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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:
Overview
The Unmet Need Driving Research Into Lowering LDL
Investigational Therapies
Inhibition of Apolipoprotein B production
Apolipoprotein B (apo B) is a large protein that is present in all atherogenic lipoproteins i.e., VLDL, LDL, IDL. There is a single copy of apo B-100 in all these lipoproteins, therefore plasma levels of apo B-100 is proportionate to the concentration of circulating atherogenic lipoproteins and a predictor of cardiovascular risk.[1] From the apoB gene, the liver synthesizes apo B-100; and the intestine synthesizes apo B-48 which is required for chylomicron assemly and fat absorption. The apo B-100 serves two functions - provides structural stability to the circulating lipoproteins as well as acts as a ligand for LDL receptors (LDLR). The removal of LDL from the plasma involves the binding of apo B to LDLR, then, the resulting apo B-100-LDLR complex gets internalized into the liver for processing.[2] Mutations that lower the affinity of apo B-100 for LDLR result in decreased clearance of LDLs, a condition known as familial defective apo B with an increased risk of atherosclerotic cardiovascular diseases.[3][4] In contrast, mutations in apo B that decrease its translation or secretion, or increase its breakdown have been demonstrated to reduce the circulating LDL-C and improve cardiovascular risk.[5]
The DNA contains two strands - 'sense' and 'antisense' which run complementary to each other. The antisense strand encodes a sequence of events that initiates protein synthesis and production of messenger RNA (mRNA) which later serves as a template for protein synthesis through a process called translation. Antisense oligoneucleotides (ASOs) are short, deoxyribonucleotide strands which bind to the targeted mRNAs to inhibit gene expression. They can inhibit mRNA translation and mRNA splicing leading to its enzymatic degradation by ribonuclease (RNAse H or argonaute 2); inhibit translation or prevent the maturation of mRNA.[6]
ISIS 301012 or mipomersen, by ISIS Pharmaceuticals, is a second-generation 20 nucleotide ASO which selectively inhibits apo B gene expression via RNAse H activation.[7] Phases I and II clinical trials have demonstrated a dose-dependent reduction of plasma apo B levels by 40% and up to 50% reduction in LDL-C of a subcutaneously administered ISIS-301012 or mipomersen, even with a defective LDLR.[8][9][10] Furthermore, a phase III randomized clinical trial involving homozygous FH revealed a 15% elevation in HDL-C.[11] Despite its efficacy in lowering LDL-C, its approval have been hampered with the development of adverse effects - injection site reactions (80-100% of patients), flu-like illness, and 3-fold elevation in liver transaminases (15%).
PCSK9 Inhibition
Monoclonal Antibodies
Antisense Oligonucleotides (ASO)
Small Interfering RNAs (SiRNAs)
Microsomal Triglyceride Transfer Protein (MTP) Inhibition
Thyromimetics
Squalene Synthase Inhibition
Table
| Class | Drug Company | Agent Name | Mechanism of Action | Efficacy on Lowering LDL-C | Route of Administration | Adverse Effects | Published Clinical Trials |
|---|---|---|---|---|---|---|---|
| Inhibition of Apo B | |||||||
| PCSK9 Inhibition | |||||||
| MTP Inhibition | |||||||
| Thyromimetics | |||||||
| Squalene Synthase Inhibitors | |||||||
References
- ↑ van der Steeg, WA.; Boekholdt, SM.; Stein, EA.; El-Harchaoui, K.; Stroes, ES.; Sandhu, MS.; Wareham, NJ.; Jukema, JW.; Luben, R. (2007). "Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk". Ann Intern Med. 146 (9): 640–8. PMID 17470832. Unknown parameter
|month=ignored (help) - ↑ Hussain, MM.; Strickland, DK.; Bakillah, A. (1999). "The mammalian low-density lipoprotein receptor family". Annu Rev Nutr. 19: 141–72. doi:10.1146/annurev.nutr.19.1.141. PMID 10448520.
- ↑ Humphries, SE.; Whittall, RA.; Hubbart, CS.; Maplebeck, S.; Cooper, JA.; Soutar, AK.; Naoumova, R.; Thompson, GR.; Seed, M. (2006). "Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk". J Med Genet. 43 (12): 943–9. doi:10.1136/jmg.2006.038356. PMID 17142622. Unknown parameter
|month=ignored (help) - ↑ Marsh, JB.; Welty, FK.; Lichtenstein, AH.; Lamon-Fava, S.; Schaefer, EJ. (2002). "Apolipoprotein B metabolism in humans: studies with stable isotope-labeled amino acid precursors". Atherosclerosis. 162 (2): 227–44. PMID 11996942. Unknown parameter
|month=ignored (help) - ↑ Schonfeld, G.; Lin, X.; Yue, P. (2005). "Familial hypobetalipoproteinemia: genetics and metabolism". Cell Mol Life Sci. 62 (12): 1372–8. doi:10.1007/s00018-005-4473-0. PMID 15818469. Unknown parameter
|month=ignored (help) - ↑ Bennett, CF.; Swayze, EE. (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annu Rev Pharmacol Toxicol. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
- ↑ Ito, MK. (2007). "ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense?". Ann Pharmacother. 41 (10): 1669–78. doi:10.1345/aph.1K065. PMID 17848425. Unknown parameter
|month=ignored (help) - ↑ Kastelein, JJ.; Wedel, MK.; Baker, BF.; Su, J.; Bradley, JD.; Yu, RZ.; Chuang, E.; Graham, MJ.; Crooke, RM. (2006). "Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.". Circulation. 114 (16): 1729–35. doi:10.1161/CIRCULATIONAHA.105.606442. PMID 17030687. Unknown parameter
|month=ignored (help) - ↑ Akdim, F.; Visser, ME.; Tribble, DL.; Baker, BF.; Stroes, ES.; Yu, R.; Flaim, JD.; Su, J.; Stein, EA. (2010). "Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia". Am J Cardiol. 105 (10): 1413–9. doi:10.1016/j.amjcard.2010.01.003. PMID 20451687. Unknown parameter
|month=ignored (help) - ↑ Akdim, F.; Tribble, DL.; Flaim, JD.; Yu, R.; Su, J.; Geary, RS.; Baker, BF.; Fuhr, R.; Wedel, MK. (2011). "Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia". Eur Heart J. 32 (21): 2650–9. doi:10.1093/eurheartj/ehr148. PMID 21593041. Unknown parameter
|month=ignored (help) - ↑ Raal, FJ.; Santos, RD.; Blom, DJ.; Marais, AD.; Charng, MJ.; Cromwell, WC.; Lachmann, RH.; Gaudet, D.; Tan, JL. (2010). "Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial". Lancet. 375 (9719): 998–1006. doi:10.1016/S0140-6736(10)60284-X. PMID 20227758. Unknown parameter
|month=ignored (help)