Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 7, Issue 3, 2009

We are pleased to introduce the September issue of Current Pharmacogenomics and Personalized Medicine (CPPM) and share with you the editorial vision of the Journal as an integrated new title addressing both pharmacogenomics and personalized medicine readership effective 2008. CPPM has a unique focus on the complex challenges and promises emerging from the fusion of knowledge domains in therapeutics and diagnostics (i.e., theragnostics) in postgenomics medicine. The Journal covers issues relating to individual and population variability in drug treatment outcomes and disease susceptibility. A firm understanding of these variability questions is a prerequisite and essential foundation to achieve the overarching goal of personalized therapeutics [1-4]. We bear in mind the increasingly globalized nature of health research and services, and the diverse technologies, stakeholders and interdisciplinary expertise that collectively drive the rapidly evolving knowledge frontiers in personalized medicine. The September issue in front of you features articles that offer a transdisciplinary synthesis of the recent developments in the field. Tikki Pang asks the question if it is “too soon”, or “just-in-time” for the developing countries to consider the applications of pharmacogenomics in dealing with priority health problems. In the face of genomics research that now extends well beyond the laboratory bench to global society [5, 6], and pandemics that do not recognize national and geographical borders [7], this article makes a timely contribution at the unique intersection of personalized medicine and global public health. Following on the latter theme, Muin Khoury provides an in-depth account of the public health genomics, a multidisciplinary field concerned with the effective and responsible applications of genome-based knowledge and technologies to improve population health.

Unprecedented advances in the genomic sciences have arrived “just in time” to help alleviate a daunting spectrum of health problems in the developing world ranging from tropical infectious diseases to non-communicable diseases to the health impacts of globalization. Pharmacogenomics and personalized medicine, applied judiciously, ethically and in the context of developing world needs and realities, can help in diagnosis, prevention and treatment of infectious and chronic diseases through new interventions, better assessment of responses to drugs, evaluation of disease susceptibility, and ultimately to more efficient health care delivery. Such applications are likely to be most relevant at the public health and population level and not in the context of ‘boutique’ medicine benefiting individuals, and should address both the curative and preventive aspects of public health strategies. Complex challenges exist for effectively integrating pharmacogenomic advances in the context of improving the efficiency of weak and fragile health care delivery systems, especially during the current global financial crisis. Pharmacogenomics will also help in the development of research and development capacity which would, in turn, enable developing countries themselves to make meaningful contributions to the advancement of the field. For benefits to be equitably realized, however, close attention needs to be given to a multitude of ethical, legal, social and policy issues which includes effective communications, building public trust, adopting a multidisciplinary approach to research, developing adequate ethical and regulatory frameworks, and involving all concerned stakeholders in decision- and policy-making.

Muin J. Khoury, MD, PhD is the first and current director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC) in the United States. The Office was formed in 1997 to assess the impact of advances in human genetics and the Human Genome Project on public health and disease prevention. As an internationally recognized institution, CDC's mission is to protect the health and safety of people, to provide credible information to enhance health decisions, and to promote health through strong national and international partnerships. For more than a decade, the CDC's Office of Public Health Genomics played an important role in development of a new hybrid field of investigation, ‘public health genomics’. In the September 2009 issue of the Current Pharmacogenomics and Personalized Medicine (CPPM), Dr. Khoury shares his thoughts and immediate and long term vision on public health genomics, and why this new field of investigation is important for personalized medicine and global health. He is interviewed by a multidisciplinary team of researchers and educators: Abdallah S. Daar (McLaughlin-Rotman Centre for Global Health and School of Public Health Sciences, University of Toronto), Serge Dubé (Department of Surgery and Faculty of Medicine, University of Montreal) and Vural Ozdemir (Editor, CPPM, and Department of Social and Preventive Medicine, Faculty of Medicine, University of Montreal). Dr. Khoury received his BS degree in biology/chemistry from the American University of Beirut, Lebanon, and his medical degree and pediatric training from the same institution. He received a PhD in human genetics/genetic epidemiology and training in medical genetics from The Johns Hopkins University. Dr. Khoury is board-certified in medical genetics.

Objective: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the “exome” (all exons) and “spliceome” (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. Methods: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. Results: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. Conclusions: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery-oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceomeprofiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry.

While human nutrigenomics research and efforts for targeted nutritional interventions intensified over the past few years, there are fundamental lessons to be learned from Drosophila and evolutionary biology for human nutrient-gene interactions. With the advent of inexpensive whole genome sequencing, single-nucleotide polymorphisms (SNPs) and insertions-deletions (INDELs) can now be associated with specific nutrient-by-genotype interactions that affect the lifespan and health of Drosophila. Because of the increase in statistical power in using inbred Drosophila lines that are freely available to investigators rather than outbred humans, the SNP and INDEL information should be invaluable to anyone interested in personal genomes and personalized medicine and nutrition. This preclinical model offers a unique opportunity to move beyond the artificial barriers among genomics, proteomics and metabolomics to integrate information from diverse omics biomarker research streams. Drosophila life span also allows an evolutionary biology perspective to forecast the long term impact of personalized nutritional interventions based on individual genetic make-up, before costly prospective clinical studies in humans are initiated. The aim of this paper is to present a critical synthesis of the ongoing work in the field of evolutionary biology in Drosophila models as a complement to human nutrigenomics. In addition, we present and synthesize several key promises and challenges in extrapolation of data from Drosophila to humans, and identify specific strategies to optimize this timely confluence of preclinical and clinical nutrigenomics research.

Nutrigenomics covers disparate fields of nutrition science and has been defined in many different ways. In fact, this emerging field of science has multiple facets, many of which do not generate the same ethical issues. In particular, different ethical issues emerge concerning the extent to which nutrigenomics may actually improve global health, i.e., in terms of worldwide improvement of health, reduction of disparities, and protection against global threats that disregard national borders. Nutrigenomics raises many hopes and expectations on that score. However, it remains unclear and controversial whether nutrigenomics studies and their actual or potential applications will actually benefit developing countries and their populations. Different forces may drive the choice of research priorities and shape the claims that are made when communicating the goals or the results of nutrigenomics studies and applications. This article proposes to assess expectations and claims in nutrigenomics, with respect to their respective potential impact on global health and the ethical issues they raise. Nutrigenomics is and should be more than premature claims and much debated promises about personalized nutritional interventions on individuals. Beyond questionable commercial claims, nutrigenomics is also knowledge about and recognition of the considerable impacts of underfeeding and malnutrition on the genome (and epigenome) integrity and stability. As such, nutrigenomics research is a valuable opportunity to revive and give strength to the debate about the unacceptable consequences of hunger and malnutrition worldwide, and to support a newly and potentially significant convergence in research priorities that could benefit both developed and developing countries.

Diabetic retinopathy is a leading cause of blindness in the Western world. However, treatment options for diabetic retinopathy are limited and display poor efficacy with marked patient-to-patient variation in therapeutic outcomes. Discovery of new molecular entities acting on mechanistically novel biological pathways remains as one of the key research priorities in diabetic retinopathy. Moreover, given the variable success of the existing treatment modalities, a targeted and personalized drug development strategy could be more fruitful for rational and successful transition of preclinical discoveries to the clinical realm. This review is focused on cannabidiol, a non-psychoactive native cannabinoid, as an emerging and novel therapeutic modality based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy - one of the retinal diseases associated with vascular neuroinflammation. We present the postulated and preclinically documented novel mechanisms that may underlie cannabidiol mode of action in diabetic retinopathy. We discuss the interindividual variation in pharmacokinetic pathways as well as in the SLC29A1 gene, a molecular target for cannabidiol. We emphasize that the novel mode of action of cannabidiol and the previous failures with nontargeted interventions in diabetic retinopathy collectively demand a more rational and personalized clinical development strategy for compounds that have shown promise at the preclinical stage. Moreover, it is noteworthy that ophthalmology, as a medical specialty, has fewer examples (e.g., compared to oncology) of personalized medicine and biomarker applications thus far. Understanding the biological action of cannabidiol in preclinical studies is therefore a rational first step to proactively map the pertinent biomarker strategies in clinical proof of concept studies in diabetic retinopathy, and to allow advances at the hitherto neglected intersection of personalized medicine and ophthalmology.

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