By a News Reporter-Staff News Editor at Heart Disease Weekly From Washington, D.C., NewsRx journalists report that a patent application by the inventors Hussain, Mahmood (Woodbury, NY); Soh, James (Brooklyn, NY), filed on January 12, 2017, was made available online on May 11, 2017 (see also Pharmaceutical Companies).
The patent's assignee is The Research Foundation for The State University of New York.
News editors obtained the following quote from the background information supplied by the inventors: "Complications from excess plasma lipid accumulation are one of the most common causes of death in Western societies (1;2) because they enhance risks for various cardiovascular and metabolic disorders such as hyperlipidemia, atherosclerosis, heart disease, and metabolic syndrome. In plasma, lipids are transported on lipoproteins that provide endogenously produced and dietary lipids to tissues. Plasma lipid levels are controlled by lipoprotein assembly and their catabolism. Hence, reducing lipoprotein production can be a useful approach to prevent and/or treat various cardiovascular and metabolic disorders.
"Lipoproteins are synthesized by the intestine and liver using a structural protein, apolipoprotein B (apoB) with the assistance of microsomal triglyceride transfer protein (MTP) (3;4). The assembly of apoB-containing lipoproteins requires two steps. The first step occurs within the endoplasmic reticulum that involves the synthesis of particles that contain only a small fraction of the lipid core found in the secreted lipoprotein. A larger core of lipid is added to the nascent particle in a second step. MTP is considered essential for the transfer of various lipids to apoB during the first step of the process.
"Pharmacologic inhibition of MTP with Bristol-Myers Squibb's BMS-201038, a potent chemical inhibitor of MTP, reduced low density lipoprotein cholesterol (LDL-C) in volunteers with hypercholesterolemia. However, steatorrhea, elevation of serum transaminases and hepatic fat accumulation were observed. Thus, Bristol-Myers Squibb decided that these side effects made it unlikely that BMS-201038 could be developed as a drug for large scale use in the treatment of hypercholesterolemia. Combinations using MTP inhibitors and other cholesterol or triglyceride drugs have been previously disclosed (U.S. Pat. Nos. 6,066,653 and 5,883,109) but suffer the same drawbacks as described above for MTP inhibitors used alone. Thus, novel approaches are needed to harness beneficial effects of reduced MIT activity.
"Hypercholesterolemia is a well-known risk factor for atherosclerotic cardiovascular disease (ASCVD), the major cause of mortality in the Western world. Numerous epidemiological studies have clearly demonstrated that pharmacological lowering of total cholesterol (TC) and Low-density Lipoprotein (LDL) Cholesterol (LDL-C) is associated with a significant reduction in clinical cardiovascular events. Hypercholesterolemia is often caused by a polygenic disorder in the majority of cases and modifications in lifestyle and conventional drug treatment are usually successful in reducing cholesterol levels. However, in few cases, as in familial hypercholesterolemia, the cause is a monogenic defect and the available treatment in homozygous patients can be much more challenging and far from optimal because LDL-C levels remain extremely elevated despite aggressive use of combination therapy. Therefore, for this group of high-risk patients, effective medical therapy is urgently needed.
"Triglycerides are common types of fats (lipids) that are essential for good health when present in normal amounts. They account for about 95 percent of the body's fatty tissue. Abnormally high triglyceride levels can result from such causes as cirrhosis of the liver, underactive thyroid (hypothyroidism), poorly controlled diabetes, or pancreatitis (inflammation of the pancreas). Researchers have also identified elevated triglycerides as a risk factor for heart disease.
"Higher-than-normal triglyceride levels are often associated with known risk factors for heart disease, such as low levels of HDL ('good') cholesterol, high levels of LDL ('bad') cholesterol and obesity. Triglycerides may also contribute to thickening of artery walls, which is linked to the development of atherosclerosis.
"MicroRNAs (miRs) are small noncoding RNA molecules that can cause post-transcriptional silencing of specific genes, either by the inhibition of translation or through degradation of the targeted mRNA. Since the initial discovery of miRs as regulators of gene expression (11), a role of miRs in development of various diseases such as cancer (12) has been identified. MiRs interact with the 3'-untranslated region (3'-UTR) of target mRNAs and reduce protein synthesis by enhancing mRNA degradation and/or by interfering with its translation (13). A microRNA can be completely complementary or can have a region of noncomplementarity with a target nucleic acid, consequently resulting in a 'bulge' at the region of non-complementarity.
"Two miRs have been shown to be involved in lipid metabolism. miR-122 is linked to fatty acid synthesis and oxidation and is currently being tested as a therapeutic target against hepatitis C infection (1). miR-33 regulates expression of ABCA1 and ABCG1, two proteins involved in reverse cholesterol transport (14-18).
"A further understanding of the regulation of lipid metabolism by miRs can reveal new physiological mechanisms to reduce lipoprotein production, hyperlipidemia and atherosclerosis."
As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "This disclosure provides a novel role for microRNA (miR) regulation of lipid metabolism via the MTP pathway, leading to reductions in apoB secretion and blood lipid levels. MiR regulation of the MTP pathway is shown herein to reduce hyperlipidemia and atherosclerosis in vivo. Therefore, inhibition of MTP expression and activity by miR regulation is identified as a new therapeutic target for treatment of cardiovascular disease and conditions or diseases associated with cardiovascular disease such as hyperlipidemia, atherosclerosis, and metabolic syndrome.
"In one embodiment, this disclosure provides a method for treating cardiovascular disease, hyperlipidemia, atherosclerosis, or metabolic syndrome in a subject in need thereof, comprising administration of a miR-30c homolog or agonist in an amount effective to treat the disease in said subject. A particular embodiment further provides administration of the miR-30c homolog or agonist in combination with at least one additional cholesterol reducing agent, such as a statin.
"In another embodiment, this disclosure provides a method for reducing serum lipids in a subject in need thereof, comprising administration of a miR-30c homolog or agonist in an amount effective to reduce serum lipids in said subject. A particular embodiment further provides administration of the miR-30c homolog or agonist in combination with at least one additional cholesterol reducing agent, such as a statin.
"In an additional embodiment, this disclosure provides a method for reducing MTP activity in a subject in need thereof, comprising administration of a miR-30c homolog or agonist in an amount effective to reduce MTP activity in said subject.
"In another embodiment, this disclosure provides a pharmaceutical composition for the treatment of cardiovascular disease, hyperlipidemia, atherosclerosis, or metabolic syndrome, comprising an effective amount of a miR-30c homolog or agonist.
"In a further embodiment, this disclosure provides a method of identifying an agent for the treatment of cardiovascular disease, hyperlipidemia, atherosclerosis, obesity, diabetes, Hepatitis C infection, or metabolic syndrome, comprising contacting a cell expressing a miR-30c homolog with a candidate agent, and assaying the expression of the miR-30c homolog; wherein an increase in expression of the miR-30c homolog identifies the agent as a miR-30c homolog agonist useful for the treatment of cardiovascular disease, hyperlipidemia, atherosclerosis, or metabolic syndrome.
"In another embodiment, this disclosure provides a method of reducing lipid synthesis in a subject in need thereof, comprising administration of a miR-30c homolog or agonist in an amount effective to reduce lipid synthesis in said subject.
"Another embodiment provides a method of coordinately suppressing lipid synthesis and lipid secretion by the liver to lower plasma lipids while avoiding build up of lipids in the liver by administering an effective dose of miR-30c homolog or agonist in said subject."
For additional information on this patent application, see: Hussain, Mahmood; Soh, James. Method of Treating Hyperlipidemia and Atherosclerosis with Mir-30c. Filed January 12, 2017 and posted May 11, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170121713%22.PGNR.&OS=DN/20170121713&RS=DN/20170121713
Keywords for this news article include: Pharmaceutical Companies, Blood, Plasma, Genetics, Hepatitis, Cardiology, Healthcare, Hematology, Epidemiology, Lipoproteins, Dyslipidemias, Heart Disease, Atherosclerosis, Hyperlipidemias, Arteriosclerosis, Gastroenterology, Metabolic Syndrome, Risk and Prevention, Hypercholesterolemia, Lipid Metabolism Disorders.
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