Review of the scientific evolution of gene therapy for the treatment of homozygous familial hypercholesterolaemia: past, present and future perspectives

Abstract

Familial hypercholesterolaemia (FH) is a devastating genetic disease that leads to extremely high cholesterol levels and severe cardiovascular disease, mainly caused by mutations in any of the main genes involved in low-density lipoprotein cholesterol (LDL-C) uptake. Among these genes, mutations in the LDL receptor (LDLR) are responsible for 80%–90% of the FH cases. The severe homozygous variety (HoFH) is not successfully treated with standard cholesterol-lowering therapies, and more aggressive strategies must be considered to mitigate the effects of this disease, such as weekly/biweekly LDL apheresis. However, development of new therapeutic approaches is needed to cure HoFH. Because HoFH is mainly due to mutations in the LDLR, this disease has been proposed as an ideal candidate for gene therapy. Several preclinical studies have proposed that the transference of functional copies of the LDLR gene reduces circulating LDL-C levels in several models of HoFH, which has led to the first clinical trials in humans. Additionally, the recent development of clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 technology for genome editing has opened the door to therapies aimed at directly correcting the specific mutation in the endogenous LDLR gene. In this article, we review the genetic basis of the FH disease, paying special attention to the severe HoFH as well as the challenges in its diagnosis and clinical management. Additionally, we discuss the current therapies for this disease and the new emerging advances in gene therapy to target a definitive cure for this disease.

Is Liver Transplant Curative in Homozygous Familial Hypercholesterolemia? A Review of Nine Global Cases

“…Gene therapies for HoFH are under development and may offer new alternatives in the treatment of HoFH [ 53 ].…”

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

“…Arterial cells (macrophages, pericytes, and smooth muscle cells) take up these particles in an unregulated manner bypassing the specialized LDL receptor [3][4][5]. The mechanism of interaction of native (unmodified) LDL with a specific cell receptor is currently well known [5][6][7][8]. This interaction does not lead to excessive deposition of intracellular lipids since the lipid components of LDL are utilized by cells, and the excess is removed.…”

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

“…Two subtypes of FH are known as homozygous (HoFH) and heterozygous FH (HeFH). Recent data have shown that the incidence of homozygotic FH is 1 in 1,000,000, while HeFH is 2000 times more frequent (1:500) [ 49 ]. LT is considered to be a gold standard treatment, but it is invasive and may cause other complications [ 50 ].…”

“…LDL apheresis is another therapeutic option, limited due to high costs and difficulty to apply [ 51 ]. Furthermore, administration of statins, such as atorvastatin, only reduced the plasma LDL-C level by 10 to 25% [ 49 ].…”