Gene therapy for lipid disorders

Introduction

A reduction in plasma cholesterol levels is associated with a substantial reduction in cardiovascular events [1]. Methods for reducing cholesterol levels and specifically low-density lipoprotein (LDL) cholesterol include lifestyle changes and drug therapy, including statins, niacin, bile acid sequestrants, and fibrates [2]. However, many patients cannot achieve optimal LDL cholesterol levels with existing cholesterol-lowering therapies [2]. The majority of these patients have genetic disorders that cause severe hypercholesterolemia that is partly refractory to existing therapies, whereas other patients do not tolerate existing therapies. Hypercholesterolemia therefore remains an important target for the development of novel therapies.

Plasma triglycerides are increasingly recognized as a risk factor for cardiovascular disease [3], and severe hypertriglyceridemia is associated with acute pancreatitis. Although triglyceride levels can frequently be decreased with a combination of lifestyle changes and drug therapy such as fibrates and niacin, there remain a substantial number of individuals in which triglycerides remain significantly elevated. Hypertriglyceridemia is therefore also a target for the development of novel therapies.

Finally, low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with significantly increased cardiovascular risk [4]. Low-HDL cholesterol is one of the most common lipid disorders in patients with premature coronary artery disease [5]. There are a variety of genetic causes of low-HDL cholesterol [6]. A variety of data from animals and from humans suggest that increasing the HDL cholesterol concentration is beneficial. However, the majority of patients have difficulty raising the HDL cholesterol level despite lifestyle changes and drug therapy such as niacin and fibrates. Low-HDL cholesterol is therefore a very important target for the development of novel therapies.

There is much interest in the development of new small molecules that decrease LDL cholesterol, decrease triglycerides, or raise HDL cholesterol levels. In addition, gene therapy has been considered as a potential approach to some of these targets. The purpose of this article is to review the specific lipid disorders that are potential candidates for the development of clinical gene therapy, to discuss the specific issues involved for these disorders, to summarize the proof-of-principle studies in animals where such studies exist, and to comment on the potential progress toward clinical trials of gene therapy for these disorders.

Lipid disorders that are candidates for gene therapy

Disorders associated primarily with hypercholesterolemia or...