Abstract
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp(a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp(a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. However, effective therapies to specifically reduce plasma Lp(a) levels are lacking. Recent animal and human studies have shown that Lp(a) can be specifically targeted with second generation antisense oligonucleotides (ASOs) that inhibit apo(a) mRNA translation. In apo(a) transgenic mice, an apo(a) ASO reduced plasma apo(a)/Lp(a) levels and their associated oxidized phospholipid (OxPL) levels by 86 and 93%, respectively. In cynomolgus monkeys, a second generation apo(a) ASO, ISIS-APO(a)Rx, significantly reduced hepatic apo(a) mRNA expression and plasma Lp(a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO(a)Rx ASO reduced Lp(a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO(a)Rx represents the first specific and potent drug in clinical development to lower Lp(a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis.
Highlights
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis
Among the various therapeutic platforms amenable to selective inhibition of Lp(a), antisense oligonucleotide (ASO) drugs have emerged as a Abbreviations: ASO, antisense oligonucleotide; h-apoB, human APOB; HDL-C, HDL cholesterol; KIV, kringle IV; KV, kringle V; LDL-C, LDL cholesterol; Lp(a), lipoprotein (a); MOE, 2′-O-(2-methoxyethyl); m/s/year, meters per second per year; OxPL, oxidized phospholipid; OxPL-apoB, oxidized phospholipid on apoB-containing lipoprotein; P=S, phosphorothioate
In light of the promising activity observed in the transgenic mouse studies described above and the desire to identify an optimized human clinical candidate, a high density screen of over 2,200 second generation ASOs designed to complementary sites spanning the entire human apo(a) transcript were tested for their ability to dose-dependently reduce apo(a) mRNA expression in transgenic LPA mouse primary hepatocytes
Summary
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. In the first described antisense study performed in vitro, a human apo(a) ribozyme oligonucleotide containing P=S DNA and RNA was designed to target KIV of the apo(a) mRNA without altering plasminogen transcript levels [28].
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