Splice correction therapies for familial hypercholesterolemic patients with low-density lipoprotein receptor mutations

Abstract

Purpose of review Antisense oligomers (ASOs) have been available for decades: however, only recently have these molecules been applied clinically. This review aims to discuss the possible development of antisense-mediated splice correction therapies as precision medicines for familial hypercholesterolemic patients carrying mutations that compromise normal splicing of the low-density lipoprotein receptor ( LDLR ) gene transcript. Recent findings Three antisense drugs are currently being assessed in ongoing clinical trials for dyslipidemias, aiming to lower the plasma concentrations of lipoproteins that lead to end-organ damage, principally coronary artery disease. Although a handful of drugs may be applicable to many patients with familial hypercholesterolemia (FH), mutation-specific personalised antisense drugs may be even more effective in selected patients. Currently, there is no therapy that effectively addresses mutations in the LDLR , the major cause of FH. Many mutations in the LDLR that disrupt normal pre-mRNA processing could be applicable to splice correction therapy to restore receptor activity. Summary Precision medicine could provide long-term economic and social benefits if they can be implemented effectively and sustainably. Many mutations found in the LDLR gene could be amendable to therapeutic splice correction and we should consider developing a therapeutic ASO platform for these mutations.

Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin

“…Volanoesorsen is a highly effective ASO agent designed to reduce elevated triglycerides in familial chylomicronemia syndrome (Lazarte and Hegele, 2021). Splice correction ASOs are also under investigation for the treatment of FH patients with mutations in LDL-R gene (McIntosh et al, 2021). Inclisiran (brand LEQVIO) was developed by Alnylam and marketed by Novartis, which received approval by the FDA in December 2021 for the treatment of heterozygous FH and ASCVD for adult patients to lower LDL-C (Lamb, 2021).…”

LDLR gene variant rs688 TT genotype; genetic association with obesity in Familial Hypercholesterolemia patients

“…The main aim of this present study was to explore whether the single nucleotide polymorphism rs688 in the LDLR gene is associated with the development of obesity in familial hypercholesterolemia patients. The variant rs688 of LDLR gene plays rule as a modulator for alterative exon splicing, due to which there occurs shift in the reading frame along with gene transcript alteration and have been testified to cause familial hypercholesterolemia (McIntosh, 2021). Therefore, this study figures out the frequency of LDLR (rs688C > T) gene polymorphism in obese familial hypercholesterolemia patients.…”