Therapeutics in paediatric genetic diseases: Current and future landscape

There are more than 7,000 paediatric genetic diseases (PGDs) but less than 5% have treatment options. Treatment strategies targeting different levels of the biological process of the disease have led to optimal health outcomes in a subset of patients with PGDs, where treatment is available. In the past 3 decades, there has been rapid advancement in the development of novel therapies, including gene therapy, for many PGDs. The therapeutic success of treatment relies heavily on knowledge of the genetic basis and the disease mechanism. Specifically, gene therapy has been shown to be effective in various clinical trials, and indeed, these trials have led to regulatory approvals, paving the way for gene therapies for other types of PGDs. In this review, we provide an overview of the treatment strategies and focus on some of the recent advancements in therapeutics for PGDs.

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)

Nuevos problemas de un nuevo sistema de salud: la creación de una política pública nacional de atención de enfermedades raras en Brasil (1990-2014) / New problems of a new health system: the creation of a national public policy of rare diseases care in Brazil (1990s-2010s)

RESUMEN En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.

ABSTRACT This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.

Genetic disease in the family: trajectories and experiences in public health services / Enfermedad genética en la familia: trajetorias y experiencias en servicios públicos de salud / Doença genética na família: trajetórias e experiências em serviços públicos de saúde

Abstract Objective: To identify the trajectories and experiences of families of children with genetic diseases in health services. Method: A qualitative study, with data collected through interviews with 15 families and caregivers of children with Genetic Disease, living in the northern region of Rio Grande do Sul. Interviews were conducted from March to May 2018. Data analysis was based on thematic analysis. Results: A genetic disease diagnosis led to families' changes due to the demands of treatment, and also the needs of the child for being met by health services. To access specialized services, some families needed to travel to referral centers in larger cities. Families experienced difficulties such as unprepared health professionals, lack of organization of services, judicialization of resources, and need for structured Health Care Networks. Conclusion: The professional has the fundamental role of providing families with access to information and are responsible for decision making and for the organization and management of health and nursing services to meet the demands imposed on the individual and the family by the genetic disease.

Resumen Objetivo: Identificar trayectorias y experiencias en servicios de salud de familias que poseen hijos con enfermedades genéticas. Método: Estudio de abordaje cualitativo, cuyos datos fueron recolectados por medio de entrevistas con 15 familias representadas por las madres cuidadoras que poseen hijos con enfermedad genética, residentes en la región norte de Rio Grande do Sul, de marzo a mayo de 2018. El análisis de los datos ocurrió a través del análisis temático. Resultados: El diagnóstico de la enfermedad genética trajo cambios en las familias, por la demanda de tratamiento junto a los servicios de salud para atender a las necesidades del hijo. Para acceder a servicios especializados, algunas familias necesitaban desplazarse a centros de referencia en ciudades más grandes. Las familias experimentaron dificultades como la falta de preparo de los profesionales de salud, falta de organización de los servicios, procesos de judicialización de los recursos y necesidad de Redes de Atención a la salud estructuradas. Conclusión: El profesional enfermero asume un papel fundamental para proporcionar a las familias acceso a la información, a la toma de decisiones y a la organización de la gestión y gestión de los servicios de salud y enfermería para satisfacer a las demandas que las enfermedades genéticas condicionan al individuo y a la familia.

Resumo Objetivo: Identificar trajetórias e experiências em serviços de saúde de famílias que possuem filhos com doenças genéticas. Método: Estudo de abordagem qualitativa, cujos dados foram coletados por meio de entrevistas com 15 famílias representadas pelas mães cuidadoras que possuem filhos com Doença Genética, residentes na região norte do Rio Grande do Sul, de março a maio de 2018. A análise dos dados ocorreu através da análise temática. Resultados: O diagnóstico da doença genética acarretou mudanças nas famílias, pela procura de tratamento junto aos serviços de saúde para atender as necessidades do filho. Para ter acesso a serviços especializados, algumas famílias precisaram deslocar-se para centros de referência em cidades maiores. As famílias vivenciaram dificuldades como despreparo dos profissionais de saúde, falta de organização dos serviços, processos de judicialização dos recursos e necessidade de Redes de Atenção à Saúde estruturadas. Conclusão: O profissional enfermeiro assume papel fundamental para prover às famílias o acesso à informação, à tomada de decisão e à organização da gestão e do gerenciamento dos serviços de saúde e de enfermagem para atender às demandas que a doença genética condiciona ao indivíduo e à família.

Da busca pelo diagnóstico às incertezas do tratamento: desafios do cuidado para as doenças genéticas raras no Brasil / From the search for diagnosis to treatment uncertainties: challenges of care for rare genetic diseases in Brazil

Resumo As doenças genéticas raras constituem um importante problema de saúde pública, mas ainda são pouco estudadas na perspectiva da Saúde Coletiva. Este artigo tem por objetivo analisar os itinerários terapêuticos de pacientes com doenças genéticas raras nas cidades do Rio de Janeiro, Salvador e Porto Alegre, tendo por foco os desafios materiais, emocionais e estruturais enfrentados na busca por diagnóstico e tratamento. Foram realizadas entrevistas semiestruturadas com pacientes/cuidadores e profissionais de saúde em serviços públicos de genética médica. Observou-se que a experiência da doença genética rara, além de ser um desafio em si pelo caráter debilitante e incapacitante, é agravada por problemas de ordem prático-relacionais e burocrático-institucionais que não se resolvem com a chegada a um serviço especializado. A existência de longos itinerários terapêuticos até o diagnóstico, o desconhecimento dos médicos não geneticistas sobre as doenças raras, as dificuldades de transporte e de acesso a especialistas, a exames diagnósticos e complementares e o acesso a medicamentos e insumos alimentares de alto custo foram comuns às narrativas nas três cidades. A adesão aos cuidados oferecidos exigem estratégias de ação que dependem de arranjos envolvendo familiares, médicos, associações de pacientes e o Estado.

Abstract Rare genetic diseases are an important public health problem, but they are still little studied in Collective Health. This article aims to analyze the 'therapeutic itineraries' of patients in search of a diagnosis and treatment for rare genetic diseases in the cities of Rio de Janeiro, Salvador and Porto Alegre. It focuses on the material challenges, emotional and structural problems faced in these trajectories. Semi-structured interviews were conducted with patients/caregivers and health professionals in the context of public health medical genetics. Our findings suggest that the experience of the rare genetic disease is aggravated by practical, inter-relational and bureaucratic/institutional problems. The reality of long and circuitous journeys to obtain a diagnosis, non-geneticists' lack of knowledge about rare diseases, difficulties in transportation and access to specialists, diagnostic and complementary examinations, and access to high-cost medicines and food supplies were common challenges in all the narratives examined in the three Brazilian cities. In addition, adherence to care provided by medical genetics requires action and strategies that depend on arrangements involving family members, physicians, patient associations, and the state.

Fibrose hepática congênita e venopatia portal obliterativa sem hipertensão portal - revisão da literatura com base em um caso assintomático / Congenital hepatic fibrosis and obliterative portal venopathy without portal hypertension - a review of literature based on an asymptomatic case

ABSTRACT The disease and the case reported here are relevant especially because of their varied clinical presentation, possibility of being associated with other disorders affecting several organs and possible differential diagnoses. Congenital Hepatic Fibrosis is an autosomal recessive disease due to mutation in the PKHD1 gene, which encodes the fibrocystin/polyductine protein. It is a cholangiopathy, characterized by varying degrees of periportal fibrosis and irregular proliferation of bile ducts. Affected patients are typically diagnosed in childhood, but in some cases the disease may remain asymptomatic for many years. The exact prevalence and incidence of the disease are not known, but it is consider a rare disease, with a few hundred cases described worldwide. It can affect all ethnic groups and occur associated with various hereditary and non-hereditary disorders. The clinical presentation is quite variable, with melena and hematemesis being initial symptoms in 30%-70% of the cases. More rarely, they may present episodes of cholangitis. The disease has been classified into four types: portal hypertension, cholestasis / cholangitis, mixed and latent. Diagnosis begins with imaging tests, but the definition is made by the histopathological sample. So far, there is no specific therapy that can stop or reverse the pathological process. Currently, the therapeutic strategy is to treat the complications of the disease.

RESUMO A patologia e o caso aqui reportados são relevantes especialmente devido sua variada apresentação clínica, possibilidade de estar associada com outras desordens acometendo diversos órgãos e pelos possíveis diagnósticos diferenciais. A fibrose hepática congênita é uma doença autossômica recessiva, devido mutação no gene PKHD1, que codifica a proteína fibrocistina/poliductina. É uma colangiopatia, caracterizada por variados graus de fibrose periportal e proliferação irregular de ductos biliares. Os pacientes acometidos são tipicamente diagnosticados na infância, mas em alguns casos a doença pode permanecer assintomática por muitos anos. Exatas prevalência e incidência da doença não são conhecidas, mas sabe-se que é uma doença bastante rara, com algumas centenas de casos descritos no mundo. Pode afetar todos grupos étnicos e ocorrer associada com diversas desordens hereditárias e não-hereditárias. A apresentação clínica é bastante variável, com melena e hematêmese sendo sintomas iniciais em 30%-70% dos casos. Mais raramente, podem apresentar episódios de colangite. A doença tem sido classificada em quatro tipos: hipertensão portal, colestática/colangite, mista e latente. O diagnóstico inicia com exames de imagem, mas a definição é feita pela amostra histopatológica. Até o momento, não há terapia específica que possa parar ou reverter o processo patológico e a estratégia terapêutica atual é tratar as complicações da doença.

Trajetórias Terapêuticas Familiares: doenças raras hereditárias como sofrimento de longa duração / Family Therapeutic Trajectories: rare hereditary diseases involving long-term suffering

Resumo Este artigo analisa elementos comuns na trajetória de pessoas afetadas por doenças raras hereditárias no Brasil, tendo por cerne a busca por diagnóstico e tratamento, e a reprodutibilidade da família. Classificam-se como "raras" as doenças que afetam 65 pessoas a cada 100 mil. São condições geralmente crônicas e degenerativas, muitas delas sem cura ou tratamento efetivo. Cerca de 80% das doenças raras têm origem genética e são hereditárias. Este dado traz implicações importantes no que diz respeito às políticas de atenção à saúde da família, à reprodução e ao cuidado para condições clínicas que, em alguns casos, atravessam várias gerações. Para análise dos dados, articulam-se dois eixos teóricos: os estudos de família e parentesco e as análises sobre os sofrimentos de longa duração. A pesquisa desenvolveu-se junto a pessoas afetadas por doenças raras hereditárias e seus familiares, nos cenários políticos nos quais esses atores transitam, como associações de pacientes, congressos científicos e audiências públicas. Evidencia-se a necessidade de construção de uma pauta contínua sobre as doenças raras no Brasil, capaz de promover de fato o acesso universal e integral das pessoas afetadas ao sistema público de saúde, e buscar soluções para minorar sofrimentos que ameaçam a própria continuidade da família.

Abstract This article analyzes common elements in the trajectory of people affected by rare hereditary diseases in Brazil, focusing on the search for diagnosis and treatment, and the reproducibility in the family. Rare diseases affect 65 people in every 100 thousand. These are usually chronic and degenerative conditions, many incurable or without effective treatment. About 80% of rare diseases are genetic in origin and can be inherited. This fact has important implications for family health care policies, reproduction, and care for clinical conditions that, in some cases, spanned generations. To analyze the data, two theoretical axes are articulated: family and kinship studies, and analyzes of long-term suffering. The research investigated people affected by rare hereditary diseases and their families, in the political scenarios in which these actors circulate, such as patient associations, scientific congresses and public hearings. There is evidence of the need to build a continuous agenda on rare diseases in Brazil capable of effectively promoting universal and integral access of the affected persons to the public health system, and seeking for solutions to alleviate suffering that threatens the very continuity of the family.

Impacto de la enfermedad genética en los ingresos hospitalarios en un Servicio de Pediatría / Prevalence of genetic diseases in admissions to a tertiary care hospital pediatric service

Background: With the epidemiological changes, the role of genetic factors as a cause of morbidity and mortality is increasing, changing disease patterns of patients admitted to pediatric hospitals. Aim: To describe the prevalence of genetic diseases (GD) in patients admitted to a tertiary-care hospital Pediatric Service. Material and Methods: The clinical records of consecutive admissions to a Pediatric Service of a clinical hospital in 2011 were reviewed. Two categories were assigned: with GD and without GD. Both groups were compared according to days of hospitalization, type of admission, readmissions and mortality. Results: We reviewed the 98.1% of the 1,781 total annual admissions (1,459 cases), 322 of them were readmissions (187 cases). The mean age at admission was 54.8 ± 54 months and 55% were male. The mean hospitalization length was 4.9 ± 10 days. Of total admissions and individual cases, 52.7% (938/1,781) and 48% (705/1,459) were cases with GD, respectively. Within this group, 85% (597/705) were sub-categorized as having a significant genetic base. The differences between gender, age average income and hospital mortality were not significant between the two categories. Readmissions were more common for GD than for patients without GD (Odds ratio (OR): 2.6, confidence intervals (CI): 1.9-3.6). Average hospital stay was 27% higher among GD patients (p < 0.01). Conclusions: Our findings confirm the high prevalence of GD in pediatric hospitals (52.7%), with a higher risk for readmission in cases with GD compared with those without GD.

Arritmias genéticas: como investigar e como tratar? / Inherited arrhythmias: how to investigate and how to treat?

As arritmias hereditárias são responsáveis por uma proporção significante de mortes cardíacas súbitas em indivíduos jovens aparentemente saudáveis. As canalopatias, como síndrome de Brugada, síndrome do QT longo/curto e taquicardia ventricular polimórfica catecolaminérgica, contribuem com essa incidência e não são marcadas por anomalias estruturais. A cardiomiopatia genética, como cardiomiopatia arritmogênica doventrículo direito e cardiomiopatia hipertrófica, também são causas de morte súbita por arritmia. Novos consensos têm sido publicados para orientar melhor as ferramentas dediagnóstico, os escores de estratificação e o tratamento. Os testes genéticos têm papel importante no diagnóstico, na estratificação de risco e no tratamento de pacientes e de suas famílias. Os avanços da genética molecular nas duas últimas décadas revelaram a base genética subjacente da doença, e podem levar a tratamentos mais personalizados...

Inherited arrhythmias account for a significant proportion of sudden cardiac deaths in apparently healthy and young individuals. Ion channelopathies such as Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardiacontribute to this incidence and are marked by no structural abnormalities. Genetic cardiomyopathy such as Right Ventricular Arrhythmogenic Cardiomyopathy and HypertrophicCardiomyopathy are also causes of arrhythmogenic sudden death. New consensuses are published to better guide the diagnostic tools, stratification scores and treatment. Genetic testing plays somehow an important role in the diagnosis, risk-stratification and treatment of patients and family members. Molecular genetic advances in the last 2 decades have revealed the underlying genetic basis and these may lead to a personalized medicine...

Allogeneic haematopoietic stem cell transplantation: The Army hospital experience.

Background. We analysed the results of allogeneic haematopoietic stem cell transplantation (HSCT) in various genetic disorders, bone marrow failures and haematological malignancies done from 2002 to 2010 at the Army Hospital, Research and Referral, Delhi. Methods. A total of 119 matched-related allogeneic- HSCTs (allo-HSCTs) were done in 114 patients (men 76, women 38) aged between 2 and 60 years. Peripheral blood stem cells (n=75) and bone marrow (n=43) were used as the source of stem cells. Results. The overall survival was 62.3% (71/114) at a median follow-up of 34 months. Graft versus host disease (GVHD) was seen in 42 (36.8%) patients; grade III/IV acute GVHD in 17 (15%) and chronic GVHD in 24 (21%) patients. There were 4 (3.5%) graft rejections and one nonengraftment. The overall mortality was 37.7% (n=43) and the main causes of death were GVHD (32%), infections (26%), relapse (23%) and regimen-related toxicity (11%). Conclusion. Our results are comparable to published data in most disease conditions. With improvements in GVHD prophylaxis and better supportive care, we need to further reduce our mortality and morbidity.

Terapia génica: opción terapéutica para neoplasias, infecciones y enfermedades monogénicas / Gene therapy: a therapeutic option for neoplasias, infections and monogenic diseases

Durante las últimas dos décadas, los resultados de varios protocolos de terapia génica llevaron al descreimiento de la comunidad médica. Sin embargo, en años recientes se obtuvieron resultados muy exitosos que la reposicionaron como una opción prometedora para el tratamiento de muchas enfermedades. Frente a este resurgimiento del interés de la comunidad científca internacional en la terapia génica, resulta apropiado que el médico generalista comprenda sus fortalezas y limitaciones. El objetivo de este artículo es comentar la forma en que la terapia génica encara actualmente el tratamiento de patologías tan diversas como neoplasias, infecciones y enfermedades monogénicas.

During the last two decades, the outcome of various gene therapy protocols lead to medical community disbelief. Nevertheless, successful results obtained in recent years, repositioned gene therapy as a promising option for treatment of several diseases. Facing this renaissance of the international scientifc community interest on gene therapy, it seems to be necessary for the generalist physician to understand its strength and limitations. The objective of this article is to comment the way gene therapy addresses nowadays the treatment of such different pathologies as neoplasias, infections and monogenic diseases.

Stem cell through present and future.

Stem cell transplantation (SCT) has the potential to transform the lives of children with a wide variety of genetic diseases, ranging from inherent defects of hemopoietic cell production or function through to metabolic diseases mostly affecting solid organs. For these children life expectancy or quality of life would otherwise be very poor. It ranks as one of the most remarkable therapeutic advances of the past 40 years. Despite rapid technological improvements, however, there are still many short term risks and potential long term toxicities. Consequently, the rapid emergence of alternative therapies (including new drugs, enzyme and gene therapies), necessitate constant re-evaluation of the risk/benefit ratio for each disease and hence the appropriateness of SCT. This review describes the major aspects of the transplant process, indications for transplantation, outcome statistics, and areas where alternative therapies are becoming available. SCT remains a highly experimental therapy. Due to the relatively short history of the discipline no data exists on truly long term follow up. This is important as some organs benefit relatively poorly or problems may emerge which were never apparent as part of the untreated disease. The speed of technological change makes randomised trials on these diseases, which are individually quite rare, almost impossible to perform.

efficiency of CD40 down regulation by siRNA and antisense ODN: comparison of lipofectamine and FuGENE6

Dendritic cells [DCs] are ideal accessory cells in the field of gene therapy. Delivery of DNA and siRNA into mammalian cells is a useful technique in treating various diseases caused by single gene defects. Selective gene silencing by small interfering RNAs [siRNAs] and antisense oligodeoxynucleotides [ODN]s is an efficient method for the manipulation of cellular functions. An efficient, functional delivery system with no toxicity problems would be attractive. We compared two commercially available cationic lipids, Lipofectamine and FuGENE6, in the delivery of both siRNA and antisense ODNs into mice spleen-derived DCs. Cellular uptake was measured by the means of fluorescein-labelled non-silencing siRNA and antisense ODNs as a model system using flow cytometry. Cytotoxicity of the two delivery systems was compared with propidium iodide and annexin-V staining, and quantified with flow cytometry. The efficiency of our oligonucleotide delivery systems was compared by measuring CD40 expression by flow cytometry. CD40 expression in DCs was 38%. After siRNA transfection by Lipofectamine, CD40 expression decreased to 13%, and after transfection by FuGENE6, it decreased to 18%. The difference was statistically significant. CD40 down regulation in DCs transfected with the two different antisense sequences by Lipofectamine was 21% and 23%, and down regulation after transfection by FuGENE6 was 19% and 18%, respectively. The differences were not statistically significant. The effects of siRNA and antisense ODNs were specific. Lipofectamine was a more potent delivery system in siRNA effect, followed by FuGENE6. There was no significant difference between Lipofectamine and FuGENE6 as a delivery system of antisense ODNs

Principles of gene therapy.

Genes are specific sequences of bases that encode instructions to make proteins. When genes are altered so that encoded proteins are unable to carry out their normal functions, genetic disorders can result. Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. This article reviews the fundamentals in gene therapy and its various modes of administration with an insight into the role of gene therapy in Periodontics and future percepts and the technical and ethical issues of using gene therapy.

Recent advances in approach to treatment of genetic disorders: clinicians perspective.

There is no cure for most of the genetic disorders. The only option in most situations is prevention by counseling and prenatal diagnosis. However, over a decade, with the completion of the human genome project and other advances there is better understanding of pathogenesis, improvement in diagnostic strategies and various treatment avenues are opening up for these disorders. The aim of this article is to make the pediatricians aware of the approaches to treatment of common genetic disorders and recent available therapeutic interventions.

Biología molecular de los vectores adenovirales / Molecular biology of adenoviral vectors

La terapia con genes postula el uso terapéutico del DNA como una nueva alternativa de la biomedicina para el tratamiento de las enfermedades humanas. Todas las proteínas están codificadas en el DNA, y muchas enfermedades resultan de: a) la ausencia o expresión aberrante de uno o más genes; b) la ausencia de formas funcionales; c) alteraciones en su proceso de regulación, transporte o degradación. Por lo tanto, tales enfermedades pueden ser potencialmente tratadas, restableciendo la expresión de la proteína involucrada en las células afectadas. Sin embargo, para lograr una transferencia exitosa del material genético al sitio blanco y evitar la destrucción del DNA o del vehículo seleccionado antes de llegar al sitio de interés, se han desarrollado varios sistemas virales. Entre los virus más conocidos están: el virus del herpes simple, adenovirus tipo 5, virus adenoasociado y algunos retrovirus complejos (lentivirus). En este artículo se exponen las características biológicas, la manipulación genética y propiedades de los adenovirus, así como su empleo en la medicina actual como vectores para transferir genes y su potencial implicación en la terapia génica.

Gene therapy is based on the use of DNA as a therapeutic material as an alternative therapeutic tool for treatment of human diseases. All proteins are codified into the DNA and several diseases result from the absence or aberrant expression of one or related genes, absence of expression of functional proteins, and alterations for regulation process in transport and degradation mechanisms. In this regard, several diseases could be potentially treated through the expression of the normal form of the involved protein. However, the main objective is to achieve a successful genetic material delivery into the target site and avoid the destruction of DNA or the selected vehicle before arrival at the final destination. Several efficient viral gene transfer systems have been developed. Viral-mediated gene delivery for experimental models has been designed from herpes virus (HV), adenovirus (adenovirous), adeno-associated virus (AAV) and retroviruses (lentiviral vectors). In this review we will discuss the specific biological and cloning properties of adenoviral vectors as a gene transfer tool and potential medical implications for gene therapy.

Odontología genómica: la medicina oral del siglo XXI / Genomic dentistry: the oral medicine of 21st century

Los avances tecnológicos y la culminación del Proyecto Genoma Humano y con él la secuencia de 3.200 millones de los nucleótidos o de las letras (A-T/G-C) que la componen, y los aproximadamente 1.400 genes que pueden ser las causas de enfermedades consideradas hasta este momento como genéticas, han cambiado la cara de las investigaciones biológicas y han colocado a la genómica en la vanguardia de la ciencia biomédica. En la periodontología, así como en la medicina, estamos muy interesados en la genética y en los diferentes acomodos o polimorfismos de los nucleótidos (SNIPs), tanto en los humanos como en los patógenos, así como la interacción genética entre ellos