Modified Periostin Promoter AAV Vector for Cardiac Myofibroblast Targeting
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Solution Overview
Problem
Current gene therapy approaches have not effectively targeted cardiac fibroblasts or myofibroblasts in vivo, limiting the ability to modulate their behavior post-myocardial infarction and hindering cardiac regeneration and wound healing processes.
Innovation Solution
A recombinant AAV vector system utilizing a modified periostin promoter is developed to selectively target and induce gene expression in cardiac myofibroblasts, minimizing off-target expression in cardiomyocytes, allowing for controlled gene therapy post-myocardial infarction to promote cardiac regeneration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If AAV vectors are used to transduce cardiac fibroblasts in vivo, then gene expression in myofibroblasts can be achieved, but off-target expression in cardiomyocytes occurs
Solution Approach 1:
The patent applies local quality by using a modified periostin promoter that is specifically active in cardiac myofibroblasts but not in cardiomyocytes. This promoter contains fibroblast-specific regulatory elements that confer cell-type-specific gene expression, thereby achieving local (cell-specific) quality control to prevent off-target effects while enabling targeted gene delivery to myofibroblasts.
2Productivity
If AAV6 is used for fibroblast transduction based on in vitro success, then high transgene expression is achieved in culture, but in vivo transduction of cardiac fibroblasts remains inefficient
Solution Approach 1:
The patent applies parameter changes by switching from AAV6 to AAV9 serotype for in vivo administration. This serotype change fundamentally alters the viral capsid properties, enabling efficient in vivo transduction of cardiac fibroblasts and myofibroblasts while maintaining high transgene expression levels. The parameter change (serotype selection) bridges the gap between in vitro success and in vivo efficacy.
3Reliability
If gene therapy targets cardiomyocytes, then cardiac muscle function can be improved, but myofibroblast behavior cannot be modulated
Solution Approach 1:
The patent applies segmentation by separating the therapeutic targeting from cardiomyocytes to myofibroblasts. Using the modified periostin promoter enables independent targeting of myofibroblasts distinct from cardiomyocytes. This segmentation allows for versatile therapy that can modulate myofibroblast behavior (scar formation, remodeling) separately from cardiac muscle function, expanding the adaptability of gene therapy approaches.
Data Source
AI summary
The present application discloses a recombinant AAV vector comprising a promoter that targets gene expression to myofibroblast-like lineage of cells in the heart. The present application, also discloses the preparation and use of AAV expression cassettes using a modified periostin promoter that successfully drives gene expression in cardiac myofibroblast-like cells. The present invention encompasses compositions and methods useful for treating myocardial infarction. Further comprising compositions and methods for preparing and using AAV vectors for targeting cells and inducing gene expression. The compositions and methods of the invention are useful for efficiently targeting cardiac myofibroblasts following a cardiac injury, disease, or disorder. Further comprising a kit for effecting alleviation of the various diseases or disorders recited herein.