Targeting Cardiomyocyte Endoreplication to Prevent Hypertrophic Cardiomyopathy
This invention provides methods for preventing and treating hypertrophic cardiomyopathy by inhibiting key protein interactions (PCNA and POLD1). It addresses the need for therapies that reduce pathologic myocardial hypertrophy by specifically targeting cardiomyocyte endoreplication pathways.
- Gene therapy applications using viral vectors (e.g., AAV9) to deliver therapeutic genes.
- Development of small-molecule inhibitors targeting PCNA and/or POLD1 to regulate cardiomyocyte growth.
- Therapeutics for preventing myocardial hypertrophy and diastolic dysfunction.
- Targeted Approach: Provides a novel approach to reduce pathologic myocardial hypertrophy by targeting specific endoreplication pathways in cardiomyocytes.
- Cellular-Level Efficacy: Overexpression of the p21 protein can effectively reduce cardiomyocyte hypertrophy.
- Regulation of Protein Interactions: The method works by inhibiting the interaction between two key proteins, PCNA and POLD1, to control endoreplication and hypertrophy.
- Diastolic Function Improvement: Targeting these pathways can prevent the development of diastolic dysfunction.
Description
The invention is a method that works by regulating specific cell cycle proteins to prevent pathologic cardiomyocyte growth. It targets and inhibits PCNA (Proliferating Cell Nuclear Antigen) and POLD1 (DNA Polymerase Delta 1). In hypertrophic cardiomyopathy, increased DNA synthesis leads to cardiomyocyte endoreplication and DNA damage. This invention leverages the fact that increased p21 expression can inhibit the interaction between PCNA and POLD1, which in turn reduces cardiomyocyte hypertrophy and endoreplication. The technology also utilizes a strategy of overexpressing p21 to achieve these effects.Applications
- Pharmaceutical development for treating hypertrophic cardiomyopathy.- Gene therapy applications using viral vectors (e.g., AAV9) to deliver therapeutic genes.
- Development of small-molecule inhibitors targeting PCNA and/or POLD1 to regulate cardiomyocyte growth.
- Therapeutics for preventing myocardial hypertrophy and diastolic dysfunction.
Advantages
- Prevention and Treatment: Offers a method for preventing and treating hypertrophic cardiomyopathy.- Targeted Approach: Provides a novel approach to reduce pathologic myocardial hypertrophy by targeting specific endoreplication pathways in cardiomyocytes.
- Cellular-Level Efficacy: Overexpression of the p21 protein can effectively reduce cardiomyocyte hypertrophy.
- Regulation of Protein Interactions: The method works by inhibiting the interaction between two key proteins, PCNA and POLD1, to control endoreplication and hypertrophy.
- Diastolic Function Improvement: Targeting these pathways can prevent the development of diastolic dysfunction.