Overcoming Limitations in Drug Discovery with Human Genetics
Explore how human genetics could revolutionize drug discovery by leveraging naturally occurring mutations to prioritize molecular targets, with a focus on PCSK9 alleles and their impact on LDL levels and coronary heart disease.
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Presentation Transcript
Limitations in drug discovery More than 90% compounds entering clinical trials fail to demonstrate safety and efficacy in human, despite evidence of safety and effectiveness in pre- clinical models High failure rates indicate the limited ability of pre-clinical models to predict patient benefit in human populations. 1
Potential of Human genetics to overcome limitations in drug discovery Human genetics as Experiment of nature to prioritize molecular targets in drug discovery => naturally occurring conditions (mutations) that modulate (gain- or loss-of function) a biological target (gene) with reproducible effect (decreased or increased risk) on human physiology (trait = appropriate proxy for drug efficacy) -> mimic the effect of therapeutic modulation of a target -> serve as estimate of dose-response curves (function-phenotype curves) 2
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 3
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 4
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 5
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 6
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 3. PCSK9LOF alleles: protect against CHD 2006 3 4. 7
PCSK9, LDL levels and coronary heart disease 1. PCSK9GOF alleles: increased LDL levels 2003 1 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 3. PCSK9LOF alleles: protect against CHD 2006 3 4. PCSK9LOF alleles: no obvious adverse events 2006 4 8
PCSK9, LDL levels and coronary heart disease high 1. PCSK9GOF alleles: increased LDL levels 2003 1 PCSK9 GOF alleles 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 Risk of CHD 3. PCSK9LOF alleles: protect against CHD 2006 3 4. PCSK9LOF alleles: no obvious adverse events 2006 4 PCSK9 LOF alleles low low high LDL levels 9
PCSK9, LDL levels and coronary heart disease high 1. PCSK9GOF alleles: increased LDL levels 2003 1 PCSK9 GOF alleles 2. PCSK9LOF alleles: decreased LDL levels 2005-2006 2 Risk of CHD 3. PCSK9LOF alleles: protect against CHD 2006 3 4. PCSK9LOF alleles: no obvious adverse events 2006 4 5. Clinical trials: monoclonal antibody to PCSK9 2012 5 PCSK9 LOF alleles low low high LDL levels 10
