Cardiac Reprogramming with MYOCD and ASCL1
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Solution Overview
Problem
Current methods for generating induced cardiomyocytes for treating heart conditions, such as heart failure and myocardial infarction, require the use of multiple reprogramming factors, which can be complex and inefficient, and there is a need for simpler and more effective approaches to directly reprogram non-cardiomyocytes into cardiomyocytes.
Innovation Solution
The use of MYOCD and either ASCL1 or MYF6, with optional additional factors like MEF2C and TBX5, to directly reprogram human cardiac fibroblasts into cardiomyocytes using vector systems that include polynucleotides encoding these proteins, allowing for the generation of induced cardiomyocytes with fewer factors and potentially improved efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple reprogramming factors are used to generate induced cardiomyocytes, then the reprogramming efficiency and completeness are improved, but the complexity of the treatment protocol and vector system increases
Solution Approach 1:
The patent combines multiple reprogramming factors (MYOCD, ASCL1, and optionally MEF2C or TBX5) into a single integrated vector system that delivers all necessary factors simultaneously. This merging approach maintains high reprogramming efficiency while reducing the complexity of managing multiple separate treatment protocols.
Solution Approach 2:
The vector system is designed to be universal, capable of delivering multiple reprogramming factors through a single administration. The system can accommodate different factor combinations (MYOCD+ASCL1, MYOCD+ASCL1+MEF2C, or MYOCD+ASCL1+TBX5) within the same platform, providing multi-functionality that simplifies the overall treatment approach.
2Device complexity
If a reduced set of reprogramming factors is used, then the protocol simplicity is improved, but the reprogramming efficiency and completeness may deteriorate
Solution Approach 1:
The patent identifies and utilizes specific parameter thresholds and factor combinations that optimize reprogramming efficiency. By carefully selecting which factors to include (MYOCD and ASCL1 as core, with MEF2C or TBX5 as optional enhancements), the system achieves high reprogramming efficiency with minimal factors, balancing simplicity and effectiveness.
3Reliability
If the standard GMT factor combination is used for direct cardiac reprogramming, then the cardiomyocyte differentiation is improved, but the reprogramming time and treatment duration increase
Solution Approach 1:
The patent extracts and emphasizes the most critical reprogramming factors (MYOCD and ASCL1) from the broader GMT combination, demonstrating that these two factors alone are sufficient to achieve effective cardiomyocyte differentiation. This extraction reduces the treatment duration by eliminating unnecessary factors while maintaining differentiation quality.
Solution Approach 2:
The patent applies partial action by using a subset of factors (MYOCD and ASCL1) that provides sufficient reprogramming capability without requiring the full GMT combination. This partial approach achieves the necessary cardiomyocyte differentiation more quickly, reducing overall reprogramming time while maintaining effectiveness.
Data Source
AI summary
The present disclosure provides methods for generating induced cardiomyocytes and/or inducing a cardiomyocyte phenotype in cells in vivo or in vitro, such as by expression of ASCL1 or MYF6 and MYOCD. The present disclosure further provides gene-delivery vectors comprising one or more polynucleotides selected from ASCL1, MYF6, MYOCD, MEF2C, and TBX5. It further provides compositions comprising induced cardiomyocytes and provides methods of treating a heart condition, such as myocardial infarction. The disclosure also provides engineered myocardin proteins with an internal deletion, vectors encoding such engineered mycocardins, and methods of use thereof.