Advances in human genome research have explored a newer avenue that directs modern medicinal practices to transform healthcare. The term precision medicine was first proposed by the US National Research Council to understand disease at a deeper level towards specific targeted therapy by studying genomic tools to make the treatment more accurate and precise. Thus, the concept of precision medicine can attribute a paradigm shift in the healthcare system moving away from one-size-fits all concepts to pharmacogenomics-based tailoring of therapy. In 2015, US President Barack Obama proposed a vision for a National Precision Medicine Initiative where he highlighted the genesis of the drug ivacaftor, which was developed for patients suffering from cystic fibrosis (autosomal recessive disease). The variability and mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene have been found responsible for the dysfunction of lungs, pancreas, and sweat glands linked with cellular chloride transit. The recent development of CFTR modulators promises to transform the therapeutic landscape in CF in a precision-based fashion. Another instance of precision medicine evolved from the genetic predisposition of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, which is associated with autosomal dominant hypercholesterolaemia. The pharmacogenomics attribution of PCSK9 gene thus serves as a major target of drug development by inhibiting the protein for the treatment of high cholesterol. Thus, the understanding of the genomic anatomy, whole-genome sequencing will be able to develop some pharmacogenomics based molecular markers that can revolutionize patient care by personalizing their therapy, in other words tailoring the therapy.
Precision medicine in pharmacogenomics era
Pharmacogenomics plays an important role in precision medicine already is already being embraced by pharmaceutical companies in the drug development process. First of all it can guides pharmaceutical companies in drug discovery and development and secondly it can serve as a decisive factor for the physicians in selecting the right drug for patients based on their genetic make-up, in avoiding ADR, and in maximizing drug efficacy by prescribing the right dose. It has been observed that genetic differences among individuals can affect virtually all aspects of a disease and its treatment with regard to their occurrence, progression or recurrence, therapeutic dose, drug toxicity and many more. In the above context, variation in genetic trait in patients governs drug’s ADME profile (absorption, distribution, metabolism, excretion), safety profile and further explore some pharmacogenomic markers which can predispose to drug related toxicities such as immune reactions. A single neucleotide polymorphism map involved in the patient genetic variation in the pathogenesis of some complex disease such as asthma, diabetes mellitus, atherosclerosis and psychiatric disorders. Thus, the SNP database serve a tool of pharmacogenomics investigations in specific pharmacogenomic marker research during clinical development.
Precision Medicine in Drug Development
Precision medicine target specific genetic, molecular and cellular markers and provide patients with personalized and targeted treatments, are highly attractive targets for drug developers. It embodies an effort to understand the underlying cause of disease in individual patients. The most prominent application of precision medicine has been found in the field of oncology to overcome the cytotoxicity and severe side effects of existing ‘one-size-fits-all’ cancer drugs as potential drug targets. This is due to the fact that, classic chemotherapy agents offer variable efficacies for different tumour types that often affect both cancerous and vulnerable healthy cells. To overcome the challenges most of the anticancer therapy should be designed in such a manner so that it can target cancer cells more precisely, in more personalized way. The pattern of genetic expression profile linked with variety of tumors, including leukemias and breast cancer open up some necessary pathways to address target-based therapy as well as immune based therapy to generate a response against cancer cells. Pathway-based targeted therapies depend on prior knowledge of specific tumour biology which acts by modulating an aberrant protein or pathway essential for spare healthy cells and it also support the substratification of tumour types, allowing tailored based therapy with respective targets respectively. For example, platelet-derived growth factor receptor-α (PDGFRα) was explored as a specific target targeted in the treatment of gastrointestinal stromal tumours (GISTs). Another small-molecule kinase inhibitor Imatinib (Gleevec; Novartis) was developed in the treatment of chronic myelogenous leukaemia (CML) related to the protein product of the BCR–ABL fusion gene.
In the field of personalized medicine, the promising outcome of several target-based molecules has poured light extensively on the research meadow. We have distinguished three different conditions such as Mendelian disease (Cystic fibrosis, Long QT syndrome, Duchenne muscular dystrophy, Malignant hyperthermia susceptibility, Familial hypercholesterolemia, Dopa responsive dystonia, Thoracic aortic aneurysm, Left ventricular hypertrophy), precision oncology (Lung adenocarcinoma, breast cancer, gastrointestinal stromal tumor, melanoma), and Pharmacogenomics (sensitivity of warfarin, clopidogrel, thiopurine, codeine, simvastatin). In all these cases, particular target genes are responsible for the condition, and inhibition or searching for alternative therapy has been effectual. If we consider precision oncology, targeting genes like ALK, EGFR, KIT etc. with targeted kinase inhibitors (Gefitinib), KIT kinase activity inhibitor (Imatinib) etc. are very much potent for the above-mentioned conditions. Pharmacogenomics has immensely contributed to drug sensitivity to find out the alternative therapy for the particular gene or to find out what happens if the dose is reduced. Thus, personalized medicine has provided an excellent pathway to speed up the discovery as well as improve the quality of the future healthcare system.
The ultimate goal of personalized medicine is to define disease at the molecular level so that preventive resources and therapeutic agents can be directed at the right population of people while they are still well. The application of new technologies and the integration of data from an individual will lead to a new paradigm in patient care that will emerge from strategies employed in pharmaceutical research and development – a paradigm that will, for the first time, allow physicians to take a global molecular view of an individual patient’s disease. During chronic disease with a long clinical prodrome, the research and product development strategies for personalized medicine aims to impact the course of the disease at six major points. Genetic variants can be used to predict the predisposition of an individual for future disease development. Genetic variants associated with increased or decreased risk of disease will be the basis of genotype-directed treatment recommendations. Individuals deemed at high risk of disease can be targeted for preventive therapy or lifestyle modifications. Preventive therapies have been fully embraced by the medical community, as evidenced by the use of selective estrogen receptor modulators for patients at risk of breast cancer14 and osteoporosis15, and the use of statins in patients at risk of developing coronary artery disease16. High-risk individuals should be periodically screened (using protein-based markers, serum analytes, and/or molecular imaging) for preclinical disease detection. The molecular equivalent of the pap smear, mammogram or blood-pressure measurement will define more precisely the predilection for disease development. In patients with preclinical or symptomatic disease, molecular diagnosis based on gene- or protein-expression fingerprints might differentiate diverse diseases with similar clinical phenotypes. A set of different molecular markers could determine prognosis (the slope of the curve), distinguishing those with an aggressive form and rapid progression of the disease from individuals with slower disease progression, tailoring therapy accordingly. In choosing a therapeutic, the decision is guided by molecular markers (pharmacogenomics) that correlate with the safety and efficacy of specific compounds. Finally, monitoring the disease progression following therapy will utilize many of the molecular markers developed for screening and diagnosis
Precision medicine is a young and growing field. Many of the technologies that will be needed to meet the goals of the Precision Medicine Initiative are in the early stages of development or have not yet been developed. For example, researchers will need to find ways to standardize the collection of the clinic and hospital data from more than 1 million volunteers around the country. They will also need to design databases to store large amounts of patient data efficiently. The Precision Medicine Initiative also raises ethical, social, and legal issues. It will be critical to find ways to protect participants’ privacy and the confidentiality of their health information. Participants will need to understand the risks and benefits of participating in research, which means researchers will have to develop a rigorous process of informed consent. Cost is also an issue with precision medicine. The Precision Medicine Initiative itself will cost many millions of dollars, and the ongoing initiative will require Congress to approve funding over multiple years. Technologies such as sequencing large amounts of DNA are expensive to carry out (although the cost of sequencing is decreasing quickly). Additionally, drugs that are developed to target a person’s genetic or molecular characteristics are likely to be expensive. Reimbursement from third-party payers (such as private insurance companies) for these targeted drugs is also likely to become an issue. If precision medicine approaches are to become part of routine healthcare, doctors and other healthcare providers will need to know more about molecular genetics and biochemistry. They will increasingly find themselves needing to interpret the results of genetic tests, understand how that information is relevant to treatment or prevention approaches, and convey this knowledge to patients.
Keywords: Precision medicine, personalised medicine, drug development, pharmacogenomics
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- Ashley, Euan A. “Towards Precision Medicine.” Nature Reviews Genetics, vol. 17, no. 9, Sept. 2016, pp. 507–22. DOI.org (Crossref), doi:10.1038/nrg.2016.86.
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