Low density lipoprotein future or investigational therapies: Difference between revisions
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==Investigational Therapies== | ==Investigational Therapies== | ||
===Inhibition of Apolipoprotein B production=== | ===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.<ref>{{Cite journal | last1 = van der Steeg | first1 = WA. | last2 = Boekholdt | first2 = SM. | last3 = Stein | first3 = EA. | last4 = El-Harchaoui | first4 = K. | last5 = Stroes | first5 = ES. | last6 = Sandhu | first6 = MS. | last7 = Wareham | first7 = NJ. | last8 = Jukema | first8 = JW. | last9 = Luben | first9 = R. | title = Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. | journal = Ann Intern Med | volume = 146 | issue = 9 | pages = 640-8 | month = May | year = 2007 | doi = | PMID = 17470832 }}</ref> From the apoB gene, the liver synthesizes apo B-100; and the intestine synthesizes apo B-48. 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.<ref name="Hussain-1999">{{Cite journal | last1 = Hussain | first1 = MM. | last2 = Strickland | first2 = DK. | last3 = Bakillah | first3 = A. | title = The mammalian low-density lipoprotein receptor family. | journal = Annu Rev Nutr | volume = 19 | issue = | pages = 141-72 | month = | year = 1999 | doi = 10.1146/annurev.nutr.19.1.141 | PMID = 10448520 }}</ref> Mutations that lower the affinity of apo B-100 for LDLR | 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.<ref>{{Cite journal | last1 = van der Steeg | first1 = WA. | last2 = Boekholdt | first2 = SM. | last3 = Stein | first3 = EA. | last4 = El-Harchaoui | first4 = K. | last5 = Stroes | first5 = ES. | last6 = Sandhu | first6 = MS. | last7 = Wareham | first7 = NJ. | last8 = Jukema | first8 = JW. | last9 = Luben | first9 = R. | title = Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. | journal = Ann Intern Med | volume = 146 | issue = 9 | pages = 640-8 | month = May | year = 2007 | doi = | PMID = 17470832 }}</ref> From the apoB gene, the liver synthesizes apo B-100; and the intestine synthesizes apo B-48. 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.<ref name="Hussain-1999">{{Cite journal | last1 = Hussain | first1 = MM. | last2 = Strickland | first2 = DK. | last3 = Bakillah | first3 = A. | title = The mammalian low-density lipoprotein receptor family. | journal = Annu Rev Nutr | volume = 19 | issue = | pages = 141-72 | month = | year = 1999 | doi = 10.1146/annurev.nutr.19.1.141 | PMID = 10448520 }}</ref> 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.<ref name="Humphries-2006">{{Cite journal | last1 = Humphries | first1 = SE. | last2 = Whittall | first2 = RA. | last3 = Hubbart | first3 = CS. | last4 = Maplebeck | first4 = S. | last5 = Cooper | first5 = JA. | last6 = Soutar | first6 = AK. | last7 = Naoumova | first7 = R. | last8 = Thompson | first8 = GR. | last9 = Seed | first9 = M. | title = Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. | journal = J Med Genet | volume = 43 | issue = 12 | pages = 943-9 | month = Dec | year = 2006 | doi = 10.1136/jmg.2006.038356 | PMID = 17142622 }}</ref> 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.<ref name="Schonfeld-2005">{{Cite journal | last1 = Schonfeld | first1 = G. | last2 = Lin | first2 = X. | last3 = Yue | first3 = P. | title = Familial hypobetalipoproteinemia: genetics and metabolism. | journal = Cell Mol Life Sci | volume = 62 | issue = 12 | pages = 1372-8 | month = Jun | year = 2005 | doi = 10.1007/s00018-005-4473-0 | PMID = 15818469 }}</ref> | ||
===PCSK9 Inhibition=== | ===PCSK9 Inhibition=== | ||
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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. 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] 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.[4]
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) - ↑ 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)