ABHD5 and HDAC4-NT Fragments for Heart Failure Treatment
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Solution Overview
Problem
Current therapies lack effective means to address myocardial remodeling and heart failure, particularly in managing the signaling pathways influenced by sustained catecholaminergic stress, which exacerbates heart failure.
Innovation Solution
The use of Abhydrolase containing domain 5 (ABHD5) and its variants, along with the N-terminal fragment of histone deacetylase 4 (HDAC4-NT), to inhibit proteolytic cleavage and modulate signaling pathways, thereby preventing myocardial remodeling and treating heart failure through cardiomyocyte-specific expression and vector-based delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full-length HDAC4 is used, then histone deacetylase activity is maintained, but proteolytic cleavage occurs to generate harmful N-terminal fragments that promote myocardial remodeling
Solution Approach 1:
The patent extracts and removes the harmful N-terminal fragment (HDAC4-NT) generated by proteolytic cleavage of full-length HDAC4. By selectively eliminating this harmful fragment while maintaining the functional C-terminal portion, the invention prevents myocardial remodeling without losing essential histone deacetylase activity.
Solution Approach 2:
The patent segments the HDAC4 protein into functional domains, separating the harmful N-terminal fragment from the beneficial C-terminal region. This segmentation allows selective removal of the pathogenic portion while preserving the functional aspects of the protein that prevent cardiac remodeling.
2Stability of the object's composition
If ABHD5 is overexpressed to inhibit proteolytic cleavage, then HDAC4 stability increases, but off-target effects and toxicity may occur
Solution Approach 1:
The patent applies local quality by creating cardiomyocyte-specific expression of ABHD5 using muscle-specific promoters. This ensures that ABHD5 is expressed only in the heart muscle cells where it is needed to stabilize HDAC4, while avoiding expression in other tissues that could cause off-target effects and toxicity.
Solution Approach 2:
The patent changes the expression parameter of ABHD5 from constitutive to inducible and tissue-specific. By controlling ABHD5 expression to occur only in cardiomyocytes and only under specific conditions, the invention achieves HDAC4 stabilization while minimizing systemic side effects.
3Adaptability or versatility
If cardiomyocyte-specific expression vectors are used, then therapeutic specificity improves, but delivery complexity increases
Solution Approach 1:
The patent employs universal vectors (such as adenoviruses or adeno-associated viruses) that can be adapted for cardiomyocyte-specific expression. These vectors serve multiple functions: they can deliver various therapeutic genes, can be modified for different promoters, and can be administered through standardized routes, thereby reducing overall system complexity while maintaining tissue specificity.
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
ABHD5 and HDAC4-NT variants effectively inhibit myocardial remodeling, reduce cardiac dysrhythmia risk, and improve cardiac output, as demonstrated by echocardiography and decreased natriuretic peptide levels, providing a novel approach to treating and preventing heart failure.
Implementation Method 1
Full-length histone deacetylase 4 (HDAC4) is proteolytically processed by a previously unknown enzyme yielding an N-terminal fragment (HDAC4-NT) comprising 201 amino acids
Implementation Method 2
In vitro, HDAC4-NT selectively represses myocyte enhancer factor 2 (MEF2)
Data Source
AI summary
The present invention relates to Abhydrolase containing domain 5 (ABHD5) and N-terminal fragments of HDAC4 (HDAC4-NT) and variants of the aforementioned peptides for the treatment and prevention of heart failure. The present invention further provides vectors for the cardiomyocyte-specific expression of said peptides and a test system comprising ABHD5 for the identification of novel compounds which are useful for the treatment of heart failure.