Personalized Medicine in Ophthalmology: From Pharmacogenetic Biomarkers to Therapeutic and Dosage Optimization.
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ABSTRACT:
SUBMITTER: Ong FS
PROVIDER: S-EPMC3947950 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4-ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR-ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RAR? for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia.
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Project description:Ophthalmology has been an early adopter of personalized medicine. Drawing on genomic advances to improve molecular diagnosis, such as next-generation sequencing, and basic and translational research to develop novel therapies, application of genetic technologies in ophthalmology now heralds development of gene replacement therapies for some inherited monogenic eye diseases. It also promises to alter prediction, diagnosis and management of the complex disease age-related macular degeneration. Personalized ophthalmology is underpinned by an understanding of the molecular basis of eye disease. Two important areas of focus are required for adoption of personalized approaches: disease stratification and individualization. Disease stratification relies on phenotypic and genetic assessment leading to molecular diagnosis; individualization encompasses all aspects of patient management from optimized genetic counseling and conventional therapies to trials of novel DNA-based therapies. This review discusses the clinical implications of these twin strategies. Advantages and implications of genetic testing for patients with inherited eye diseases, choice of molecular diagnostic modality, drivers for adoption of personalized ophthalmology, service planning implications, ethical considerations and future challenges are considered. Indeed, whilst many difficulties remain, personalized ophthalmology truly has the potential to revolutionize the specialty.
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Project description:BackgroundStudies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).ObjectivesWe conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.Data sourcesOriginal research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.Study appraisal and synthesis methodsStudy characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.ResultsFrom 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of >or=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.Conclusions and implications of key findingsThe high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered.
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Project description:IntroductionThe heritability of alcohol use disorder (AUD) is estimated to be ~50%; however, the genetic basis of the disease is still poorly understood. The genetic variants identified thus far only explain a small percentage of AUD phenotypic variability. While genome-wide association studies (GWAS) are impacted by technical and methodological limitations, genetic variants that have been identified independently of GWAS findings can moderate the efficacy of AUD medications.Areas coveredThis review discusses findings from clinical pharmacogenetic studies of AUD medications. While the pharmacogenetic studies reviewed involve several genetic variants in the major neurotransmitter systems, genetic loci in the opioid system have garnered the most attention.Expert opinionThe clinical utility of pharmacogenetics in AUD populations is uncertain at this time. There are several ongoing prospective clinical trials that will enhance knowledge regarding the applicability of pharmacogenetics in clinical populations. We recommend that future work in this area consider reverse translating from genotype to phenotype, mapping genes to stages of the addiction cycle, mapping genes to neural circuits, and harnessing large population-based cohorts.
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Project description:Thyroid over-activity or hyperthyroidism constitutes a significant morbidity afflicting the world. The current medical practice of dose titration of anti-thyroid drug (ATD) treatment for hyperthyroidism is relatively archaic, being based on arbitrary and time-consuming trending of thyroid function that requires multiple clinic monitoring visits before an optimal dose is found. This prompts a re-examination into more deterministic and efficient treatment approaches in the present personalized medicine era. Our research project seeks to develop a personalized medicine model that facilitates optimal drug dosing via the titration regimen. We analysed 49 patients' data consisting of drug dosage, time period and serum free thyroxine (FT4). Ordinary differential equation modelling was applied to describe the dynamic behaviour of FT4 concentration. With each patient's data, an optimization model was developed to determine parameters of synthesis rate, decay rate and IC50. We derived the closed-form time- and dose-dependent solution which allowed explicit estimates of personalized predicted FT4. Our equation system involving time, drug dosage and FT4 can be solved for any variable provided the values of the other two are known. Compared against actual FT4 data within a tolerance, we demonstrated the feasibility of predicting the FT4 subsequent to any prescribed dose of ATD with favourable accuracy using the initial three to five patient-visits' data respectively. This proposed mathematical model may assist clinicians in rapid determination of optimal ATD doses within allowable prescription limits to achieve any desired FT4 within a specified treatment period to accelerate the attainment of euthyroid targets.
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Project description:The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution.
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Project description:Personalized medicine, otherwise called stratified or precision medicine, aims to better target intervention to the individual to maximize benefit and minimize harm. This review discusses how diabetes aetiology, pathophysiology and patient genotype influence response to or side effects of the commonly used diabetes treatments. C-peptide is a useful biomarker that is underused to guide treatment choice, severe insulin deficiency predicts non-response to glucagon-like peptide-1 receptor agonists, and thiazolidinediones are more effective in insulin-resistant patients. The field of pharmacogenetics is now yielding clinically important results, with three examples outlined: sulphonylurea sensitivity in patients with HNF1A maturity-onset diabetes of the young; sulphonylurea sensitivity in patients with Type 2 diabetes with reduced function alleles at CYP2C9, resulting in reduced metabolism of sulphonylureas; and severe metformin intolerance associated with reduced function organic cation transporter 1 (OCT1) variants, exacerbated by drugs that also inhibit OCT1. Genome-wide approaches and the potential of other 'omics', including metagenomics and metabolomics, are then outlined, highlighting the complex interacting networks that we need to understand before we can truly personalize diabetes treatments.
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Project description:BackgroundThe use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost-effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing.MethodsA systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument.ResultsIn the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost-effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost-savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated.ConclusionPharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.
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Project description:Myasthenia gravis (MG) is an autoimmune disease caused by antibodies which attack receptors at the neuromuscular junction. One of the main difficulties in predicting the clinical course of MG is the heterogeneity of the disease, where disease progression differs greatly depending on the subgroup that the patient is classified into. MG subgroups are classified according to: age of onset [early-onset MG (EOMG; onset ? 50 years) versus late-onset MG (LOMG; onset > 50 years]; the presence of a thymoma (thymoma-associated MG); antibody subtype [acetylcholine receptor antibody seropositive (AChR+) and muscle-specific tyrosine kinase antibody seropositive (MuSK+)]; as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue score, do not necessarily reflect disease progression. Hence, there is a great need for reliable objective biomarkers in MG to follow the disease course as well as the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patients' sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, the miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decrease in accordance with the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody-seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.
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