PCSK9 inhibition: Difference between revisions
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The role of PCSK9 was first discovered in 2003 when the cause of [[familial hypercholesterolemia]] in some french families was found to be associated with a 'gain of function' mutation of PCSK9 gene.<ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June|pmid = 12730697 | doi = 10.1038/ng1161 }}</ref> Two years later, a causative association was found between 'loss of function mutations in PCSK9 and low LDL-C levels in 2% of the African-American population but rare in European Americans (<0.1%), and were associated with a 40% reduction in plasma levels of LDL cholesterol.<ref name="Cohen-2005">{{Cite journal | last1 = Cohen | first1 = J. | last2 = Pertsemlidis | first2 = A. | last3 = Kotowski | first3 = IK. | last4 = Graham | first4 = R. | last5 = Garcia | first5 = CK. | last6 = Hobbs | first6 = HH. | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. | journal = Nat Genet | volume = 37 | issue = 2 | pages = 161-5 | month = Feb | year = 2005 | doi = 10.1038/ng1509 | PMID = 15654334 }}</ref> | The role of PCSK9 was first discovered in 2003 when the cause of [[familial hypercholesterolemia]] in some french families was found to be associated with a 'gain of function' mutation of PCSK9 gene.<ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June|pmid = 12730697 | doi = 10.1038/ng1161 }}</ref> Two years later, a causative association was found between 'loss of function mutations in PCSK9 and low LDL-C levels in 2% of the African-American population but rare in European Americans (<0.1%), and were associated with a 40% reduction in plasma levels of LDL cholesterol.<ref name="Cohen-2005">{{Cite journal | last1 = Cohen | first1 = J. | last2 = Pertsemlidis | first2 = A. | last3 = Kotowski | first3 = IK. | last4 = Graham | first4 = R. | last5 = Garcia | first5 = CK. | last6 = Hobbs | first6 = HH. | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. | journal = Nat Genet | volume = 37 | issue = 2 | pages = 161-5 | month = Feb | year = 2005 | doi = 10.1038/ng1509 | PMID = 15654334 }}</ref> | ||
== Structure and Function== | == Structure and Function== | ||
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease that in humans is encoded by the PCSK9 [[gene]].<ref name=seidah>{{cite journal | author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 |doi = 10.1073/pnas.0335507100 }}</ref> PCSK9 encodes a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.<ref name="Zaid-2008">{{Cite journal | last1 = Zaid | first1 = A. | last2 = Roubtsova | first2 = A. | last3 = Essalmani | first3 = R. | last4 = Marcinkiewicz | first4 = J. | last5 = Chamberland | first5 = A. | last6 = Hamelin | first6 = J. | last7 = Tremblay | first7 = M. | last8 = Jacques | first8 = H. | last9 = Jin | first9 = W. | title = Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. | journal = Hepatology | volume = 48 | issue = 2 | pages = 646-54 | month = Aug | year = 2008 | doi = 10.1002/hep.22354 | PMID = 18666258 }}</ref> This gene encodes a [[proprotein convertase]] belonging to the [[proteinase K]] subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble [[zymogen]] that undergoes autocatalytic intramolecular processing in the [[endoplasmic reticulum]]. The protein may function as a [[proprotein convertase]]. This protein plays a major regulatory role in [[cholesterol]] homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of [[low-density lipoproteins]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol | title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol | author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref> PCSK9 | Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease that in humans is encoded by the PCSK9 [[gene]].<ref name=seidah>{{cite journal | author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 |doi = 10.1073/pnas.0335507100 }}</ref> PCSK9 encodes a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.<ref name="Zaid-2008">{{Cite journal | last1 = Zaid | first1 = A. | last2 = Roubtsova | first2 = A. | last3 = Essalmani | first3 = R. | last4 = Marcinkiewicz | first4 = J. | last5 = Chamberland | first5 = A. | last6 = Hamelin | first6 = J. | last7 = Tremblay | first7 = M. | last8 = Jacques | first8 = H. | last9 = Jin | first9 = W. | title = Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. | journal = Hepatology | volume = 48 | issue = 2 | pages = 646-54 | month = Aug | year = 2008 | doi = 10.1002/hep.22354 | PMID = 18666258 }}</ref> This gene encodes a [[proprotein convertase]] belonging to the [[proteinase K]] subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble [[zymogen]] that undergoes autocatalytic intramolecular processing in the [[endoplasmic reticulum]]. The protein may function as a [[proprotein convertase]]. This protein plays a major regulatory role in [[cholesterol]] homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of [[low-density lipoproteins]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol | title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol | author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref> PCSK9 also have a role in the differentiation of cortical neurons,<ref name=seidah>{{cite journal |author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 | doi = 10.1073/pnas.0335507100 }}</ref> and may also modulate apoB-containing lipoprotein production, independently | ||
of the LDL receptors.<ref name="Sun-2012">{{Cite journal | last1 = Sun | first1 = H. | last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. | title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol | volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref> PCSK9 and LDL recptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins | of the LDL receptors.<ref name="Sun-2012">{{Cite journal | last1 = Sun | first1 = H. | last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. | title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol | volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref> PCSK9 and LDL recptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins,<ref name="Lambert-2007">{{Cite journal | last1 = Lambert | first1 = G. | title = Unravelling the functional significance of PCSK9. | journal = Curr Opin Lipidol | volume = 18 | issue = 3 | pages = 304-9 | month = Jun | year = 2007 | doi = 10.1097/MOL.0b013e3281338531 | PMID = 17495605 }}</ref> and an experimental resistin,<ref name="Melone-2012">{{Cite journal | last1 = Melone | first1 = M. | last2 = Wilsie | first2 = L. | last3 = Palyha | first3 = O. | last4 = Strack | first4 = A. | last5 = Rashid | first5 = S. | title = Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. | journal = J Am Coll Cardiol | volume = 59 | issue = 19 | pages = 1697-705 | month = May | year = 2012 | doi = 10.1016/j.jacc.2011.11.064 | PMID = 22554600 }}</ref> which is an adipose-tissue derived adipokine. | ||
PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.<ref name=pollack>{{cite web | url =http://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | author = Pollack A | date = November 5, 2012 | work = | publisher = New York Times }}</ref> | |||
PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.<ref name=pollack>{{cite web | url =http://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | author = Pollack A | date = November 5, 2012 | work = | publisher = New York Times }}</ref> | |||
== Clinical significance == | == Clinical significance == | ||
Revision as of 17:52, 11 September 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]
Overview
Increased low-density lipoprotein cholesterol (LDL-C) levels in the plasma is associated with the development and progression of atherosclerosis and associated diseases such as myocardial infarction and stroke. LDL receptors, which are responsible for clearing LDL-C from the circulation, gets recycled back into the plasma membrane in order to bind more LDL-C. A novel approach to lipid management focuses on inhibiting a serine protease, PCSK9, which is involved in the degradation of LDL receptors subsequently preventing the binding of new LDLs to be cleared from the circulation.
Historical Perspective
The role of PCSK9 was first discovered in 2003 when the cause of familial hypercholesterolemia in some french families was found to be associated with a 'gain of function' mutation of PCSK9 gene.[1] Two years later, a causative association was found between 'loss of function mutations in PCSK9 and low LDL-C levels in 2% of the African-American population but rare in European Americans (<0.1%), and were associated with a 40% reduction in plasma levels of LDL cholesterol.[2]
Structure and Function
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease that in humans is encoded by the PCSK9 gene.[3] PCSK9 encodes a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.[4] This gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase. This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of low-density lipoproteins (LDL), which could lead to hypercholesterolemia.[5] PCSK9 also have a role in the differentiation of cortical neurons,[3] and may also modulate apoB-containing lipoprotein production, independently of the LDL receptors.[6] PCSK9 and LDL recptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins,[7] and an experimental resistin,[8] which is an adipose-tissue derived adipokine.
PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.[9]
Clinical significance
Variants of PCSK9 can reduce or increase circulating cholesterol.
LDL cholesterol is removed from the blood when it binds to LDL receptors on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to the LDL receptor, the receptor is destroyed along with the LDL. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.[9]
Some variants, which only reduce cholesterol by 15% in whites, are associated with a reduction in coronary heart disease by 50%.
Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[10][1][11] The mutations increase its protease activity, reducing LDL receptor levels and preventing the uptake of cholesterol into the cells.[1]
As a drug target
Drugs can inhibit PCSK9, and lower cholesterol much more than available drugs. It is biologically plausible that this would also lower heart attacks and other diseases caused by raised cholesterol. Studies with humans, including phase III clinical trials are now underway to find out whether PCSK9 inhibition actually does lower disease, with acceptable side effects.[12][13][14][15]
Monoclonal antibodies
A number of monoclonal antibodies that bind to PCSK9 near the catalytic domain that interact with the LDLR and hence inhibit the function of PCSK9 are currently in clinical trials. These include AMG145 (Amgen), 1D05-IgG2 (Merck & Co.), and SAR236553/REGN727 (Aventis/Regeneron).[16]
Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[17]
Gene silencing
PCSK9 antisense oligonucleotide from Isis Pharmaceuticals has been shown to increase expression of the LDLR and decrease circulating total cholesterol levels in mice.[18] A locked nucleic acid from Santaris Pharma reduced PCSK9 mRNA levels in mice.[19][20]
Alnylam Pharmaceuticals has shown in initial clinical trials positive results of ALN-PCS which acts by means of RNA interference, as an effective means of PCSK9 inhibition.[21][22]
References
- ↑ 1.0 1.1 1.2 Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697. Unknown parameter
|month=ignored (help) - ↑ Cohen, J.; Pertsemlidis, A.; Kotowski, IK.; Graham, R.; Garcia, CK.; Hobbs, HH. (2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9". Nat Genet. 37 (2): 161–5. doi:10.1038/ng1509. PMID 15654334. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. Unknown parameter
|month=ignored (help) - ↑ Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W. (2008). "Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration". Hepatology. 48 (2): 646–54. doi:10.1002/hep.22354. PMID 18666258. Unknown parameter
|month=ignored (help) - ↑ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". 2012-11-11.
- ↑ Sun, H.; Samarghandi, A.; Zhang, N.; Yao, Z.; Xiong, M.; Teng, BB. (2012). "Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor". Arterioscler Thromb Vasc Biol. 32 (7): 1585–95. doi:10.1161/ATVBAHA.112.250043. PMID 22580899. Unknown parameter
|month=ignored (help) - ↑ Lambert, G. (2007). "Unravelling the functional significance of PCSK9". Curr Opin Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605. Unknown parameter
|month=ignored (help) - ↑ Melone, M.; Wilsie, L.; Palyha, O.; Strack, A.; Rashid, S. (2012). "Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9". J Am Coll Cardiol. 59 (19): 1697–705. doi:10.1016/j.jacc.2011.11.064. PMID 22554600. Unknown parameter
|month=ignored (help) - ↑ 9.0 9.1 Pollack A (November 5, 2012). "New Drugs for Lipids Set Off Race". New York Times.
- ↑ "Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9".
- ↑ Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004). "Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1454–9. doi:10.1161/01.ATV.0000134621.14315.43. PMID 15178557. Unknown parameter
|month=ignored (help) - ↑ Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia". Drug News Perspect. 21 (6): 323–30. doi:10.1358/dnp.2008.21.6.1246795. PMID 18836590.
- ↑ Steinberg D, Witztum JL (2009). "Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257. Unknown parameter
|month=ignored (help) - ↑ Mayer G, Poirier S, Seidah NG (2008). "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels". J. Biol. Chem. 283 (46): 31791–801. doi:10.1074/jbc.M805971200. PMID 18799458. Unknown parameter
|month=ignored (help) - ↑ "Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease". Press Release. FierceBiotech. 2008-04-08. Retrieved 2010-09-18.
- ↑ Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK (2012). "The PCSK9 decade". J. Lipid Res. 53 (12): 2515–24. doi:10.1194/jlr.R026658. PMC 3494258. PMID 22811413. Unknown parameter
|month=ignored (help) - ↑
- ↑ Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (2007). "Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice". J. Lipid Res. 48 (4): 763–7. doi:10.1194/jlr.C600025-JLR200. PMID 17242417. Unknown parameter
|month=ignored (help) - ↑ Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM (2010). Deb, Sumitra, ed. "A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo". PLoS ONE. 5 (5): e10682. doi:10.1371/journal.pone.0010682. PMC 2871785. PMID 20498851.
- ↑ Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T (2012). "PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates". Mol. Ther. 20 (2): 376–81. doi:10.1038/mt.2011.260. PMC 3277239. PMID 22108858. Unknown parameter
|month=ignored (help) - ↑ "Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia". Press Release. BusinessWire. 2011-01-04. Retrieved 2011-01-04.
- ↑ Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K (2008). "Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11915–20. doi:10.1073/pnas.0805434105. PMC 2575310. PMID 18695239. Unknown parameter
|month=ignored (help)