Open Access
Epigenomics and proteomics of brain disorders
(SciTech Central, 2017-11-30) Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Epigenomic mechanisms (DNA methylation, chromatin remodeling/histone modifications, miRNA regulation) are involved in the transcriptional and post-translational regulation of genes in physiological and pathological conditions leading to potentially reversible phenotypes. Mutations in the genes encoding elements of the epigenetic machinery cause epigenetic Mendelian disorders. Epigenetic aberrations contribute to the pathogenesis of neurodevelopmental, imprinting, neuropsychiatric, and age-related neurodegenerative disorders. Some brain disorders exhibit proteoepigenomic changes resulting from primary genomic traits and/or secondary epigenetic events which induce pathogenic (structural, functional, conformational) changes in key proteins. Proteomic biomarkers and epigenomic signatures may help in the prediction, early diagnosis, and prognosis of CNS disorders. Epigenetic drug discovery, application of pharmacoepigenomic procedures for personalized therapeutics, novel approaches to decode and resolve drug resistance, and targeting miRNAs in prevention and treatment of brain disorders are promising areas of future development.
Open Access
Pharmacogenomics of Alzheimer's disease: genetic determinants of phenotypic variation and therapeutic outcome
(SciTech Central, 2016-11-16) Cacabelos, Ramón; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Goldgaber, Dmitry; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Conventional anti-dementia drugs are not cost-effective, and pharmacological breakthroughs have not been achieved for the past 10 years. Major determinants of therapeutic outcome in Alzheimer's disease (AD) include age- and sex-related factors, pathogenic phenotype, concomitant disorders, treatment modality and polypharmacy, and pharmacogenetics. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety. Pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes represent the major genetic determinants of response to treatment in AD. In pharmacogenetic studies, APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments. Patients harboring a large (L) number of poly T repeats in intrón 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders whereas patients with short (S) TOMM40 poly T variants (S/S genotype), and to a lesser extent S/VL and VL/VL carriers, in haplotypes with APOE-3 are the best responders to treatment. Only 25% of the Caucasian population are extensive metabolizers for trigenic haplotypes integrating CYP2D6- CYP2C19-CYP2C9 variants. Patients harboring CYP-related por (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG- AG-CC) exhibit the lowest cholesterol levels and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Epigenetic aberrations (DNA methylation, histone modifications, miRNA dysregulation) in genes configuring the pharmacoepigenetic cascade also influence the response/resistance to drugs. Consequently, novel strategies in drug development, either preventive or therapeutic, for AD should take into consideration these pharmacogenetic determinants for treatment optimization.
Open Access
Pharmacogenetic considerations in the treatment of Alzheimer's disease
(Taylor & Francis, 2016) Cacabelos, Ramón; Torrellas, Clara; Teijido Hermida, Óscar; Carril, Juan Carlos ; Ciencias de la Salud; Osasun Zientziak
The practical pharmacogenetics of Alzheimer’s disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug–drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.
Open Access
Interrogating the epigenome to unveil the secrets of neurodegeneration: promising epigenetic therapies
(SciTech Central, 2016-07-25) Teijido Hermida, Óscar; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
According to the WHO, cerebrovascular and neurodegenerative disorders affect one billion people around the world. Pathological phenotypes of neurodegeneration result from a combination of genomic, epigenomic, metabolic, and environmental factors, which hinder their treatment. Indeed, current FDA-approved conventional drugs used for treatment of neurodegenerative disorders provide very little beneficial effects, or, at best, reduce the pathological symptoms but do not detain disease progression. Furthermore, the unacceptable side effects of most of these treatments make them unsuitable for chronic treatments. One of the main reasons for this historical setback correlates with the poor knowledge about the molecular mechanisms of these pathologies, which results in the inappropriate drug target selection. Genetic components did not fully explain the mechanisms of those diseases. Furthermore, most treatments target symptomatic features of disease but they are not antipathogenic. During the last 15 years, the study of the role of the epigenetic machinery on gene regulation opens new and promising perspectives for a more accurate and effective treatment. Aberrant alterations in the epigenetic machinery result in dysregulation of gene expression at different levels in pathological conditions compared to healthy controls. The epigenetic approach allows the identification of key pathological targets in complex disorders that cannot be detected using genetic-based methods. Many of these epigenetic targets may be detected in early asymptomatic stages of the disease, which facilitates its treatment. Furthermore, the reversibility and potential restoring of epigenetic aberrations, unlike genetic mutations, sited epigenetic-based therapy as a promising tool to treat those complex disorders. This manuscript reviews the main epigenetic mechanisms involved in the most relevant neurodegenerative disorders nowadays, as well as the potential epigenetic-based drugs currently used in clinical trials for treatment of those disorders and future perspectives.

Teijido Hermida, Óscar

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