novel therapeutic target of pcsk9
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Evolving Scientific Insights into the
Novel Therapeutic Target of PCSK9
Prof. John J.P. Kastelein, MD PhD FESC
Dept. of Vascular Medicine
Academic Medical Center / University of Amsterdam
The Netherlands
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PCSK9: Protein and Function
PCSK9: The Enzyme Proprotein Convertase Subtilisin Kexin type 9
Lambert et al. (2009) Atherosclerosis
H N S
PCSK9: The Chaperone
(Binds to the LDLR)
EGFA
domain
PCSK9 LDLR
CHRD
Prodomain
Catalytic
domain
Seidah et al. (2014) Circ Res
Endocytosis
PCSK9-LDLR Binding LDLR Conformation
Kd=750±80nM (at pH 7,5) Open (at pH 7,5)
Kd= 10±1nM (at pH 5,5) Closed (at pH 5,5) alone
Open (at pH5,5) bound to PCSK9 Surdo et al. (2011) EMBO Reports
PCSK9 Targets the LDLR to the Lysosome for
Degradation
LDLR Endosome Merge
+ P
CS
K9
PCSK9 Reduces LDLR Cell Surface Expression
Dose Dependently
MFI: median fluorescence intensity
* p<0,05, ** p<0,01 vs. condition no PCSK9 (0)
Lambert et al. (2014) J Am Coll Cardiol
PCSK9:
A Natural Inhibitor of the LDL Receptor
Lambert et al. (2012) J. Lipid Res.
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PCSK9: Genetics and
Consequences
GOF and LOF in the PCSK9 gene
Davignon, J et al. 2010 Curr. Athero Reports 12: 308-315
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PCSK9: Gain of Function
PCSK9: Gain of Function Mutations
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PCSK9 Gain of Function Mutations:
Clinical Phenotype
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● FH-associated pathognomonic clinical signs
● Coronary artery disease
● Premature myocardial infarction
● Stroke
FH caused by PCSK9 GOF mutations leads to a
clinical phenotype similar to that due to
mutations in the LDL-R and ApoB genes
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PCSK9: Loss of Function
PCSK9 Loss of Function Mutations:
Clinical Phenotype
14Cohen et al. NEJM 2006;354:1264-72
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Kathiresan S. N Engl J Med 2008; 358:2299-2300
PCSK9 R46L Reduces Risk of Early-Onset MI in
European and American Cohorts
Replication of Findings on PCSK9 R46L and
C679X for Reduced CAD risk in 56,000
Caucasians and Blacks
Peloso GM et al. Am J Hum Genet 2014;94:223-32
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AJHG 2006;79:514-2332 yo woman Compound heterozygote for 2 LOF alleles in PCSK9LDL-C 0.36 mmol/LFertile, college educated, physically coordinated (fitness instructor)
Atherosclerosis 2007;193:445-8African womanHomozygous C679XLDL-C 0.40 mmol/LHealthy with children
PCSK9 Loss of Function Mutations and very low LDL-C from Birth
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PCSK9: Target for
Pharmacotherapy?
Target Identification by Genetics:
PCSK9
19Schunkert H et al. Nature Genetics 2011;43:333-338
Manhattan Plot of the 13 Susceptibility
Loci for CAD
20Schunkert H et al. Nature Genetics 2011;43:333-338
• PCSK9 is a natural circulating inhibitor of the LDLR that targets the receptor for degradation following endocytosis.
• PCSK9 and LDLR genes are co-regulated by intracellular cholesterol content and statin treatment.
• Targeting plasma PCSK9 is conceptually a promising approach to lower LDL-C levels in monotherapy as well as on top of statins.
• Phase III trials of Alirocumab and Evolocumab indicate a reduction of CVD risk.
PCSK9 in Brief:
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