Office of Technology Transfer – University of Michigan

Discover KLF14 as a Key Mediator for HDL Metabolism and Identify a KLF14 Activator for the Treatment of Coronary Heart Disease

Technology #5698

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Categories
Researchers
Yuqing (Eugene) Chen
Managed By
Tiefei Dong
Senior Licensing Specialist, Life Sciences 734-763-5332
Patent Protection
PCT Patent Application 2017/044607

UM File # 5698

Background

Technology Description

Applications
Advantagespeutic target for increasing apolipoprotein A1 (apoA1) and high densilty lipoprotein (HDL) for treatment of cardiovascular disease

Levels of high density lipoprotein (HDL), commonly referred to as good cholesterol, is inversely correlated with cardiovascular disease (CVD). Apolipoprotein A1 (ApoA1) is the major protein component required for the synthesis of HDL. In animal models, increasing apoA1 levels has been shown to increase HDL, induce regression of atherosclerotic plaques and reduce atherosclerotic progression. Researchers at the University of Michigan have identified a novel role of a gene whose protein product functions as a direct transcriptional activator of apoA1 gene. Overexpression of the gene in liver tissue culture cells and in mouse increased the expression apoA1 protein, increased blood HDL levels and, increased the rate of cholesterol efflux from the blood. Through a screen targeted to increase the expression of the gene, the researchers identified a small molecule that when injected into mice led to an increase in apoA1 and blood HDL levels. More importantly, the mechanism of action (MOA) of the compound in increasing apoA1 and HDL levels occurs independently of the MOA of the therapies currently in use to increase HDL levels. Thus, this compound and other therapies targeted towards this gene may potentially be developed as a new therapy that can be used independently or in combination with current drugs used in CVD treatment.

Limitations in current therapies for managing cholesterol levels and cardiovascular disease Cardiovascular disease (CVD) is the leading cause of death worldwide and represents ~30% of all global deaths. In 2008, one in every three deaths in the US is attributed to CVD with 2200 Americans dying of CVD each day. Cholesterol levels have long been associated with CVD risk. The main cholesterol-carrying lipoproteins are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Excess LDL accumulates in the artery wall where they initiate an inflammatory response that leads to the development and progression of atherosclerosis, the main underlying cause of cardiovascular disease (CVD). In contrast, HDL levels are inversely correlated with CVD and this is attributed to the function of HDL in collecting cholesterol from peripheral tissue and returning it to the liver for breakdown or recycling. Statin therapy, targeted towards inhibiting cholesterol synthesis in the liver and lowering LDL levels, is the leading approach in primary and secondary prevention of CVD. However, patients who have reached targeted LDL levels with statin therapy but have low HDL levels are still associated with a high risk of cardiovascular events. Currently, there is an active search for therapeutic agents that increase HDL levels as treatment for CVD.

Applications

• Target for increasing apoA1 expression

• New role for a compound in treating CVD

Advantages

• New therapeutic target and activator of the target that regulates expression of several genes involved in HDL synthesis

• Therapeutic that can be used in combination with agents that lower LDL levels and/or increase HDL