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

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.

Download Full-text

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia

Cholesterol ◽

10.1155/2017/9375818 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

V. A. Korneva ◽

T. Yu. Kuznetsova ◽

T. Yu. Bogoslovskaya ◽

D. S. Polyakov ◽

V. B. Vasilyev ◽

...

Keyword(s):

Ldl Cholesterol ◽

Familial Hypercholesterolaemia ◽

Receptor Gene ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Gene Mutations ◽

Density Lipoprotein ◽

Single Strand Conformation Polymorphism ◽

Polymorphism Analysis ◽

Cholesterol Levels

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

Download Full-text

Diagnosis of Familial Hypercholesterolaemia Using DNA Probes for the Low-Density Lipoprotein (LDL) Receptor Gene

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328802500203 ◽

1988 ◽

Vol 25 (2) ◽

pp. 142-149 ◽

Cited By ~ 3

Author(s):

A E Armston ◽

S A Iversen ◽

J F Burke

Keyword(s):

Heart Disease ◽

Familial Hypercholesterolaemia ◽

Recombinant Dna ◽

Receptor Gene ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Recombinant Dna Technology ◽

Cholesterol Levels ◽

Dna Technology

Familial hypercholesterolaemia (FH) is one of the most commonly inherited diseases. It is characterised by an abnormal LDL receptor resulting in a selective elevation of serum LDL and cholesterol levels. The correlation between FH and premature heart disease means that these patients contribute significantly to the number of individuals presenting with coronary heart disease. In the work described here cDNA probes to LDL-receptor were used to assess the usefulness of recombinant DNA technology to diagnose familial hypercholesterolaemia. A 3′ probe to the LDL-receptor which detects a restriction fragment length polymorphism (RFLP) in linkage disequilibrium with normal and mutant LDL-receptor genes, was found to be potentially informative in 20% of the families studied. In addition a 5′ probe to the LDL-receptor may be capable of directly detecting mutations in some 6% of families. We suggest that until further work has established other RFLP's or oligonucleotide probes are synthesised to directly detect mutant LDL-receptor genes, recombinant DNA technology is only of limited value for diagnosing familial hypercholesterolaemia.

Download Full-text

Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades

Cardiology in the Young ◽

10.1017/s1047951113000528 ◽

2013 ◽

Vol 24 (3) ◽

pp. 437-441 ◽

Cited By ~ 9

Author(s):

Avishay Elis ◽

Rong Zhou ◽

Evan A. Stein

Keyword(s):

Children And Adolescents ◽

Familial Hypercholesterolaemia ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Cholesterol Levels ◽

Heterozygous Familial Hypercholesterolaemia

AbstractBackground:This study evaluated the effectiveness of long-term intensive lipid-lowering therapy in children and adolescents with familial hypercholesterolaemia.Methods:The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ∼1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia.Results:Of the 89 patients, 51% were male; the mean age at diagnosis was 8 ± 4 years, and the mean follow-up was 13 ± 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 ± 50 and 142 ± 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation.Conclusions:Long-term statin-based therapy can reduce low-density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly.

Download Full-text

Investigation of a novel defect in patients with familial hypercholesterolaemia (FH): Identification of a protein that binds to the cytoplasmic tail of the low density lipoprotein (LDL) receptor

Atherosclerosis ◽

10.1016/s0021-9150(00)81100-4 ◽

2000 ◽

Vol 151 (1) ◽

pp. 242-243

Author(s):

J. Burden ◽

E. Eden ◽

X-M. Sun ◽

A. Soutar

Keyword(s):

Familial Hypercholesterolaemia ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Cytoplasmic Tail ◽

Low Density

Download Full-text

Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional

Human Molecular Genetics ◽

10.1093/hmg/ddz238 ◽

2019 ◽

Vol 29 (8) ◽

pp. 1229-1238

Author(s):

Thea Bismo Strøm ◽

Katrine Bjune ◽

Trond P Leren

Keyword(s):

Ligand Binding ◽

Bone Morphogenetic Protein ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Linker Region ◽

Cholesterol Levels ◽

Morphogenetic Protein ◽

Bone Morphogenetic Protein 1

Abstract The cell-surface low-density lipoprotein receptor (LDLR) internalizes low-density lipoprotein (LDL) by receptor-mediated endocytosis and plays a key role in the regulation of plasma cholesterol levels. The ligand-binding domain of the LDLR contains seven ligand-binding repeats of approximately 40 residues each. Between ligand-binding repeats 4 and 5, there is a 10-residue linker region that is subject to enzymatic cleavage. The cleaved LDLR is unable to bind LDL. In this study, we have screened a series of enzyme inhibitors in order to identify the enzyme that cleaves the linker region. These studies have identified bone morphogenetic protein 1 (BMP1) as being the cleavage enzyme. This conclusion is based upon the use of the specific BMP1 inhibitor UK 383367, silencing of the BMP1 gene by the use of siRNA or CRISPR/Cas9 technology and overexpression of wild-type BMP1 or the loss-of-function mutant E214A-BMP1. We have also shown that the propeptide of BMP1 has to be cleaved at RSRR120↓ by furin-like proprotein convertases for BMP1 to have an activity towards the LDLR. Targeting BMP1 could represent a novel strategy to increase the number of functioning LDLRs in order to lower plasma LDL cholesterol levels. However, a concern by using BMP1 inhibitors as cholesterol-lowering drugs could be the risk of side effects based on the important role of BMP1 in collagen assembly.

Download Full-text

Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism

Human Molecular Genetics ◽

10.1093/hmg/5.9.1325 ◽

1996 ◽

Vol 5 (9) ◽

pp. 1325-1331 ◽

Cited By ~ 48

Author(s):

J. Webb

Keyword(s):

Genetic Variation ◽

Branch Point ◽

Familial Hypercholesterolaemia ◽

Receptor Gene ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Mrna Splicing ◽

Low Density ◽

Rare Mutation

Download Full-text

Clinical Efficacy and Cholesterol-Lowering Effects of Inclisiran

10.5742/mewfm.2021.94166 ◽

2021 ◽

Vol 20 (11) ◽

Author(s):

Muhammad Danial bin Daud

Keyword(s):

Cardiovascular Disease ◽

Clinical Trials ◽

Clinical Efficacy ◽

Large Scale ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Cholesterol Lowering ◽

Cholesterol Levels ◽

The Uk

Inclisiran, a drug developed by Novartis, is a recent medication designed to alleviate cardiovascular disease symptoms through improving low-density lipoprotein cholesterol levels. Mechanistically, inclisiran is a chemically synthesized small interfering RNA (siRNA) molecule targeting serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9), resulting in degradation of the LDL receptor. Positive, large-scale clinical trials on the use of inclisiran demonstrate the drug’s efficacy in reducing LDL cholesterol levels in patients afflicted with cardiovascular disease. Moreover, Novartis and the National Health Services (NHS) of the UK have very recently come to an agreement (September 1st, 2021) on the drug’s utility, as the NHS has enabled inclisiran’s use in more than 300,000 patients with a history of cardiovascular disease. However, despite the promising clinical trials on inclisiran as well as its use in the UK, the U.S. Food and Drug Administration (FDA) has yet to approve the drug as a treatment strategy for cardiovascular disease. This review will analyze and discuss the clinical efficacy of inclisiran based on the recent clinical evidence for its pharmacological use in the treatment of cardiovascular diseases. Key words: Inclisiran, efficacy, cholesterol-lowering

Download Full-text

PCSK9 inhibition-based therapeutic approaches: an immunotherapy perspective

Current Medicinal Chemistry ◽

10.2174/0929867328666211027125245 ◽

2021 ◽

Vol 28 ◽

Author(s):

Amir Abbas Momtazi-Borojeni ◽

Matteo Pirro ◽

Suowen Xu ◽

Amirhossein Sahebkar

Keyword(s):

Clinical Studies ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Cost Effective ◽

Atherosclerotic Cardiovascular Disease ◽

Therapeutic Approaches ◽

Pcsk9 Inhibitors ◽

Therapeutic Tools ◽

Pcsk9 Inhibition

: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9-I) are novel therapeutic tools to decrease cardiovascular risk. These agents work by lowering the low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients who are statin resistant/intolerant. Current clinically approved and investigational PCSK9-I act generally by blocking PCSK9 activity in the plasma or suppressing its expression or secretion by hepatocytes. The most widely investigated method is the disruption of PCSK9/LDL receptor (LDLR) interaction by fully-humanized monoclonal antibodies (mAbs), evolocumab and alirocumab, which have been approved for the therapy of hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Besides, a small interfering RNA called inclisiran, which specifically suppresses PCSK9 expression in hepatocytes, is as effective as mAbs but with administration twice a year. Because of the high costs of such therapeutic approaches, several other PCSK9-I have been surveyed, including peptide-based anti-PCSK9 vaccines and small oral anti-PCSK9 molecules, which are under investigation in preclinical and phase I clinical studies. Interestingly, anti-PCSK9 vaccination has been found to serve as a more widely feasible and more cost-effective therapeutic tool over mAb PCSK9-I for managing hypercholesterolemia. The present review will discuss LDL-lowering and cardioprotective effects of PCSK9-I, mainly immunotherapy-based inhibitors including mAbs and vaccines, in preclinical and clinical studies.

Download Full-text