Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

ABSTRACT

Introduction: Anti-sense oligonucleotide (ASO) therapies are a new development in clinical pharmacology offering greater specificity compared to small molecule inhibitors and the ability to target intracellular process’ not susceptible to antibody-based therapies.

Areas covered: This article reviews the chemical biology of ASOs and related RNA therapeutics. It then reviews the data on their use to treat hyperlipidaemia. Data on mipomersen – an ASO to apolipoprotein B-100(apoB) licensed for treatment of homozygous familial hypercholesterolaemia (FH) is presented. Few effective therapies are available to reduce atehrogenic lipoprotein (a) levels. An ASO therapy to apolipoprotein(a) (ISIS Apo(a)_Rx) specifically reduced lipoprotein (a) levels by up to 78%. Treatment options for patients with familial chylomicronaemia syndrome (lipoprotein lipase deficiency; LPLD) or lipodystrophies are highly limited and often inadequate. Volanesorsen, an ASO to apolipoprotein C-3, shows promise in the treatment of LPLD and severe hypertriglyceridaemia as it increases clearance of triglyceride-rich lipoproteins and can normalise triglycerides in these patients.

Expert opinion: The uptake of the novel ASO therapies is likely to be limited to selected niche groups or orphan diseases. These will include homozygous FH, severe heterozygous FH for mipomersen; LPLD deficiency and lipodystrophy syndromes for volanesorsen and treatment of patients with high elevated Lp(a) levels.

KEYWORDS:

• Familial hypercholesterolaemia
• lipoprotein(a)
• lipoprotein lipase deficiency
• familial chylomcronaemia syndrome
• lipodystrophy
• angiopoietin-like protein 3 (ANGPTL3)
• antisense oligonucleotide
• treatment

Article highlights

• Antisense oligonucleotides are a novel therapeutic intervention offering unique properties compared to previous technologies

• Antisense oligonucleotides can be modified at a variety of position to improve stability in plasma and binding to target sequences

• Mipomersen- an antisense oligonucleotide to apolipoprotein B100 is licensed for the treatment of homozygous familial hypercholesterolaemia

• Antisense oligonucleotide therapy to apolipoprotein(a) substantially reduces levels of the atherogenic lipoprotein(a) in early trials

• Antisense oligonucleotide therapy to apolipoprotein C-3 (volanesorsen) adds to other approaches in the treatment of severe hypertriglyceridaemia

This box summarizes key points contained in the article.

Declaration of interest

A Viljoen has received meeting sponsorship and lecture honoraria from Amgen, SanofiAventis, Eli-Lilly and NovoNordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.