Cacabelos Ramón
EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, 15165-Bergondo, Coruña, Spain.
Expert Rev Mol Diagn. 2009 Sep;9(6):567-611. doi: 10.1586/erm.09.42.
Recent advances in genomic medicine have contributed to the acceleration of our understanding regarding the pathogenesis of dementia, improving diagnostic accuracy with the introduction of novel biomarkers and personalizing therapeutics with the incorporation of pharmacogenetic and pharmacogenomic procedures to drug development and clinical practice. Most neurodegenerative disorders, including Alzheimer's disease (AD), share some common features, such as a genomic background in which hundreds of genes might be involved, genome-environment interactions, complex pathogenic pathways, poor therapeutic outcomes and chronic disability. The main aim of a cost-effective treatment is to halt disease progression via modification of the functional cascade involving AD genomics, transcriptomics, proteomics and metabolomics. Unfortunately, the drugs available for the treatment of dementia are not cost effective. The pharmacological treatment of dementia accounts for 10-20% of direct costs, and fewer than 20% of the patients are moderate responders to conventional drugs, some of which may cause important adverse drug reactions. Future antidementia drugs must address the complex pathogenic niche of the disease from a multifactorial perspective. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. In addition to antidementia drugs, patients with AD or with other forms of dementia need concomitant medications for the treatment of diverse disorders of the CNS associated with progressive brain dysfunction. Approximately 60-80% of drugs acting on the CNS are metabolized via enzymes of the CYP gene superfamily, and 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. Only 26% of the patients are pure extensive metabolizers for the trigenic cluster integrated by allelic variants of the CYP2D6, CYP2C19 and CYP2C9 in combination. Although many genes have been suggested to be associated with AD, with the exception of APOE, most polymorphic variants of potential risk exhibit a very weak association with AD. APOE-4/4 carriers exhibit a dramatic biological disadvantage in comparison with other genotypes, and AD patients harboring this homozygous condition are the worst responders to conventional drugs. The incorporation of pharmacogenetic/pharmacogenomic protocols into AD research and clinical practice can foster the optimization of therapeutics by helping to develop cost-effective biopharmaceuticals and improving drug efficacy and safety.
基因组医学的最新进展加快了我们对痴呆症发病机制的理解，通过引入新型生物标志物提高了诊断准确性，并通过将药物遗传学和药物基因组学程序纳入药物研发和临床实践实现了治疗的个性化。大多数神经退行性疾病，包括阿尔茨海默病（AD），都有一些共同特征，比如可能涉及数百个基因的基因组背景、基因与环境的相互作用、复杂的致病途径、不佳的治疗效果以及慢性残疾。具有成本效益的治疗的主要目标是通过改变涉及AD基因组学、转录组学、蛋白质组学和代谢组学的功能级联反应来阻止疾病进展。不幸的是，现有的痴呆症治疗药物并不具有成本效益。痴呆症的药物治疗占直接成本的10%-20%，且对传统药物中度有反应的患者不到20%，其中一些药物可能会引起重要的药物不良反应。未来的抗痴呆药物必须从多因素角度应对该疾病复杂的致病生态位。药物遗传学和药物基因组学因素可能占药物处置和药效学中药物变异性的60%-90%。除了抗痴呆药物外，AD患者或其他形式痴呆症患者还需要使用辅助药物来治疗与进行性脑功能障碍相关的各种中枢神经系统疾病。大约60%-80%作用于中枢神经系统的药物是通过CYP基因超家族的酶进行代谢的，10%-20%的高加索人是有缺陷的CYP2D6多态性变体的携带者，这些变体会改变许多精神药物的代谢。在由CYP2D6、CYP2C19和CYP2C9的等位基因变体组成的三联基因簇中，只有26%的患者是纯广泛代谢者。尽管许多基因被认为与AD有关，但除了APOE外，大多数潜在风险的多态性变体与AD的关联都非常弱。与其他基因型相比，APOE-4/4携带者表现出明显的生物学劣势，患有这种纯合状态的AD患者对传统药物的反应最差。将药物遗传学/药物基因组学方案纳入AD研究和临床实践有助于开发具有成本效益的生物制药，提高药物疗效和安全性，从而促进治疗的优化。
