Approach 1:
The patent segments HFpEF patients into distinct endotypes based on their molecular pathway characteristics. Specifically, it identifies patients with impaired NO-cGMP-PKG signaling axis versus those with intact signaling. This segmentation allows for differentiated treatment strategies: sGC modulators are prescribed only to patients with impaired signaling (identified through biomarkers like nitrotyrosine levels or NOX5 expression), while other patients receive alternative therapies. This resolves the contradiction by maintaining treatment simplicity through clear classification while improving effectiveness through targeted therapy.
Solution Approach 2:
The patent applies local quality by customizing treatment intensity and type based on individual patient pathway status. Patients with severe NO-cGMP-PKG impairment receive aggressive sGC modulator therapy, while those with mild or alternative pathway issues receive tailored interventions. This localized approach to treatment quality optimizes effectiveness for each patient subgroup without complicating the overall treatment framework.
2Manufacturing precision
If sGC modulators are used to treat HFpEF patients with impaired NO-cGMP-PKG signaling, then treatment precision is improved, but the complexity of patient selection and assessment increases
Solution Approach 1:
The patent replaces complex multi-parameter clinical assessment with biomarker-based identification systems. Instead of requiring comprehensive functional testing and complex clinical scoring, the invention uses measurable biomarkers (nitrotyrosine levels in plasma, NOX5 protein expression, or simplified signaling axis assays) to automatically classify patients into endotypes. This substitution maintains high treatment precision while dramatically reducing assessment complexity and enabling routine clinical application.
3Reliability
If biomarker-based patient stratification is implemented, then treatment effectiveness is improved through targeted therapy, but the cost and complexity of diagnostic assessment increase
Solution Approach 1:
The patent employs cost-effective, readily available biomarkers for patient stratification. Instead of using expensive, complex genomic sequencing or advanced imaging, the invention utilizes measurable proteins (nitrotyrosine, NOX5) that can be detected through standard laboratory assays. These biomarkers serve as disposable, one-time assessment tools that provide sufficient precision for treatment selection without requiring repeated or complex diagnostic procedures, thereby maintaining cost-effectiveness while improving treatment effectiveness.
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 provides a high-precision, causal therapy for HFpEF by restoring NO-cGMP-PKG signaling, effectively treating and preventing HFpEF in patients with compromised signaling pathways.
Implementation Method 1
Acting as stimulators and activators, these agents increased the enzymatic activity of sGC to generate cGMP independently of exogenous NO donors
Implementation Method 2
This previously unrecognized pathway heterogeneity will inevitably dilute the therapeutic effect if it is not considered
Implementation Method 3
Moreover, as the present inventors have found, clinical HFpEF is not a molecularly monolithic disease but rather the common final endpoint of different endotypes
Data Source
AI summary
The present invention relates to compositions and methods for treating and/or preventing heart failure with preserved ejection fraction (HFpEF), especially in subjects with an impaired NO-cGMP-PKG signalling axis. The inventors established that not all patients with clinically defined HFpEF suffer from insufficient NO-cGMP-PKG signalling. In accordance with the invention, patients with an HFpEF diagnosis can be selected/stratified based on biomarkers such as NADPH oxidase Type 5 (Nox5) plasma levels, nitration of tyrosine residues on plasma proteins and/or cell-based assays. Moreover, the inventors have found that treating this signalling network at two or more nodes, especially sGC and NO synthase, achieves the first-in-class mechanism-based, causal and high precision therapy for HFpEF endotype which is defined by insufficient NO-cGMP-PKG signalling.