Genomics and Cardiovascular Drug Development

Abstract

In the last half century, phenomenal advances have been made in understanding the pathophysiology of cardiovascular disease and in developing therapies to reduce cardiovascular risk. Nevertheless, cardiovascular disease remains the leading cause of death and morbidity in the industrialized world, with rapidly rising prevalence in developing countries, accounting for approximately 30% of all deaths worldwide. Since the initial availability of statin drugs in 1987, few novel cardiovascular therapies have emerged. Whereas statins reduce the mortality and morbidity from atherosclerotic heart disease by approximately 30%, the staggering 70% residual cardiovascular risk underscores the persistent need for novel therapies. Substantial advances in genomic research offer promise to greatly facilitate cardiovascular drug development. Over the past decade, often termed "the genomics revolution," such advancements as the emergence of genome-wide genotyping in humans, the industrialization of messenger ribonucleic acid expression profiling, and the maturation of proteomic and metabolomic methodologies have been made. In addition, the advancement of informatics to allow the intersection of multiple complex datasets has led to the field of systems biology. Genomic approaches are already being utilized to drive novel compound pipelines by helping with the identification and validation of novel targets. In the future, the study of genomics is expected to support biomarker discovery and development and the identification of responder patient segments. The focus of the present review is the application of genomics to the development of novel atherosclerosis therapies.

Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator

“…Therapeutic interest in CCN1 was initially triggered by a genomics study in humans, 1 which resembles the path of other investigations that have used genomic approaches to drive novel compound pipelines. 48 Before any antiinflammatory approach is undertaken, it will be crucial to delineate the distinction between acute inflammation that supports tissue repair and regeneration versus chronic inflammation without reparative advantage but that induces progressive tissue injury. With respect to the latter type of inflammation, further investigation of CCN1 as a new parent compound for immune cell migration modulation appears warranted, as well as of cRGD peptides as a first class of partially CCN1-mimetic drugs with immediate potential for clinical evaluation in cardiac disorders associated with chronic pathogenic inflammation (eg, autoimmune heart disease and cardiac transplant rejection).…”

Optimisation and Validation of a High Throughput Screening Compatible Assay to Identify Inhibitors of the Plasma Membrane Calcium ATPase Pump - a Novel Therapeutic Target for Contraception and Malaria

“…Unsurprisingly, pharmaceutical companies are suffering a shortfall in profitability and productivity [40] which is exemplified by cardiovascular R&D that was adversely affected when Pfizer withdrew cardiovascular research funding in 2008 [42]. Recently, there has been more focus on bench-to-bedside approaches, with genomic studies unveiling more promising therapeutic targets for novel therapies [43] offering potential to ATPases that are implicated in various diseases.…”

Biomarkers in Cardiovascular Clinical Trials: Past, Present, Future

“…In particular, that the process of drug development has become increasingly difficult is evidenced by the fact that since the introduction of statins in 1987, only 4 classes of major CV drugs (angiotensin receptor blockers, BNP mimics, glycoprotein IIb/IIIa inhibitors, and direct renin inhibitors) have become available (62 ). There are numerous reasons for this state of affairs, including the large costs and long timelines associated with drug development and the high attrition rates in preclinical and early clinical trials.…”

“…This approach may incorporate novel biomarkers of efficacy or risk in early-phase clinical trials as initial biological signals for moving forward with additional testing of a new compound or for using mechanistic information gleaned from the study of large sample collections from within clinical trials of specific disease states. One approach that is becoming more common is that of systems biology, the science of establishing multiple genomic datasets that may be intersected and queried with sophisticated informatics approaches in order to establish causal associations of gene pathways with disease (62 ). In addition to genetic information, this approach uses RNA profiling, proteomics, and metabolomics.…”