Drug Therapy and Personalized Health Care: Pharmacogenomics in Perspective
Drug Therapy and Personalized Health Care: Pharmacogenomics in Perspective
复制标题
药物治疗和个性化医疗保健：药物基因组学视角
DOI：
10.1007/s11095-008-9702-4
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发表时间：
2008
影响因子：
3.7
通讯作者：
W. Sadee
中科院分区：
文献类型：
--
作者：
W. Sadee
药物发现是由保罗·埃尔利希在20世纪初创造的“神奇子弹”时代塑造的。通过药物治疗治愈的期望似乎在感染疾病的抗生素治疗中实现了--但耐药性的出现提醒人们应该宣布胜利。那么，在这个史无前例的药物治疗时代，我们处于什么位置？我们是否期待从人类基因组计划提供的新见解中涌现出更强大的药物--开启一个加速药物发现的新时代？虽然基因组学产生了许多潜在的新药靶点，但它也揭示了单个细胞的复杂性，更不用说整个有机体了。用单一的化学物质治疗复杂的疾病可能是一个不切实际的期望。因此，目前的治疗方法正朝着药物组合的方向发展，以达到不同的生物靶点，如艾滋病毒/艾滋病和癌症的治疗。这篇文章的目的是解决药物基因组学如何产生临床上有用的生物标记物来指导个别受试者治疗的问题。虽然新的分子靶向疗法前景看好，尤其是在癌症方面，但像人体这样的复杂系统需要的不仅仅是简单或单一的解决方案。治疗方面最显著和最显著的进步将来自哪里，它们将是什么样子？当然，新药发现将继续发挥关键作用，包括针对单一蛋白质或非编码RNA等调控因子的蛋白质药物和基因治疗策略。然而，尽管有‘基因组学革命’，但新化学实体的流水线不足以维持现有战略(重磅炸弹药物)的制药业。可能需要更有针对性的方法来提高效益/成本比(针对明确界定的病理生理的利基市场)。另一方面，在重新兴起的个性化医疗时代，我们可以合理地预期，为每个患者优化药物治疗可以显著改善治疗结果，即使使用现有的药物也是如此。作为第三种选择，我们开始看到其他治疗方式，包括使用复杂的生物系统作为治疗方法，如干细胞、归巢淋巴细胞、神经组织和自体工程器官。细胞能够接受来自周围组织的指令，调整和进化所需的功能，例如作为神经植入。最后，我们开始认为免疫系统是健康和疾病的重要贡献者，因此是干预措施的目标。此外，人类微生物群的非凡多样性，以及由适应性共同进化形成的共生伙伴(1)。肠道细菌菌群的宏基因组学揭示了人类肠道中共存的约10万亿个微生物细胞中存在的数百万个基因，这些基因对肥胖和炎症等人类疾病的影响在很大程度上尚不清楚。显然，人类健康和疾病治疗的进步必须来自所有这些领域，反映出人类在生物、种族和文化上的复杂性。
Drug discovery was shaped by the era of the ‘magic bullet’, coined by Paul Ehrlich early in the twentieth century. Expectations of a cure achieved through drug therapy seemed to have come true with antibiotic treatments of infectious diseases—but the emergence of drug-resistance cautions one to declare victory. Where then do we stand in this unprecedented age of pharmacotherapy? Do we anticipate ever more powerful drugs, emerging from new insights provided by the human genome project—ushering in a new era of accelerated drug discovery? While genomics has yielded numerous potential new drug targets, it also reveals the complexity of a single cell, not to mention an entire organism. Curing complex diseases with single chemical entities may have been an unrealistic expectation. As a result, current therapies move towards drug combinations to hit diverse biological targets, as seen in the treatment of HIV/AIDS and cancer. The purpose of this essay is to address the question how pharmacogenomics can yield clinically useful biomarkers that guide therapy of individual subjects. While novel molecularly targeted therapies hold much promise, particularly in cancer, complex systems such as the human body require more than simple—or single minded—solutions. Where will the most dramatic and significant advances in therapy come from, and how will they look like? Certainly, novel drug discovery will continue to play a key role, including protein drugs and gene therapy strategies targeting single proteins, or regulatory factors such as noncoding RNAs. Yet despite the ‘genomics revolution’, the pipeline of new chemical entities is insufficient to maintain the pharmaceutical industry with current strategies (blockbuster drugs). A more targeted approach may be needed to enhance the benefit/cost ratio (niche markets tackling well defined pathophysiologies). On the other hand, we can reasonably expect that optimizing drug therapy for each patient could significantly improve treatment outcomes, even with existing drugs, in the re-emerging era of personalized medicine. As a third option, we are beginning to see other treatment modalities, including the use of complex biological systems as therapies, such as stem cells, homing lymphocytes, neuronal tissues, and autologous engineered organs. Cells are capable of receiving instructions from surrounding tissues, adjusting and evolving desirable functions, for example as neural implants. Lastly, we are beginning to consider the immune system as an important contributor to health and disease, and therefore a target for interventions. Add to this the extraordinary diversity of the human microbiome, commensal partners shaped by adaptive co-evolution (1). Metagenomics of the bacterial flora in the gut is revealing millions of genes present in the~ 10 trillion microbial cells coexisting in the human gut, with yet largely uncharted effects on human diseases, such as obesity and inflammation. Clearly, advances in human health and disease therapy will have to come from all of these areas, reflecting human complexity, both biologically, ethnically, and culturally.