BDNF TrkB Agonist Therapy for Heart Failure

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for heart failure lack effective therapies that target the BDNF/TrkB pathway, which is crucial for myocardial function and protection against hemodynamic stress, and are sensitive to βAR signaling and GRK2 levels.

Innovation Solution

Administering a composition comprising BDNF or TrkB agonists in combination with βAR-blockers to modulate BDNF production and TrkB signaling, thereby improving cardiac function and preventing heart failure progression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Force

If βAR agonists are used for long-term treatment, then cardiac force generation is improved, but catecholamine toxicity occurs

Engineering Contradiction:

Improvecardiac force generationVSAvoidcatecholamine toxicity

Core Design Contradiction:

ForceVSObject-generated harmful factors

Solution Approach 1:

The patent introduces BDNF/TrkB signaling as an intermediary pathway to mediate cardiac protection. Instead of directly stimulating βAR with agonists, the invention uses BDNF agonists to activate TrkB receptors, which then triggers downstream protective signaling cascades (including Akt and eNOS pathways) that achieve cardiac force enhancement without catecholamine toxicity. This intermediary mechanism allows decoupling of the desired therapeutic effect from the harmful side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces the mechanical/chemical system of catecholamine-βAR interaction with a neurotrophic signaling system. By substituting βAR agonists with BDNF/TrkB agonists, the invention transitions from a catecholamine-based mechanism to a neurotrophin-based mechanism, thereby eliminating catecholamine toxicity while preserving and potentially enhancing cardiac protective effects through alternative signaling pathways.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If βAR antagonists are used to reduce catecholamine toxicity, then mortality is improved, but cardiac force generation during stress is reduced

Engineering Contradiction:

Improvemortality reductionVSAvoidcardiac force generation

Core Design Contradiction:

ReliabilityVSForce

Solution Approach 1:

The patent combines βAR antagonists with BDNF/TrkB agonists in a dual-therapy approach. The βAR antagonist component continues to provide mortality benefit by blocking harmful catecholamine effects, while the BDNF/TrkB agonist component compensates for the loss of cardiac force generation by activating alternative protective signaling pathways. This combination therapy merges the advantages of both approaches while mitigating their individual limitations.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The BDNF/TrkB pathway serves as an intermediary mechanism that compensates for the blocked βAR signaling. When βAR antagonists prevent catecholamine from binding to βAR, the BDNF/TrkB pathway acts as an alternative intermediary to trigger protective cardiac responses through different downstream effectors (Akt, eNOS), thereby maintaining cardiac function despite βAR blockade.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If BDNF/TrkB pathway is activated, then cardiac protection is enhanced, but the mechanism is not yet fully understood

Engineering Contradiction:

Improvecardiac protectionVSAvoidmechanism understanding

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The patent employs feedback mechanisms to better understand and optimize BDNF/TrkB pathway activation. By measuring downstream markers (such as phosphorylated Akt, eNOS activity, and other signaling intermediates) and correlating them with therapeutic outcomes, the invention creates a feedback loop that provides information about pathway activation status and effectiveness, thereby reducing the information loss about mechanism understanding while enhancing cardiac protection.

Inventive Principle:

Principle #23Feedback

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 combination of BDNF or TrkB agonists with βAR-blockers enhances myocardial BDNF production, reduces cardiac dysfunction, and prevents adverse remodeling and fibrosis, offering a therapeutic benefit for heart failure by activating eNOS and stabilizing cardiac function.

Implementation Method 1

Brain-derived neurotrophic factor (BDNF) induces a more 'tonic' influence on myocardial function by specifically binding to its specific sarcolemmal tyrosine kinase B receptor, TrkB

Methodology Applied

Scientific EffectReceptor binding:

Implementation Method 2

βAR antagonists (βAR-blockers) can improve mortality and function of the failing heart

Methodology Applied

Scientific EffectReceptor antagonism:

Implementation Method 3

Methodology Applied

Scientific EffectEnzyme activation:

Data Source

PatentUS11235029B2Methods for treating heart failure with a TRKB agonist

Publication Date: 2022.02.01 JOHNS HOPKINS TECH VENTURES

AI summary

The present invention relates to compositions and methods for the treatment of heart failure.