CRISPR-Cas, el editor de genes / CRISPR, gene editor

El término CRISPR, por su acrónimo en inglés refiere a Clustered Regularly Interspaced Short Palindromic Repeats, es decir, repeticiones palindrómicas cortas, agrupadas y regularmente esparcidas, por sus características en el genoma, pertenece naturalmente al sistema de defensa de bacterias y arqueas. Este ha sido adaptado biotecnológicamente para la edición del ADN de células eucariotas, incluso de células humanas. El sistema CRISPR-Cas para editar genes consta, en forma generalizada, de dos componentes: una proteína nucleasa (Cas) y un ARN guía (sgRNA). La simplicidad del complejo lo hace una herramienta molecular reprogramable capaz de ser dirigida y de editar cualquier sitio en un genoma conocido. Su principal foco son las terapias para enfermedades hereditarias monogénicas y para el cáncer. Sin embargo, además de editor de genes, la tecnología CRISPR se utiliza para edición epigenética, regulación de la expresión génica y método de diagnóstico molecular. Este artículo tiene por objetivo presentar una revisión de las aplicaciones de la herramienta molecular CRISPR-Cas, particularmente en el campo biomédico, posibles tratamientos y diagnósticos, y los avances en investigación clínica, utilizando terapia génica con CRISPR/Cas más relevantes hasta la fecha. (AU)

CRISPR are Clustered Regularly Interspaced Short Palindromic Repeats, which naturally belong to the defense system of bacteria and archaea. It has been biotechnologically adapted for editing the DNA of eukaryotic cells, including human cells. The CRISPR-Cas system for editing genes generally consists of two components, a nuclease protein (Cas) and a guide RNA (sgRNA). The simplicity of the complex makes it a reprogrammable molecular tool capable of being targeted and editing any site in a known genome. Its main focus is therapies for monogenic inherited diseases and cancer. However, in addition to gene editor, CRISPR technology is used for epigenetic editing, regulation of gene expression, and molecular diagnostic methods. This article aims to present a review of the applications of the CRISPR-Cas molecular tool, particularly in the biomedical field, possible treatments and diagnoses, and the advances in clinical research, using the most relevant CRISPR-Cas gene therapy to date. (AU)

Pharmaco-epigenomics: On the Road of Translation Medicine.

Epigenomics refers to the study of genome-wide changes in epigenetic mechanisms including DNA methylation, histone modifications and non-coding RNAs expression. The alterations in normal DNA methylation and histone acetylation/deacetylation patterns lead to deregulated transcription and chromatin organization resulting in altered gene expression profiles that facilitates tumor development and progression. In consequence, novel therapeutic strategies aimed at reversing aberrant epigenetic marks in cancer cells have been developed and used in recent molecular studies and clinical trials. Pharmaco-epigenomics is a research area, which refers to the study of epigenome changes in cancer development and how chemotherapeutic agents can reverse these aberrant epigenetic marks by targeting the epigenetic machinery. Besides, the effects of genome-wide polymorphisms in populations leading to variations in drug response are also study subject of pharmaco-epigenomics and are being studied extensively in cancer. Recent findings showed that drug response could be largely influenced by the presence of aberrant epigenetic marks of the whole genome. This implies that biological pathways and cellular processes are under the impact of epigenome status. However, data about the relationship between drug response and the epigenomic variations is still scarce mainly because the epigenome is highly variable between individuals. The present chapter reviewed the advances on the epigenetics changes mainly DNA methylation and histones modifications on cervical and breast human cancers. A special emphasis in how they could be used as targets for the development and use of novel drugs in cancer therapy is delineated.

Network Medicine: A Mandatory Next Step for Inflammatory Bowel Disease.

Despite unquestionable progress in the management of inflammatory bowel disease (IBD) and the much improved clinical results achievable today in Crohn's disease (CD) and ulcerative colitis (UC) patients, the overall therapeutic outcome remains far from optimal. The main reason of this partial success is that all current medications only block individual components of a highly complex disease process that results from the integration of multiple and incompletely identified pathogenic components. Thus, if further progress is to be achieved in IBD therapeutics and we want to move from the current success rate to nearly 100%, bold new ideas must be entertained and new approaches put into practice. Both are necessary because in IBD we are dealing with a prototypical complex disease superimposed to the background of the extreme biological diversity of humans in response to injury. An unresolved challenge mandates the adoption of new solutions specifically designed to address the unique features of that challenge. Translated to a disease condition, and IBD in particular, the unresolved challenges of CD and UC demand bold new thinking leading to the conception and implementation of totally innovative therapies. In this article, we propose that one such new thinking is the notion of network medicine for IBD, and that the development of brand new treatments should be based on the identification of the molecular structure of the IBD interactome with the purpose of targeting its controlling elements (central nodes or hubs). This specific targeting of the underlying molecular disease modules will lead to the disruption of the IBD interactome and foster the resolution of intestinal inflammatory process.

Epigenómica social y conflicto armado: ¿por qué apostarle a la paz? / Social epigenomics and armed conflict: ¿why rooting for peace? / Epigenómica social e conflito armado: o porquê apostar à paz?

This paper presents a summary of the scientific evidence that accounts for the epigenetic effects and their phenotypic ex-pression of exposure to chronic stress environments, typical of populations exposed to armed conflict, considering also the potential implications for the achievement of wellbeing.Materials and methods. A narrative review of the literature of the last 10 years was conducted in Medline, Science Direct and Lilacs databases and repositories of journals such as: Scie-lo and BIREME. An initial filter was carried out through titles and abstracts according to the inclusion and exclusion criteria. Afterwards, full text reading was performed in the selected ar-ticlesResults. 33 articles were obtained for full text reading. Among the main documented effects, the alteration of gene expression to stress was reported through neuronal activation (hypothala-mic-pituitary-adrenal axis) with greater sensitivity to glucocor-ticoids, leading to chronic stress and increased prevalence of non-transmittable chronic diseases.

O presente trabalho apresenta um resumo da evidencia cien-tífica que dá conta dos efeitos epigenéticos e a sua expressão fenotípica da exposição a ambientes de estrese crónico, pró-prios de populações expostas ao conflito armado, consideran-do além das implicações potenciais para atingir um bom viver.Materiais e Métodos. Realizou-se uma revisão narrativa de li-teratura dos últimos 10 anos nas bases de dados Medline e Science Direct e repositórios como SciELO e BIREME. Foram filtrados artigos a traves de critérios de inclusão e exclusão, posteriormente foi realizada uma leitura completa dos tex-to selecionados.Resultados. Foram lidos 33 artigos para leitura de texto com-pleto. Entre os principais efeitos documentados foram repor-tados a alteração da expressão genética ao estresse a través da activação neuronal (eixo hipotálamo -pituitaria- suprarenal) com maior sensibilidade aos glucocorticoides, conducente ao estrese crónico e aumento da prevalência de doenças crónicas não transmissíveis.

El presente trabajo presenta un resumen de la evidencia científica que da cuenta de los efectos epigenéticos y la expresión fenotípica, de la expo-sición a ambientes de estrés crónico, propios de poblaciones expuestas al conflicto armado; considerando, además, las implicaciones potenciales para el logro de un buen vivir.Materiales y métodos. Se hizo una revisión narrativa de la literatura cien-tífica de los últimos 10 años, en bases de datos Medline y Science Direct y repositorios de revistas como SciELO y BIREME. Se llevó a cabo un filtro inicial mediante títulos y resúmenes, de acuerdo con los criterios de inclu-sión y exclusión. Posteriormente, se hizo la lectura del texto completo en los artículos seleccionados.Resultados. Se obtuvieron 33 artículos para lectura de texto completo. Entre los principales efectos documentados, se reportó la alteración de la expresión génica al estrés mediante activación neuronal (eje hipotála-mo-hipófiso-suprarrenal) con mayor sensibilidad a los glucocorticoides, conducente a estrés crónico y aumento de prevalencia de enfermedades crónicas no transmisibles.

Brazilian Society for Food and Nutrition position statement: nutrigenetic tests

Position statement: The Brazilian Society for Food and Nutrition (SBAN) bases the following position statement on acritical analysis of the literature on nutritional genomics and nutrigenetic tests: (1) Nutrigenetic tests are predictive and not diagnostic, should not replace other evaluations required to treatment, and should only be used as an additional tool to nutritional prescription; (2) Nutritionists/registered dietitians and other health professionals must be able to interpret the nutrigenetic tests and properly guide their patients, as well as build their professional practice ongeneral ethical principles and those established by regulatory authorities; (3) It is extremely important to highlight that them is interpretation of nutrigenetic tests can cause psychological and health problems to the patient; (4) Currently, there is insufficient scientific evidence for the recommendation of dietary planning and nutritional supplementation based only on nutrigenetic tests. This position statement has been externally reviewed and approved by the board of SBAN and has not gone through the journal's standard peer review process.

Epigenetics and Precision Oncology.

Epigenetic alterations such as DNA methylation defects and aberrant covalent histone modifications occur within all cancers and are selected for throughout the natural history of tumor formation, with changes being detectable in early onset, progression, and ultimately recurrence and metastasis. The ascertainment and use of these marks to identify at-risk patient populations, refine diagnostic criteria, and provide prognostic and predictive factors to guide treatment decisions are of growing clinical relevance. Furthermore, the targetable nature of epigenetic modifications provides a unique opportunity to alter treatment paradigms and provide new therapeutic options for patients whose malignancies possess these aberrant epigenetic modifications, paving the way for new and personalized medicine. DNA methylation has proven to be of significant clinical utility for its stability and relative ease of testing. The intent of this review is to elaborate upon well-supported examples of epigenetic precision medicine and how the field is moving forward, primarily in the context of aberrant DNA methylation.

The impact of DNA methylation technologies on drug toxicology.

INTRODUCTION: Drug toxicology is central to drug development. Despite improvements in our understanding of molecular and cell biology, high attrition rates in drug development continue, speaking to the difficulties of developing unequivocal methods to predict the efficacy and safety of drugs. AREAS COVERED: In this review, the authors provide a short overview of the 'omics' technologies that have been applied to drug toxicology, with an emphasis on a whole-genome DNA methylation analysis. Preliminary results from DNA methylation analysis technologies that may help in predicting response and efficacy of a drug are discussed. EXPERT OPINION: Currently, we cannot fully contextualize the application of epigenetics to the field of drug toxicology, as there are still many challenges to overcome before DNA methylation-based biomarkers can be effectively used in drug development. Comprehensive whole-genome DNA methylation methods for a unbiased analysis based on either microarray or next-generation sequencing need to be evaluated in drug toxicology in an intensive and systematic manner. Additionally, robust analysis systems need to be developed to decode the large amounts of data generated by whole-genome DNA methylation analyses as well as protocol standardization for reproducibility to develop meaningful databases that can be applied to drug toxicology.