Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 9, Issue 4, 2011

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In 2011, genetic privacy bills were introduced in two US states proposing that genetic information and material are an individual's exclusive property. Using the bills as a catalyst for broader discussion, the author introduces several themes. On a primary level, the scientific, medical, and broader community should be cognizant of the bills as they may be precursors to new legislation with potential future impact on genomics and personalized medicine. Their privacythrough- property approach contains definitional ambiguities (such as using the legal phraseology of “real property”), erects barriers to research and innovation, differs conceptually and procedurally from current genetic privacy legislation, and could herald a return to reductionist genetic exceptionalism. Since genetic research and personalized medicine operate in a borderless (transnational) world where natural and social system divisions are highly porous, patchwork legislation can impede advancement of knowledge transfer, health outcome delivery, and international harmonization and coordination. While these are US bills, they can set precedence with potential traction in globally networked innovation ecosystems that share, and are shaped by, legislation and international norms. Too often, law and science are artificially situated in silos. Yet law is not a disembodied system of ideas; it is a corpus embedded in a larger social structure that includes science and personalized medicine. Broader elements of society must be engaged and educated from the earliest stage of legal reform so that future legislation that impacts genomics and personalized medicine can be steered in a form more closely tuned to social values and the lessons learned from the past history of genetic/genomics research.

Proteomics, the study of entire compendium of proteins encoded by a genome, is now established as a leading technological platform for numerous areas of clinical research in personalized medicine: understanding of disease pathogenesis, detection of disease specific biomarkers and identification of novel drug and vaccine targets, to name a few. The successful integration of nanotechnology with proteomics has introduced a novel hybrid analytical platform known as “nanoproteomics”. Recent advances in the field of nanoproteomics have introduced nano-based approaches into personalized medicine and targeted therapeutics. Amongst the miscellaneous promising candidates, quantum particles, carbon nanotubes and nanowires, nanoscopic gold particles are promising for diagnostic and therapeutic applications due to their high sensitivity, versatile dynamic range, real-time monitoring power, multiplexing and high-throughput capability. Personalized medicine and targeted therapeutics are rapidly advancing frontiers of healthcare that is informed by the individual person's unique clinical, genetic, genomic, proteomic and environmental information. This paper synthesizes the promising applications of nanoproteomic technologies in context of personalized medicine and molecular therapeutics as well as its impacts on clinical research. Finally, we share our recent experience in employing nanoproteomics technology platforms in India. We provide an outlook of why proteomics-based approaches might offer unique and complementary advantages in personalized medicine R&D that has hitherto relied to a large extent on genomics technology platforms. We conclude that genomics and nanoproteomics, when used in combination, can be a powerful approach that can propel personalized healthcare from the discovery lab to clinic and global public health practice.

A properly validated biological marker (biomarker) would offer undeniable value as a prognostic or diagnostic indicator of a disorder and/or its response to a therapeutic intervention. However, upon their discovery, a biomarker candidate must traverse a rigorous and exhaustive testing protocol aimed to challenge the validity of its proposed application. This validation trajectory establishes both the quality of a biomarker's analytical testing protocol and the efficacy of its clinical utilization. The successful completion of such testing is a requisite for the acceptance of a biomarker's intended surrogacy. Such testing also prevents the premature translation of invalid putative markers into an environment in which they may inflict unintended harm to a patient or public health more generally. To aid in their potential clinical translation, numerous publications have described detailed evaluation and validation protocols for putative biomarkers. These also serve as an aid to prevent promising putative indicators from being lost in the often complex bench-to-bedside translation and/or drug development process. However, convergent and divergent views do remain among stakeholders in terms of the evidentiary framework(s) that should be applied on the biomarker innovation trajectory. Such guidelines, policy statements and recommendations detail and shape the relevant tenets for biomarker assessment and validation. An overview of these analytical and clinical schemas and their experimental principles are provided in this paper. Such protocols represent examples of both the fundamental research required for evaluating newly discovered putative biomarkers and the scientific community's attempts to bridge the current translation chasm facing biomarker research on the critical path to personalized medicine. Further, these concepts are directly applicable to parallel personalized medicine and biomarker research being undertaken in developing countries and resource limited settings.

Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of ‘hepatic pharmacogenes’ such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.

In pharmacogenomics studies, the analysis of gene-gene interactions increasingly plays a crucial role in characterizing a phenotypic trait that involves complex pharmacological mechanisms. Genetic association studies using individual genes may overlook the significant associations which can only be identified when the combinations of multiple genomic loci are employed. Indeed, by employing the candidate-gene approach and the genome-wide association study (GWAS) design, accumulating evidence reveals that certain genetic variants could affect clinical drug response and side effects for antipsychotic drugs in patients with schizophrenia, when gene-gene interactions are taken into account. This is particularly the case for schizophrenia therapeutics wherein pharmacogenomics has been intensively applied in the past two decades. The mainstay treatment for schizophrenia, a devastating disorder that affects nearly 1% of the world population, is the antipsychotic medications. Some of the most notable side effects of antipsychotic therapy include metabolic syndrome, obesity, tardive dyskinesia, restless legs syndrome, drug-induced parkinsonism, and drug-induced QT prolongation. This paper provides a synthesis of the findings from candidate gene studies of antipsychotics, with special emphasis on the importance of gene-gene interactions. For example, the interactions of two insulin-induced genes, designated INSIG1 and INSIG2, were found to be associated with metabolic syndrome in schizophrenic patients treated with antipsychotics. Furthermore, we summarize the pharmacogenomics studies with the GWAS approach for antipsychotic therapy. To this end, we discuss the recent advances in GWAS and gene-gene interaction studies conducted in Asia-Pacific populations by the public and private sectors. Finally, we address the strategic directions and challenges concerning pharmacogenomics studies of antipsychotics drawing from our experience both in the Asia-Pacific and internationally.

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