Genetic Editing and Pharmacogenetics in Current And Future Therapy Of Neurocognitive Disorders

Abstract

<jats:sec> <jats:title>:</jats:title> <jats:p>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.</jats:p></jats:sec> <jats:sec> <jats:title>:</jats:title> <jats:p> 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.</jats:p></jats:sec> <jats:sec> <jats:title>:</jats:title> <jats:p> 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.</jats:p></jats:sec>

Metabolomic analysis of vascular cognitive impairment due to hepatocellular carcinoma

“…NR1I2 is a member of the nuclear receptor superfamily and is involved in encoding a transcriptional regulator that regulates cytochrome P450 (CYP) enzymes. Previous studies suggest that NR1I2 may regulate bile acid metabolism involved in promoting the progression of cognitive impairment ( 63 ). CYP2J2 is a cyclooxygenase that is involved in regulating the body's inflammatory response, cell proliferation, and other physiological functions, and plays an important role in the homeostasis ( 64 ).…”

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…78 Several interesting reviews have been published on this topic related to AD recently. 19,20,22,79 One to highlight is the work by Inoue et al where they have increased the expression of APP and/or BACE1 using CRISPR gene activation to reveal the hidden defect in γsecretase in fibroblasts of FAD which results in the increased level of Aβ42. 80…”

“…CRISPR technology has generated a broad precision mammalian genome regulatory toolbox, enabling gene knockout, insertion, activation, and suppression . Several interesting reviews have been published on this topic related to AD recently. ,,, One to highlight is the work by Inoue et al where they have increased the expression of APP and/or BACE1 using CRISPR gene activation to reveal the hidden defect in γ-secretase in fibroblasts of FAD which results in the increased level of Aβ42 …”

Neurodegenerative Dementias: A Brief Review

“…Currently approved pharmacological treatments for symptomatic management of AD dementia are cholinesterase-enzyme primarily responsible for synaptic recycling of acetylcholine in gray matter-inhibitors: donepezil (Aricept Ⓡ ), rivastigmine (Exelon), and galantamine (Razadyne) and a neuron protecting agent against glutamate excitotoxicity: memantine (Namenda) [26,27]. Both 5 mg and 10 mg daily dosing of donepezil was found effective for AD dementia: start with an initial dose 5 mg daily and increase after 1 month to maintenance dose 10 mg daily [27].…”