Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.

PURPOSE OF REVIEW: Homozygous autosomal dominant hypercholesterolemia (hoADH) is a rare genetic disorder caused by mutations in LDL receptor, apolipoprotein B, and/or proprotein convertase subtilisin-kexin type 9. Both the genetic mutations and the clinical phenotype vary largely among individual patients, but patients with hoADH are typically characterized by extremely elevated LDL-cholesterol (LDL-C) levels, and a very high-risk for premature cardiovascular disease. Current lipid-lowering therapies include bile acid sequestrants, statins, and ezetimibe. To further decrease LDL-C levels in hoADH, lipoprotein apheresis is recommended, but this therapy is not available in all countries. RECENT FINDINGS: Recently, the microsomal triglyceride transfer protein inhibitor lomitapide and the RNA antisense inhibitor of apolipoprotein B mipomersen were approved by the Food and Drug Administration/European Medicine Agency and the Food and Drug Administration, respectively. Several other LDL-C-lowering strategies and therapeutics targeting the HDL-C pathway are currently in the clinical stage of development. SUMMARY: Novel therapies have been introduced for LDL-C-lowering and innovative drug candidates for HDL-C modulation for the treatment of hoADH. Here, we review the current available literature on the prevalence, diagnosis, and therapeutic strategies for hoADH.

Reconstituted HDL elicits marked changes in plasma lipids following single-dose injection in C57Bl/6 mice.

High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-ß HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.

Nonpharmacologic approaches for the treatment of hyperlipidemia.

Coronary heart disease (CHD) is the leading cause of death in the United States. Dyslipidemias, like decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL), have been linked through epidemiologic and experimental studies with the development of atherosclerosis and an increased risk of CHD. The introduction of various classes of lipid-lowering drugs, especially the hydroxymethylglutaryl-coenzyme-A-reductase inhibitors (statins), has allowed for effective treatment of hyperlipidemia. This article reviews the following nonpharmacologic approaches to hyperlipidemia: LDL apheresis, surgery, the emergence of HDL as a therapeutic target, gene therapy, and finally, the possibility of developing a vaccine against atherosclerosis.

Failure of exogenous apoprotein E-3 to enhance cholesterol egress from J-774 murine macrophages in culture.

HDL has been shown to enhance the removal of cholesterol from cultured fibroblasts, smooth muscle cells and macrophages, but fails to stimulate cholesterol removal from J-774 macrophages. Since J-774 macrophages do not synthesize or secrete apolipoprotein E, the effect of exogenous apolipoprotein E on HDL-mediated cellular cholesterol efflux was studied in this cell line. In cholesterol loaded J-774 macrophages total cellular cholesterol increased up to 6-7-fold, mainly cholesteryl esters. HDL3 removed up to 30% of total cellular cholesterol with a decrease in cholesteryl ester levels while free cholesterol levels remained unchanged. HDL3 was slightly superior to albumin in promoting cellular cholesterol removal. Exogenous apo E, over a wide range of apo E concentrations, did not enhance the ability of HDL3 to remove cellular cholesterol from cholesterol loaded J-774 cells. Exogenous apo E did not promote HDL-mediated cholesterol efflux from cells, thus suggesting a possible role for the intracellular route of newly synthesized apo E in these processes.

Reconstituted high density lipoprotein inhibits physiologic and tumor necrosis factor alpha responses to lipopolysaccharide in rabbits.

OBJECTIVE: To determine the effect of reconstituted human high density lipoprotein (rHDL) on physiologic and cytokine responses to infusion of lipopolysaccharide. DESIGN: A blinded, randomized trial of three preparations of a purified human rHDL with apolipoprotein A-I-phosphatidyl choline-cholesterol molar ratios of 1:100:10, 1:150:10, and 1:200:0 and placebo in a rabbit lipopolysaccharide intravenous infusion model. INTERVENTIONS: Groups of six New Zealand white rabbits received either placebo or one of the three human rHDL preparations above as a single, 75-mg/kg (apolipoprotein A-I equivalent) dose intravenously over 10 minutes ending 5 minutes before the start of a 3-hour infusion of lipopolysaccharide. MAIN OUTCOME MEASURES: Mean arterial pressure, base excess, and plasma tumor necrosis factor alpha (TNF-alpha) production were determined. RESULTS: The human rHDL suppressed TNF-alpha production with the products having the highest fraction of phosphatidyl choline producing the greatest suppression of TNF-alpha production. The human rHDL 1:200:0 group maintained a low, near-baseline TNF-alpha concentration and minimal decline in mean arterial pressure and base excess throughout the lipopolysaccharide infusion in contrast to the placebo group. CONCLUSION: Reconstituted human high density lipoprotein appears to be useful in inhibiting the physiologic effects and cytokine release associated with endotoxemia and may provide adjunctive treatment for patients with gram-negative sepsis.