Gene therapy for hypercholesterolemia: sweet dreams and flying machines.

Abstract

Much of our understanding of normal low-density lipoprotein (LDL) cholesterol metabolism can be traced to studies in human carriers of naturally occurring mutations, which perturb proteins acting at key metabolic checkpoints.1 The best known among these single-gene disorders is familial hypercholesterolemia (FH), which in the heterozygous state affects ≈1 in 250 to 500 individuals and classically results from a loss-of-function mutation in 1 allele of the LDLR gene encoding the LDL receptor, primarily in the liver.2 Untreated FH heterozygotes have plasma LDL cholesterol levels 2× to 3× normal and begin to express atherosclerosis symptoms and signs in the third to fourth decade of life.2 FH heterozygotes respond well to multidimensional treatment, including lifestyle modification plus medications, primarily statins plus cholesterol absorption inhibitors, and bile acid sequestrants, which all act to upregulate the 1 functional (wild-type) LDLR allele.3 In contrast, the much rarer homozygous form of FH (HoFH) affects ≈1 in 250 000 to 1 000 000 individuals, classically results from loss-of-function mutations in both LDLR alleles, is associated with plasma LDL cholesterol levels 4× to 10× normal, is expressed clinically by the second decade with significant lipid deposits affecting skin, tendons, and arteries, and is characterized by minimal response to traditional lipid-lowering therapies.4 In fact, the miniscule biochemical response to statin treatment in patients with HoFH confirms that statins reduce plasma LDL cholesterol by upregulating expression of LDL receptors, which are functionally absent in these patients. Article, see p 591 The standard of care for HoFH is weekly or biweekly plasmapheresis or LDL apheresis.5 However, this treatment is not universally available, and although it has likely improved longevity, patients with HoFH still develop early cardiovascular disease, including premature coronary atherosclerosis and significant left ventricular outflow tract disease.6 Liver transplantation has also been attempted …