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Genetic Editing and Pharmacogenetics in Current And Future Therapy Of Neurocognitive Disorders.
Current Alzheimer Research ( IF 2.1 ) Pub Date : 2020-02-29 , DOI: 10.2174/1567205017666200422152440
Michal Prendecki 1 , Marta Kowalska 1 , Ewa Toton 2 , Wojciech Kozubski 3
Affiliation  

Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most common types of dementia in adults are Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD) and Vascular Dementia (VaD), of which, AD accounts for more than half of the cases.

The most prominent symptom of AD is cognitive impairment, currently treated with four drugs: Donepezil, rivastigmine, and galantamine, enhancing cholinergic transmission; as well as memantine, protecting neurons against glutamate excitotoxicity. Despite ongoing efforts, no new drugs in the treatment of AD have been registered for the last ten years, thus multiple studies have been conducted on genetic factors affecting the efficacy of antidementia pharmacotherapy. The researchers investigate the effects of variants in multiple genes, such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22A1/2/5, SLC47A1, UGT1A6, UGT1A9 and UGT2B7, associated with numerous pathways: the development of pathological proteins, formation and metabolism of acetylcholine, transport, metabolism and excretion of antidementia drugs and transcription factors regulating the expression of genes responsible for metabolism and transport of drugs. The most promising results have been demonstrated for APOE E4, dementia risk variant, BCHE-K, reduced butyrylcholinesterase activity variant, and CYP2D6 UM, ultrarapid hepatic metabolism. Further studies investigate the possibilities of the development of emerging drugs or genetic editing by CRISPR/Cas9 for causative treatment.

In conclusion, the pharmacogenetic studies on dementia diseases may improve the efficacy of pharmacotherapy in some patients with beneficial genetic variants, at the same time, identifying the carriers of unfavorable alleles, the potential group of novel approaches to the treatment and prevention of dementia.



中文翻译:

神经认知障碍当前和未来治疗中的遗传编辑和药物遗传学。

痴呆症是西方社会的一个重要问题,在接下来的几年中,非洲和亚洲等发展中地区也会出现这个问题。成人痴呆的最常见类型是阿尔茨海默氏病(AD),路易体痴呆(DLB),额颞痴呆(FTD)和血管性痴呆(VaD),其中AD占病例的一半以上。

AD最突出的症状是认知障碍,目前使用四种药物治疗:多奈哌齐,卡巴拉汀和加兰他敏,可增强胆碱能的传递。以及美金刚胺,保护神经元免受谷氨酸兴奋性中毒。尽管正在进行的努力,在最近十年中尚未注册用于治疗AD的新药,因此已对影响抗痴呆药物治疗功效的遗传因素进行了多项研究。研究人员研究了变体在多个基因中的作用,例如ABCB1,ACE,CHAT,CHRNA7,CYP2C9,CYP2C19,CYP2D6,CYP3A4,CYP3A5,CYP3A7,NR1I2,NR1I3,POR,PPAR,RXR,SLC22A1 ,UGT1A6,UGT1A9和UGT2B7与许多途径相关:病理蛋白的发育,乙酰胆碱的形成和代谢,转运,抗痴呆药物的代谢和排泄以及调节负责药物代谢和运输的基因表达的转录因子。对于APOE E4,痴呆症风险变体,BCHE-K(降低的丁酰胆碱酯酶活性变体)和CYP2D6 UM(超快肝代谢)已证明了最有希望的结果。进一步的研究调查了CRISPR / Cas9用于病原性治疗的新兴药物的开发或基因编辑的可能性。

总而言之,对痴呆症疾病的药物遗传学研究可能会提高一些具有有益遗传变异的患者的药物治疗效果,同时,确定不良等位基因的携带者,这是治疗和预防痴呆症的新方法的潜在群体。

更新日期:2020-02-29
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