Low density lipoprotein future or investigational therapies
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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. 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.
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)