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Methods to treat heart failure by interfering and reversing detyrosination of microtubules to restore heart function.
Heart failure (HF) is a chronic condition occurring when the heart muscle doesn't pump blood as well as it should, leading to reduced oxygenation of, and blood supply to, tissues and organs. Current treatments, such as lifestyle changes and medications, are mainly palliative, and there are no effective treatments for ~50% of HF cases. These untreatable cases are often characterized by an increase in the stiffness of the heart, which impairs its ability to fill with and pump blood.
Drs. Prosser and Margulies at the University of Pennsylvania established a causal relationship between reduced contractility of the heart and level of tyrosination of its microtubules. The researchers showed that detyrosination causes stiffening of the heart muscle cells and thus restricts heart contraction. The current invention provides a new method for treating HF aimed at restoring the heart contractile function by either interfering with detyrosination of microtubules or increasing their tyrosination. Therapeutic approaches include small molecules, or gene therapy.
Reducing detyrosination speeds contraction and relaxation of failing human cardiomyocytes. A, Example of sarcomere shortening trace from myocyte responding to electrical stimulation and corresponding first derivative identifying key contractile parameters collected. B, Average traces of sarcomere shortening from cardiomyocytes isolated from NF donor hearts and from hearts from patients with HFrEF and HFpEF, with or without VASH1 KD.
Stage of Development:
Docket # 17-8222