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2 The current challenges and barriers to clinical implementation of pharmacogenomics (Adapted from Scott 2011 )
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Pharmacogenomics of today has its origins in the 1950s with pioneering studies of monogenic variations in drug metabolism and pharmacokinetics. With the completion of the Human Genome Project in 2003 and the advances in genomics such as the high-throughput genomics technologies we are now in the postgenomics era. This transition is increasingly mar...
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Citations
... Since the completion of both the Human Genome Project and the International HapMap project, "omics" technologies have an important impact on pharmacogenomics leading to the development of pharmacogenetic tests for pharmacotherapy in the context of prediction and prevention of ADRs (Aydin Son et al., 2013). Accordingly, in recent years, a wealth of pharmacogenetic tests is commercially available and some of them have been approved by the Food and Drug Administration (FDA) (http://www.fda.gov) and pharmacogenetic information was added to several drug labels. ...
A global, interdisciplinary perspective makes it possible to understand the importance and value of precision medicine as an integral part of the personalized medicine movement, itself part of the international contract-based authority movement, whose virtue is to authorize only those forms of intervention that generate fairness as well as clinical efficiency. This new format to give and to receive medical care has introduced the notion of patient-collaborator of his care, meaning patient who collaborates with the clinician to all step of his care. Finally, to improve quality and to reduce inequities, we have to fill the most important gap, namely the socioeconomic status, which remains the major challenge to achieve the “best care” for all around the world.
... Accordingly, understanding gene-environment interactions relevant to genetic variations for common and complex human diseases is an important challenge for precision medicine. Eventually, with the aid of pharmacogenetics, precision medicine could assure that patients get the right drug at the right dose at the right time, with minimum adverse drug reactions (ADRs) and maximum efficacy by translating functional genomics into rational therapeutics (Ingelman-Sundberg, 2001;Aydin Son et al., 2013). As a promising new era of personalized interventions, translation of pharmacogenomic knowledge into clinical practice by optimizing drugs and drug combinations according to each individual's unique genetic makeup remains the first priority in implementing personalized health care as an important component for "precision medicine" (Aydin Son et al., 2013;Sharma, 2014). ...
... Eventually, with the aid of pharmacogenetics, precision medicine could assure that patients get the right drug at the right dose at the right time, with minimum adverse drug reactions (ADRs) and maximum efficacy by translating functional genomics into rational therapeutics (Ingelman-Sundberg, 2001;Aydin Son et al., 2013). As a promising new era of personalized interventions, translation of pharmacogenomic knowledge into clinical practice by optimizing drugs and drug combinations according to each individual's unique genetic makeup remains the first priority in implementing personalized health care as an important component for "precision medicine" (Aydin Son et al., 2013;Sharma, 2014). Henceforth, translation of pharmacogenomic knowledge into clinical practice by optimizing drugs and drug combinations according to each individual's unique genetic makeup remains the first priority in individualized health care as an important component for "evidence-based precision medicine" (Aydin Son et al., 2013;Sharma, 2014). ...
... As a promising new era of personalized interventions, translation of pharmacogenomic knowledge into clinical practice by optimizing drugs and drug combinations according to each individual's unique genetic makeup remains the first priority in implementing personalized health care as an important component for "precision medicine" (Aydin Son et al., 2013;Sharma, 2014). Henceforth, translation of pharmacogenomic knowledge into clinical practice by optimizing drugs and drug combinations according to each individual's unique genetic makeup remains the first priority in individualized health care as an important component for "evidence-based precision medicine" (Aydin Son et al., 2013;Sharma, 2014). Since exponential growth of genetic data together with information on environmental factors is becoming an essential tool in health care, for personalized/precision medicine to be useful at the clinical level implementation of health records (EHRs) storing comprehensive, individual-specific data is crucial (Scheuner et al., 2009). ...
With the availability of high-throughput genomics technologies and the completion of the Human Genome Project in 2003, we are now in the “postgenomics era.” The concept of precision medicine evolved over time and was popularized only recently. It became a hot topic in the medical community as well as in public sphere due to president Obama's announcement of the “Precision Medicine Initiative” at the beginning of 2015. In principle, the term “precision medicine” referring to multiple omics profiles, which include genomics, pharmacogenomics, proteomics, metabolomics, transcriptomics, epigenomics, and metagenomics, takes into account family history and lifestyles to make more tailored diagnostic and therapeutic strategies to a particular patient with different monogenic and multifactorial polygenic complex diseases, such as diabetes. The term “personalized medicine” is wider, more inclusive of subjects' environment, exposure, and socioeconomic status. However, besides technical issues, as a cornerstone of individual approach, precision medicine can fulfill its promise and build its sustainable existence by addressing and asking precision questions regarding structural deficiencies in health care system for the most vulnerable patients and pathologies including neglected diseases and global epidemic of complex noncommunicable diseases, such as diabetes in the society of not only high-income but also in low- and middle-income countries.
... A better understanding of which genes are not only associated with drug response but also causally involved would add tremendous value to pharmacogenomics data, permitting a more intelligent utilization of such genes as diagnostic signatures, and as putative drug targets to improve drug response. 1,18 In addition to speeding up the functional validation of gene lists from association-based pharmacogenomics data, high-throughput screening strategies for genome-scale functional analysis can potentially be a more relevant starting point for pharmacogenomics analyses. In such approaches, targets, which are involved in regulating drug response, are identified, and their putative clinical associations with drug response are subsequently validated. ...
... Hence, there is clearly an unmet need to develop and apply genome-compatible strategies and technologies to identify functional modulators of drug response. 1,18 Although siRNAs are powerful silencers of gene regulation and have aided in our understanding of gene function in numerous cell lines and organisms, several challenges of the siRNA technology remain to be addressed. Specifically, the main problems related to RNAi analysis involve sequence specificity, delivery, and off-target effects. ...
RNA interference (RNAi) is a naturally existing endogenous mechanism for post-transcriptional gene regulation, nowadays commonly utilized for functional characterization of genes and development of potential treatment strategies for diseases. RNAi-based studies for therapy, after being examined for over a decade, are finally in the pipeline for developing a potential treatment for the mutated transthyretin (TTR) gene, which gives rise to a dysfunctional TTR protein. This dysfunctional protein causes TTR amyloidosis (ATTR), an inherited, progressively incapacitating, and often fatal genetic disorder. TTR is a protein produced in the liver, and functions as a carrier for retinol-binding protein and also thyroxine. This protein facilitates the transport of vitamin A around the human body. A mutation or misprint in the code of this protein results in an abnormal folding of the protein. Therefore, not only does the transportation of the vitamin A become disabled, but also there will be formation of clusters called amyloid deposits, which attack the heart and the nerves causing some patients to be unconditionally bound to bed. ATTR is a hereditary autosomal dominant disease with a 50% chance of inheritance by offspring, even with just one of the parents having a single defective allele of this gene. Alnylam Pharmaceuticals worked on the concept of RNAi therapy for years, which led to the introduction of lipid nanoparticles encircling small interfering RNAs. The drug showed extremely positive results since the first trial, and a great percentage of defective protein reduction. This drug was later named Patisiran.
... Major obstacles to RNAi mechanism involve poor pharmacokinetic property and biological handicaps such as interferon activation [5,11,20,[24][25][26] and off-target effects [27][28][29]. Long double stranded siRNAs (200 nucleotides or longer) and high concentration of siRNAs can trigger immune system activity in cells. ...
Functional characterization of genes can be determined by disruption of gene expression. This provides powerful approach in designing novel treatment strategies. RNA interference (RNAi) is a natural phenomenon that can aid in the study of posttranscriptional
regulation of genes. This mechanism can be stimulated via introduction of double stranded RNA (dsRNA) in a cell. Synthetic short/small interfering RNAs (siRNA) can be utilized to trigger down-regulation of desired genes via transfecting into mammalian cells. Recently, utilization of polymeric carriers has been an attractive approach in drug
delivery for medical applications. This review article describes the advantages of exploiting polymeric carriers for siRNA delivery, as bio-therapeutics. Here, we report the current developments, safety and delivery of bio-based siRNAs via polymeric carriers. Additionally, cancer genetics and metabolic disorders including obesity and diabetes pertaining to the progress in clinical applications have been highlighted.
... guish responders from nonresponders by studying the effects of genetic differences on the variability of individual patient responses to drugs and so predict those in whom ADRs are more likely to occur [4]. The field of pharmacogenetics, dating back to the 1950s [5], can be regarded as one of the important corner stones of personalized medicine [6,7]. As an important component for 'evidence-based personalized medicine' and by promising the delivery of the right drug to the right person at the right dose at the right time with minimum ADRs and maximum efficacy, the translation of functional genomics into rational therapeutics in clinical practice according to each individual's unique genetic makeup remains the first priority in implementing personalized healthcare [2]. ...
... Before carrying out any power calculation for determining PgV study sample size, one has to know the frequency of the ADE(s) associated with the drug of interest (effect size) in addition to the genetic polymorphisms' pattern of inheritance, linkage disequilibrium and minor allele frequency [61]. Given the limited frequency of most adverse events, a high rate of participants' inclusion is needed. ...
In this report, we review the importance of pharmacovigilance in detecting postmarketing adverse drug events and the potential for developing pharmacogenovigilance programs by integrating pharmacogenomics with pharmacovigilance. We propose to start developing such a program in primary healthcare systems that use basic features of electronic medical records and have access to large numbers of patients commonly prescribed drugs. Such programs, if carefully designed, may grow over time and hopefully enhance the collection and interpretation of useful data for the clinical applications of pharmacogenomics testing.
