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Mitochondrial targeted HDAC inhibitors for the treatment of heart failure and related diseases and disorders (MitoDACs)

Detailed Technology Description

Mitochondrial targeted HDAC inhibitors for the treatment of heart failure and related diseases and disorders (MitoDACs) Technology: Researchers at MUSC have discovered HDAC1 is present in the adult cardiac myocyte mitochondria. A series of HDAC1 inhibitors that target mitochondria have been made (MitoDACs).  One of the analog, LL-66, localizes to the mitochondria and is absent from the nucleus in isolated adult rat cardiac myocytes. Inhibiting activity of HDAC1 during the first hour of reperfusion with L66 provides similar levels of protection against ischemia reperfusion injury (IRI) compared to global inhibition of HDAC1 with MS-275. Specifically, LL-66 treatment during the first hour of reperfusion rescues viable myocardium to the same extent as MS-275. Moreover, L66 reduces the spare respiratory capacity of isolated cardiac myocytes, which correlates with a reduction in oxidative damage during reperfusion. Overall, the MitoDAC compounds may be a new effective and mitochondrial targeted treatment for IRI and other cardiac pathologies.  Overview:  Every year in the US 735,000 people have a myocardial infarction. After blood supply returns to the heart during treatment, IRI often results in inflammation and an oxidative stress response, which can lead to disability or death. Studies of IRI and attempts to control it present no clear cut solutions to date. The role of histone deacetylase enzymes and their promise as a treatment target is of great interest in cardiac research. Pharmacological inhibition of HDAC activity has been shown to be beneficial in animal models of multiple cardiac pathologies. HDAC inhibition preceding IRI in the heart can preserve left ventricular function and myocardial survival.  Importantly, selective inhibition of class I HDACs is more effective than pan-HDAC inhibition in preserving myocardial viability and function in the setting of IRI.         Applications: Myocardial infarction, ischemia reperfusion injury, Advantages:  Target HDAC inhibitor, HDAC1 inhibition, Repurfusion phase treatmentKey Words: Myocardial infarction, ischemia reperfusion injury, HDAC, HDAC inhibitors, heart attack Inventors: Donald Menick, Xiaoyang Li, Daniel Herr, James Chou       Patent Status:       Provisional patent application filed 3/13/18              MUSC-FRD Technology ID: P1755

*Abstract

None

*Principal Investigator

Name: Donald Menick, Professor

Department: Medicine - Cardiology/Bioechemistry and Molecular Biology

Name: Chung-jen (james) Chou, Assistant Professor

Department: College of Pharmacy / Pharmaceutical & Biomedical Sciences

Name: Daniel Herr, Graduate Student

Department: MCBP Program

Name: Xiaoyang Li, Post-doctoral Scholar

Department: Drug Discovery

Country/Region

USA