Presented By: Center for the Discovery of New Medicines - CDNM
Drug Discovery Lecture Series — "Molecular target identification in kidney disease across disciplines and continents"
Matthias Kretzler, M.D., Warner-Lambert/Parke-Davis Professor of Internal Medicine/Nephrology and Computational Medicine and Bioinformatics, U-M Medical School
Learn how researchers at University Michigan have used a precision medicine strategy to attack chronic kidney disease —identifying new biomarkers for disease progression, and targets for drug discovery projects to develop new therapeutics.
More than 20 million Americans — 1 in 10 adults — have some level of chronic kidney disease, making the search for better diagnostic tools and new therapies a high priority for researchers.
The current biomarkers do a poor job in predicting disease progression, and patients have few options beyond burdensome dialysis or kidney transplant. Frances Collins, Director NIH, recently highlighted the importance of Matthias’s research in a recent blog post.
http://directorsblog.nih.gov/2015/12/15/pursuing-precision-medicine-for-chronic-kidney-disease/
Abstract
Chronic kidney disease, particularly DN, leads to immeasurable individual suffering, but also present unprecedented economic challenges to our society. Endstage renal disease costs, largely driven DN, consume already more than $42 Billion/year (1.2% of the federal budget of the USA). With the ongoing obesity and diabetes epidemic we can expect, with a 12-15 year delay, a tidal wave of DN overwhelming our health care system. We have to use this narrow time window to establish effective therapies to prevent or at least augment diabetic endorgan damage. Innovative approaches are needed, as DN has not seen any novel therapies introduced over the last two decades. In response to this challenge, our research team has embraced the concept of Precision Medicine and have established a global research network linked to an analytical systems biology infrastructure at U.Michigan (UM). Over the last 2 decades we have pioneered the study of molecular regulatory programs in human renal tissue to establish a molecular taxonomy of renal disease as a prerequisite for the identification of novel treatment strategies and diagnostic markers.
A critical element was the development of a standardized clinical and sample procurement protocol for integrative –omic analysis in renal disease cohort linked to a robust bioinformatics analysis pipeline I have established in the Applied Systems Biology Core I lead in the UM Kidney Translational Core Center. Sharing our innovative cohort study designs with the key leaders in nephrology allowed us to establish cohort studies for molecular disease definition in Europe (ERCB, EURenOmics), North America (CPROBE, NEPTUNE), China (Joint Renal Institute PKU-UM, NEPTUNE-China) and sub-Saharan Africa (H3-CKD-Africa). These cohorts capture the genotype-phenotype continuum of renal disease with the goal to define key molecular drivers. Taking advantage of the access to human renal biopsy tissue to study the molecular programs, our research networks have mapped the intra-renal transcriptional programs in glomerular diseases including early and progressive CKD and DN, defined murine models recapitulating human DN pathways for target validation, identified a molecular marker panel for prediction of CKD progression and mapped genetic risk loci of DN into their functional context using a systems genetics approach. Most importantly, our studies convinced Eli Lilly and Company to test Baricitinib, a Jak2 inhibitor developed for rheumatoid arthritis, for treatment of DN, moving from target identification to successful completion of aPhase II in less than 42 month (Clinicaltrials.gov:NCT01683409), a paradigm shift in clinical trials in DN towards personalized medicine in DN. The rich data sets allow to go beyond repurposing towards development of novel therapeutic targets supported by multiple lines of evidence from human studies and animal models. The CDNM is a critical partner in this effort to pursue novel targets identified by our precision medicine approach. Access to the deeply phenotyped observational cohorts around the globe for interventional trials provides the needed infrastructure to rapidly test novel or repurposed compounds in CKD and DN to meet the challenge of this global epidemic in time.
About the speaker
The overarching goal of Kretzler’s research is to define renal disease in mechanistic terms and to use this knowledge for targeted therapeutic interventions. To reach this goal, Kretzler has developed a translational research pipeline centered on integrated systems biology analysis of glomerular disease. He is the principal investigator of the U54 Nephrotic Syndrome Research Network (Neptune) in the Rare Disease Clinical Research Network II, the Data Coordinating Center for the UM1 CureGN network, and the Director of the Applied Systems Biology Core at the O’Brien Renal Center at University of Michigan. Kretlzer has 20 years of experience in integration of bioinformatics, molecular and clinical approaches in more than 150 collaborative studies on molecular analysis of renal disease.
More than 20 million Americans — 1 in 10 adults — have some level of chronic kidney disease, making the search for better diagnostic tools and new therapies a high priority for researchers.
The current biomarkers do a poor job in predicting disease progression, and patients have few options beyond burdensome dialysis or kidney transplant. Frances Collins, Director NIH, recently highlighted the importance of Matthias’s research in a recent blog post.
http://directorsblog.nih.gov/2015/12/15/pursuing-precision-medicine-for-chronic-kidney-disease/
Abstract
Chronic kidney disease, particularly DN, leads to immeasurable individual suffering, but also present unprecedented economic challenges to our society. Endstage renal disease costs, largely driven DN, consume already more than $42 Billion/year (1.2% of the federal budget of the USA). With the ongoing obesity and diabetes epidemic we can expect, with a 12-15 year delay, a tidal wave of DN overwhelming our health care system. We have to use this narrow time window to establish effective therapies to prevent or at least augment diabetic endorgan damage. Innovative approaches are needed, as DN has not seen any novel therapies introduced over the last two decades. In response to this challenge, our research team has embraced the concept of Precision Medicine and have established a global research network linked to an analytical systems biology infrastructure at U.Michigan (UM). Over the last 2 decades we have pioneered the study of molecular regulatory programs in human renal tissue to establish a molecular taxonomy of renal disease as a prerequisite for the identification of novel treatment strategies and diagnostic markers.
A critical element was the development of a standardized clinical and sample procurement protocol for integrative –omic analysis in renal disease cohort linked to a robust bioinformatics analysis pipeline I have established in the Applied Systems Biology Core I lead in the UM Kidney Translational Core Center. Sharing our innovative cohort study designs with the key leaders in nephrology allowed us to establish cohort studies for molecular disease definition in Europe (ERCB, EURenOmics), North America (CPROBE, NEPTUNE), China (Joint Renal Institute PKU-UM, NEPTUNE-China) and sub-Saharan Africa (H3-CKD-Africa). These cohorts capture the genotype-phenotype continuum of renal disease with the goal to define key molecular drivers. Taking advantage of the access to human renal biopsy tissue to study the molecular programs, our research networks have mapped the intra-renal transcriptional programs in glomerular diseases including early and progressive CKD and DN, defined murine models recapitulating human DN pathways for target validation, identified a molecular marker panel for prediction of CKD progression and mapped genetic risk loci of DN into their functional context using a systems genetics approach. Most importantly, our studies convinced Eli Lilly and Company to test Baricitinib, a Jak2 inhibitor developed for rheumatoid arthritis, for treatment of DN, moving from target identification to successful completion of aPhase II in less than 42 month (Clinicaltrials.gov:NCT01683409), a paradigm shift in clinical trials in DN towards personalized medicine in DN. The rich data sets allow to go beyond repurposing towards development of novel therapeutic targets supported by multiple lines of evidence from human studies and animal models. The CDNM is a critical partner in this effort to pursue novel targets identified by our precision medicine approach. Access to the deeply phenotyped observational cohorts around the globe for interventional trials provides the needed infrastructure to rapidly test novel or repurposed compounds in CKD and DN to meet the challenge of this global epidemic in time.
About the speaker
The overarching goal of Kretzler’s research is to define renal disease in mechanistic terms and to use this knowledge for targeted therapeutic interventions. To reach this goal, Kretzler has developed a translational research pipeline centered on integrated systems biology analysis of glomerular disease. He is the principal investigator of the U54 Nephrotic Syndrome Research Network (Neptune) in the Rare Disease Clinical Research Network II, the Data Coordinating Center for the UM1 CureGN network, and the Director of the Applied Systems Biology Core at the O’Brien Renal Center at University of Michigan. Kretlzer has 20 years of experience in integration of bioinformatics, molecular and clinical approaches in more than 150 collaborative studies on molecular analysis of renal disease.
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