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Gene therapy, a promising treatment for familial hypercholesterolaemia.

DOI:10.1097/MOL.0000000000000402 ease (CHD) is a primary cause of death worldwide [1]. Epidemiological studies have shown that smoking, hypertension, diabetes and high plasma concentration ofLDLcholesterol (LDL-C)are strongly associated with CHD [2]. Disorders of extremes of LDL-C such as familial hypercholesterolaemia indicate a causal relationship between LDL-C and CHD [3]. Familial hypercholesterolaemia is an inherited cause of CHD and results in a lifetime of elevated LDL-C with accelerated atherosclerosis and premature CHD [3]. Normally hepatic LDLRs bind LDL-C and remove it from the circulation by receptormediated endocytosis [4]. This is the normal pathway for removal of cholesterol and is controlled by intracellular cholesterol levels [5]. Familial hypercholesterolaemia is an autosomal, dominant, inherited disorder caused predominantly by loss of function mutations in one or both of the alleles of the LDL receptor (LDLR) [6,7]. Heterozygous familial hypercholesterolaemia (HeFH) individuals have one mutant LDLR allele (approximately one in 500 people) with elevated plasma LDL-C (5.2– 10.4 mmol/L) and is characterized by premature CHD delayed or prevented by treatment to lower LDL-C. Homozygous familial hypercholesterolaemia (HoFH) individuals have two mutant LDLR alleles, (approximately one in 1 million people) with plasma LDL-C above 12.9 mmol/L [3]. More than 90% of patients with HoHF have loss of function mutations in both alleles. Patients are classified as either receptor negative (<2%) or receptor defective (2–25%). If untreated receptor negative HoHF is usually fatal within the first two decades of life [8]. Conventional statin therapy requires a functional LDLR and patients with HoFH are usually refractory to treatment [9]. Statins inhibit 3hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in cholesterol synthesis normally resulting in reduced hepatic cholesterol and upregulation of LDLRs consequently reducing circulating LDL-C levels. Nonpharmacological methods for the treatment of HoFH include LDL apheresis and liver transplants [10,11]. Gene-based therapies to lower cholesterol in patients with HoFH to therapeutic levels not