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Faye Yi Fong, Seung Soo Oh, Craig J Hawker, H Tom Soh
We report the first in vitro selection of DNA nanostructures that switch their conformation when triggered by change in pH. Previously, most pH-active nanostructures were designed using known pH-active motifs, such as the i-motif or the triplex structure. In contrast, we performed de novo selections starting from a random library and generated nanostructures that can sequester and release Mipomersen, a clinically approved antisense DNA drug, in response to pH change. We demonstrate extraordinary pH-selectivity, releasing up to 714-fold more Mipomersen at pH 5...
November 3, 2016: Angewandte Chemie
P Barton Duell, Ishwarlal Jialal
Familial hypercholesterolemia (FH) is a common genetic disorder that can manifest clinically as both the severe homozygous (HoFH) form that often presents in childhood and the commoner heterozygous (HeFH) form that is typically identified in adults. The majority of genetic causes are due to defects in low-density lipoprotein (LDL) receptor synthesis and action. Until recently, it was exceedingly difficult to achieve the goal of a 50% reduction in LDL-cholesterol or LDL-C < 70-100 in these patients. Established therapies include statins, niacin, bile-acid sequestrants, and ezetimibe in various combinations...
December 2016: Metabolic Syndrome and related Disorders
L Bonanni, A Cutolo, M Dalla Vestra
Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein (LDL) cholesterol.The extent of underdiagnosis and undertreatment of individuals with FH is largely unknown.The LDL-lowering capacity of statins in combination with other lipid-lowering drugs is maximally around 50-60%. FH patients have a strongly elevated LDL-C and in most cases maximal current treatment is not sufficient to reach the desired LDL targets.Therefore, FH patients have a large residual cardiovascular risk despite the use of statins and there is a medical need for new additional drugs to further lower LDL-C in patients with FH to improve their prognosis...
November 2016: Experimental and Clinical Endocrinology & Diabetes
Justin Parizo, Ashish Sarraju, Joshua W Knowles
Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added...
November 2016: Current Treatment Options in Cardiovascular Medicine
Peter P Toth
Although many clinical trials and meta-analyses have demonstrated that lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with proportionately greater reductions in the risk of cardiovascular disease events, not all patients with hypercholesterolemia are able to attain risk-stratified LDL-C goals with statin monotherapy. Elucidation of the pathophysiology of genetic disorders of lipid metabolism (e.g., familial hypercholesterolemia) has led to the development of several novel lipid-lowering strategies, including blocking the degradation of hepatic LDL-C receptors that are important in LDL-C clearance, or the inhibition of apoprotein synthesis and lipidation...
September 15, 2016: American Journal of Cardiology
P Barton Duell, Raul D Santos, Bridget-Anne Kirwan, Joseph L Witztum, Sotirios Tsimikas, John J P Kastelein
BACKGROUND: Familial hypercholesterolemia (FH) is characterized by severely elevated LDL-cholesterol and up to a 20-fold increase in premature cardiovascular disease (CVD). OBJECTIVE: Mipomersen has been shown to lower the levels of these atherogenic lipoproteins, but whether it lowers major adverse cardiac events (MACEs) has not been addressed. METHODS: This post hoc analysis of prospectively collected data of three randomized trials and an open-label extension phase included patients that were exposed to ≥12 months of mipomersen...
July 2016: Journal of Clinical Lipidology
Frederick J Raal, Marjet J Braamskamp, Sheryl L Selvey, Charlotte H Sensinger, John J Kastelein
BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited condition resulting in severely elevated low-density lipoprotein cholesterol levels (LDL-C) leading to premature cardiovascular disease and, often, death. Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B (apo B) synthesis, lowering LDL-C levels. Mipomersen has demonstrated efficacy in adult HoFH patients, possibly providing a therapeutic option for pediatric patients. Study objectives were to summarize mipomersen efficacy and safety in the pediatric cohort of a phase 3 randomized controlled trial (RCT) and subsequent open-label extension study (OLE)...
July 2016: Journal of Clinical Lipidology
Sotirios Tsimikas
Lipoprotein(a) [Lp(a)] is a genetic, independent and likely causal risk factor for cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS). Lp(a) levels are primarily genetically determined and tend to fluctuate only mildly around a pre-determined level. In primary care settings, one Lp(a) measurement can reclassify up to 40% of patients in intermediate risk score categories. In secondary care settings, recent data from the JUPITER and AIM-HIGH trials demonstrate that elevated Lp(a) remains part of the "residual risk" despite achievement of low-density lipoprotein cholesterol levels <70 mg/dL...
September 2016: Progress in Cardiovascular Diseases
Jacqueline L Cartier, Anne Carol Goldberg
Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants...
September 2016: Progress in Cardiovascular Diseases
Claudio Borghi, Claudio Cimminiello
The need for new lipid-lowering drugs is based on the clear-cut evidence that a considerable proportion of patients with dyslipidemia cannot reach the target of cardiovascular protection with the use of currently available drugs (statins, ezetimibe, fibrates). Among the new classes of drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (namely alirocumab and evolocumab) provide an effective solution for patients with familial hypercholesterolemia as well as for high-risk patients who do not achieve the target or complain statin-related adverse events...
April 2016: Giornale Italiano di Cardiologia
Maya S Safarova, Iftikhar J Kullo
Familial hypercholesterolemia (FH), a relatively common Mendelian genetic disorder, is associated with a dramatically increased lifetime risk of premature atherosclerotic cardiovascular disease due to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The diagnosis of FH is based on clinical presentation or genetic testing. Early identification of patients with FH is of great public health importance because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives...
June 2016: Mayo Clinic Proceedings
Anthony S Wierzbicki, Adie Viljoen
INTRODUCTION: Anti-sense oligonucleotide (ASO) therapies are a new development in clinical pharmacology offering greater specificity compared to small molecule inhibitors and the ability to target intracellular process' not susceptible to antibody-based therapies. AREAS COVERED: This article reviews the chemical biology of ASOs and related RNA therapeutics. It then reviews the data on their use to treat hyperlipidaemia. Data on mipomersen - an ASO to apolipoprotein B-100(apoB) licensed for treatment of homozygous familial hypercholesterolaemia (FH) is presented...
September 2016: Expert Opinion on Biological Therapy
Frederick J Raal, Evan A Stein
No abstract text is available yet for this article.
August 2016: Clinical Chemistry
Ezim Ajufo, Daniel J Rader
The recent developments in pharmacological interventions that reduce LDL cholesterol have been remarkable, coming more than a decade after the approval of the last LDL-cholesterol-lowering drug, the cholesterol absorption inhibitor ezetimibe. Within just a few years, four new LDL-cholesterol-lowering agents have received regulatory approval. Lomitapide and mipomersen inhibit the production of LDL, but also increase hepatic fat and are licensed specifically for homozygous familial hypercholesterolaemia. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by about 50-60%...
May 2016: Lancet Diabetes & Endocrinology
Claudia Sanna, Xavier Stéphenne, Nicole Revencu, Françoise Smets, Agnes Sassolas, Mathilde Di Filippo, Olivier S Descamps, Etienne M Sokal
Familial hypercholesterolemia (FH) is a co-dominantly inherited disorder of plasma lipoprotein metabolism. The prevalence of heterozygous FH (HeFH) is between 1/500 and 1/200 whereas that of homozygous form (HoFH) is about 1/1,000,000. Diagnosis is based on cutaneous xanthomas and untreated levels of LDL-cholesterol over 500 mg/dl before 10 years of age. Life expectancy, without treatment, does not exceed 20 years of age. The aim of this study is to characterise in details a cohort of 8 HoFH paediatric patients in order to illustrate all the current therapeutic options and to add some clinical and genetic information about this rare disease...
April 2016: Atherosclerosis
Victoria Enchia Bouhairie, Anne Carol Goldberg
Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder...
March 2016: Endocrinology and Metabolism Clinics of North America
Gissette Reyes-Soffer, Byoung Moon, Antonio Hernandez-Ono, Marija Dionizovik-Dimanovski, Marija Dionizovick-Dimanovski, Jhonsua Jimenez, Joseph Obunike, Tiffany Thomas, Colleen Ngai, Nelson Fontanez, Daniel S Donovan, Wahida Karmally, Stephen Holleran, Rajasekhar Ramakrishnan, Robert S Mittleman, Henry N Ginsberg
Mipomersen is a 20mer antisense oligonucleotide (ASO) that inhibits apolipoprotein B (apoB) synthesis; its low-density lipoprotein (LDL)-lowering effects should therefore result from reduced secretion of very-low-density lipoprotein (VLDL). We enrolled 17 healthy volunteers who received placebo injections weekly for 3 weeks followed by mipomersen weekly for 7 to 9 weeks. Stable isotopes were used after each treatment to determine fractional catabolic rates and production rates of apoB in VLDL, IDL (intermediate-density lipoprotein), and LDL, and of triglycerides in VLDL...
January 27, 2016: Science Translational Medicine
Daniel Gaudet, Diane Brisson
PURPOSE OF REVIEW: Gene-based therapies are designed to modulate gene expression in specific tissues by introducing into cells transgenes, antisense oligonucleotides, RNA interference, microRNAs, or a variety of other oligonucleotide-based compounds and their delivery systems. Several types of gene-based therapies are already available or in clinical development to treat severe lipid-related disorders and associated risk. The review briefly presents the current status and future challenges of these therapies in clinical lipidology, focusing on most advanced and promising agents or mechanisms...
December 2015: Current Opinion in Lipidology
Steven E Gryn, Robert A Hegele
PURPOSE OF REVIEW: We provide an overview of recent advances in the therapy of hypertriglyceridemia, focusing on several new therapies with potential for treating of familial chylomicronemia, other forms of hypertriglyceridemia, and for triglyceride-lowering in patients with other lipid disorders. RECENT FINDINGS: Newer triglyceride-lowering modalities under evaluation include gene therapy for lipoprotein lipase deficiency (alipogene tiparvovec), and antisense oligonucleotides against mRNA for apolipoproteins B (mipomersen) and C3 (volanesorsen, ISIS 304801)...
December 2015: Current Opinion in Lipidology
Roshni S Patel, Emily M Scopelliti, Julie Savelloni
Familial hypercholesterolemia (FH) is a genetic disorder characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) concentrations that result from mutations of the LDL receptor, apolipoprotein B (apo B-100), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Early and aggressive treatment can prevent premature atherosclerotic cardiovascular disease in these high-risk patients. Given that the cardiovascular consequences of FH are similar to typical hypercholesterolemia, traditional therapies are utilized to decrease LDL-C levels...
December 2015: Pharmacotherapy
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