Abstract 50: A Phase I Clinical Trial Evaluating the Safety of With Allogeneic Adipose Tissue-derived Multilineage Progenitor Cells-transplantation Therapy in Homozygous Familial Hypercholesterolemia Patients

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Masahiro Koseki ◽  
Shizuya Yamashita
Keyword(s):  
Clinical Trial ◽  
Liver Transplantation ◽  
Adipose Tissue ◽  
Progenitor Cells ◽  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Ldl Apheresis ◽  
Definitive Therapy ◽  
Transplantation Therapy

Familial hypercholesterolemia (FH) is an inherited disorder, mainly caused by defects in low-density lipoprotein (LDL) receptor gene. The patients are characterized by high LDL cholesterol levels in the blood and premature cardiovascular disease. Although most of heterozygous FH patients are usually treated with statin, ezetimibe and bile acid sequestrants, homozygous FH patients are resistant to drug therapy. Therefore, in Japan, many of homozygous FH patients are treated by LDL-apheresis. LDL-apheresis is a great procedure to remove LDL cholesterol from the blood and contribute to improve prognosis of homozygous FH patients. However, the effect of removing LDL cholesterol is temporary and still not enough. As a definitive therapy, liver transplantation therapy could be one of options to recover LDL receptor, but donor is limited in Japan. Therefore, based on the increase of the evidence about the safety of mesenchymal stem cells and percutaneous transhepatic portal approach in islet transplantation, we have developed a cell transplantation therapy with allogeneic adipose tissue-derived multilineage progenitor cells (ADMPCs), as an alternative treatment instead of liver transplantation. Our group has already proved that xenogenic transplantation of human ADMPCs into Watanabe heritable hyperlipidemic rabbits resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases. Here, we report a protocol for the first-in-human clinical trial, which has been approved by the institutional review board and Ministry of Health, Labour and Welfare, Japan.

scholarly journals Familial Hypercholesterolemia: Three “under” (Understood, Underdiagnosed, and Undertreated) Disease

2021 ◽  
Author(s):  
Vladimir O. Konstantinov
Keyword(s):  
Familial Hypercholesterolemia ◽  
Time Course ◽  
Ldl Cholesterol ◽  
Genetic Disorders ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Blood Cholesterol ◽  
Healthy Population ◽  
Loss Of Function

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among “healthy” population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.

Abstract 602: Development of Cell Therapy in Severe Familial Hypercholesterolemia

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Masahiro Koseki ◽  
Ayami Saga ◽  
Takuya Kobayashi ◽  
Masumi Asaji ◽  
Takeshi Okada ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cell Transplantation ◽  
Ldl Cholesterol ◽  
Phase 1 ◽  
Safety Evaluation ◽  
Current Status ◽  
Ldl Apheresis ◽  
Rejection Reaction ◽  
First Case ◽  
Premature Cardiovascular Disease

Familial hypercholesterolemia (FH) patients are characterized by high LDL cholesterol levels in the blood and premature cardiovascular disease. Although most of heterozygous FH patients are able to be treated with statin, ezetimibe and bile acid sequestrants and anti-PCSK9 antibodies, homozygous FH patients are resistant to drug therapy. Therefore, many of homozygous FH patients used to be treated by LDL-apheresis. However, the effect of removing LDL cholesterol is still not sufficient and definitive therapies need to be developed. With the increase of the evidence about the safety of mesenchymal stem cells and percutaneous transhepatic portal approach in islet transplantation, we have developed a cell transplantation therapy with allogeneic adipose tissue-derived multilineage progenitor cells, as an alternative treatment instead of liver transplantation. We have generated a protocol for the phase 1 clinical study. The primary endpoint should be safety evaluation including allergic reaction, rejection reaction, thrombosis and complications in the blood vessel by cell-transplantation. The secondary endpoint should be the efficacy including changes in serum lipid such as LDL-C, TC, HDL-C, TG and Lp(a), and Secession possibility of LDL-apheresis. We transplanted the first case in February, 2016. Then we are collecting clinical data. We would demonstrate the current status and the issues to be solved for the following study.

scholarly journals Compound Heterozygous Familial Hypercholesterolemia and Familial Defective Apolipoprotein B-100 Produce Exaggerated Hypercholesterolemia

2001 ◽  
Vol 47 (3) ◽  
pp. 438-443 ◽  
Author(s):  
E Shyong Tai ◽  
Evelyn S C Koay ◽  
Edmund Chan ◽  
Tzer Jing Seng ◽  
Lih Ming Loh ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Genetic Analysis ◽  
Familial Hypercholesterolemia ◽  
Apolipoprotein B ◽  
Ldl Cholesterol ◽  
Index Case ◽  
Ldl Receptor ◽  
Cholesterol Concentration ◽  
Apo B ◽  
First Degree Relatives

Abstract Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) represent ligand-receptor disorders that are complementary. Individuals with both FH and FDB are unusual. We report a family with both disorders and the impact of the mutations on the phenotypes of the family members. Methods: We used single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exons and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay. Fasting serum lipid profiles were determined for the index case and seven first-degree relatives. Results: One of the patient’s sisters had a missense mutation (Asp407→Lys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L. Four other first-degree relatives had hyperlipidemia but no LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg3500→Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. Her serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested. Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hypercholesterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia.

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

2007 ◽  
Vol 22 (2) ◽  
pp. 180-184 ◽  
Author(s):  
Hartmut H-J. Schmidt ◽  
Uwe J.F. Tietge ◽  
Janine Buettner ◽  
Hannelore Barg-Hock ◽  
Gisela Offner ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Familial Hypercholesterolemia ◽  
Gene Mutation ◽  
Receptor Gene ◽  
Ldl Receptor

scholarly journals Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

2019 ◽  
Vol 116 (22) ◽  
pp. 10937-10942 ◽  
Author(s):  
Wenhai Sui ◽  
Hongshi Li ◽  
Yunlong Yang ◽  
Xu Jing ◽  
Fei Xue ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Atherosclerotic Plaque ◽  
Ldl Cholesterol ◽  
Uncoupling Protein ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cerebrovascular Diseases ◽  
Plaque Development ◽  
Brown Adipose

Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E−/− (ApoE−/−) and low-density lipoprotein (LDL) receptor−/− (Ldlr−/−) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis.

Abstract 434: LDL Apheresis Significantly Alters HDL Cargo and Function in Familial Hypercholesterolemia Subjects

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Donald R Lynch ◽  
Carrie Wiese ◽  
Qi Liu ◽  
W H McDonald ◽  
Robert C Taylor ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Protein Identification ◽  
Binding Protein ◽  
Platelet Activating Factor ◽  
Ldl Receptor ◽  
Enrichment Analysis ◽  
Inherited Disease ◽  
Protective Capacity ◽  
Ldl Apheresis ◽  
Transport Pathway

In addition to cholesterol, HDL transports a wide-variety of cargo including vitamins, nucleic acids, and a diverse set of proteins. Outside of the reverse cholesterol transport pathway, HDL has alternative functions that contribute to its anti-atherogenicity, including anti-inflammatory, anti-oxidant, and signaling capacities. Recently, we found that HDL transports and delivers functional microRNAs to recipient cells, which likely confers HDL’s ability to suppress adhesion molecule expression in endothelial cells. As such, changes to HDL’s cargo impact many of these alternative functions, and thus its protective capacity. HDL dysfunction has been identified among patients with familial hypercholesterolemia (FH), an inherited disease due to mutations in the LDL receptor and associated with severe elevations in LDL-cholesterol (LDL-C) levels, which may necessitate LDL apheresis (LA) in management. Here we demonstrate that LA significantly alters HDL’s miRNA and protein signatures. We believe that these changes may have profound consequences on HDL’s protective capacity. Using density-gradient ultracentrifugation, we found 31 proteins to be significantly altered on HDL after LA, as determined by shotgun proteomics and multidimensional protein identification technology analysis. For example, vitamin D-binding protein (1.74-fold) was increased, while lipopolysaccharide-binding protein (-1.92-fold), platelet-activating factor acetylhydrolase (-2.06), and apolipoprotein A-V (-2.4-fold) were found to be decreased. Gene ontology and KEGG enrichment analysis demonstrated roles of these proteins in response to stress, coagulation, hemostasis, and vesicle-mediated transport. Fast-protein liquid chromatography was used to further purify HDL for miRNA profiling using TaqMan OpenArrays, and we found 8 HDL-miRNAs to be significantly altered -- 3 down (miR-302b -13.9-fold, miR-224 -1.8, miR-572 -2.4-fold) and 5 up (miR-7 9.8-fold, miR-208b 16.2-fold, miR-34a-3p 3-fold, miR-627 2.4-fold, miR-1183 4.8-fold). Both miR-302b and miR-224 decreased; these are miRNAs previously reported to suppress proliferation through targeting AKT2 and apoptosis, respectively. As such, these changes likely alter HDL’s function in FH subjects.

scholarly journals Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Chiharu Miyajima ◽  
Takayuki Iwaki ◽  
Kazuo Umemura ◽  
Victoria A. Ploplis ◽  
Francis J. Castellino
Keyword(s):  
Familial Hypercholesterolemia ◽  
Apolipoprotein B ◽  
Ldl Cholesterol ◽  
Genetic Model ◽  
Ldl Receptor ◽  
Normal Diet ◽  
Atherosclerotic Plaques ◽  
Key Features ◽  
Very High

A murine genetic model of LDL-cholesterol- (LDL-C-) driven atherosclerosis, based on complete deficiencies of both the LDL-receptor (Ldlr-/-) and key catalytic component of an apolipoprotein B-edisome complex (Apobec1-/-), which converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks. The general characteristics include the presence of high levels of LDL-C in plasma and macrophage-related fatty streak formation in the aortic tree, which progressively worsens with age. More specifically, plaque found in the aortic sinuses contains a lipid core with relatively high numbers of macrophages and a smooth muscle cell α-actin- and collagen-containing cap, which thins with age. These critical features of plaque progression suggest that the Ldlr-/-/Apobec1-/- mouse line presents a superior model of LDL-C-driven atherosclerosis.

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