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1.
Annu Rev Pathol ; 16: 145-166, 2021 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-33497260

RESUMO

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Doenças Genéticas Inatas/diagnóstico , Terapia Genética/tendências , Humanos
5.
Nat Biotechnol ; 38(7): 845-855, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32601435

RESUMO

Genome editing has the potential to treat an extensive range of incurable monogenic and complex diseases. In particular, advances in sequence-specific nuclease technologies have dramatically accelerated the development of therapeutic genome editing strategies that are based on either the knockout of disease-causing genes or the repair of endogenous mutated genes. These technologies are progressing into human clinical trials. However, challenges remain before the therapeutic potential of genome editing can be fully realized. Delivery technologies that have serendipitously been developed over the past couple decades in the protein and nucleic acid delivery fields have been crucial to genome editing success to date, including adeno-associated viral and lentiviral vectors for gene therapy and lipid nanoparticle and other non-viral vectors for nucleic acid and protein delivery. However, the efficiency and tissue targeting capabilities of these vehicles must be further improved. In addition, the genome editing enzymes themselves need to be optimized, and challenges regarding their editing efficiency, specificity and immunogenicity must be addressed. Emerging protein engineering and synthetic chemistry approaches can offer solutions and enable the development of safe and efficacious clinical genome editing.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/tendências , Doenças Genéticas Inatas/terapia , Terapia Genética , Doenças Genéticas Inatas/genética , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Humanos , Nanopartículas/uso terapêutico , Engenharia de Proteínas
6.
Pediatrics ; 145(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32327449

RESUMO

As the technical ability for genetic diagnosis continues to improve, an increasing number of diagnoses are made in infancy or as early as the neonatal period. Many of these diagnoses are known to be associated with developmental delay and intellectual disability, features that would not be clinically detectable at the time of diagnosis. Others may be associated with cognitive impairment, but the incidence and severity are yet to be fully described. These neonates and infants with genetic diagnoses therefore represent an emerging group of patients who are at high risk for neurodevelopmental disabilities. Although there are well-established developmental supports for high-risk infants, particularly preterm infants, after discharge from the NICU, programs specifically for infants with genetic diagnoses are rare. And although previous research has demonstrated the positive effect of early developmental interventions on outcomes among preterm infants, the impact of such supports for infants with genetic disorders who may be born term, remains to be understood. We therefore review the literature regarding existing developmental assessment and intervention approaches for children with genetic disorders, evaluating these in the context of current developmental supports postdischarge for preterm infants. Further research into the role of developmental support programs for early assessment and intervention in high-risk neonates diagnosed with rare genetic disorders is needed.


Assuntos
Deficiências do Desenvolvimento/psicologia , Deficiências do Desenvolvimento/terapia , Doenças Genéticas Inatas/psicologia , Doenças Genéticas Inatas/terapia , Deficiências do Desenvolvimento/diagnóstico , Intervenção Educacional Precoce/métodos , Doenças Genéticas Inatas/diagnóstico , Humanos , Recém-Nascido , Recém-Nascido Prematuro/fisiologia , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/psicologia , Doenças do Prematuro/terapia
8.
J Appl Genet ; 61(1): 51-65, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912450

RESUMO

Hereditary hearing loss (HHL) is a neurosensory disorder that affects every 1/500 newborns worldwide and nearly 1/3 people over the age of 65. Congenital deafness is inherited as monogenetic or polygenic disorder. The delicacy, tissue heterogeneity, deep location of the inner ear down the brainstem, and minute quantity of cells present in cochlea are the major challenges for current therapeutic approaches to cure deafness. Targeted genome editing is considered a suitable approach to treat HHL since it can target defective molecular components of auditory transduction to restore normal cochlear function. With the advent of CRISPR/Cas9 technique, targeted genome editing and biomedical research have been revolutionized. The robustness and simplicity of this technology lie in its design and delivery methods. It can directly deliver a complex of Cas9 endonuclease and single guide RNA (sgRNA) into zygote using either vector-mediated stable transfection or transient delivery of ribonucleoproteins complexes. This strategy induces DNA double strand breaks (DSBs) at target site followed by endogenous DNA repairing mechanisms of the cell. CRISPR/Cas9 has been successfully used in model animals to edit hearing genes like calcium and integrin-binding protein 2, myosin VIIA, Xin-actin binding repeat containing 2, leucine-zipper and sterile-alpha motif kinase Zak, epiphycan, transmembrane channel-like protein 1, and cadherin 23. This review discusses the utility of lipid-mediated transient delivery of Cas9/sgRNA complexes, an efficient way to restore hearing in humans, suffering from HHL. Notwithstanding, challenges like PAM requirement, HDR efficiency, off-target activity, and optimized delivery systems need to be addressed.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Perda Auditiva/genética , Perda Auditiva/terapia , Animais , Biomarcadores , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Predisposição Genética para Doença , Terapia Genética , Vetores Genéticos/genética , Células Ciliadas Auditivas/fisiologia , Humanos , Camundongos , Ligação Proteica , Interferência de RNA , Regeneração , Ribonucleoproteínas/metabolismo , Transfecção/métodos , Resultado do Tratamento
9.
Pediatr Pulmonol ; 55(3): 780-787, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31977167

RESUMO

BACKGROUND: Pediatric home ventilation (HV) has increased worldwide. A Home Ventilation Program (HVP) was started in the Pulmonary Department of the "Hospital de Pediatría Prof. Dr. J. P. Garrahan," Argentina, in 2007. This is the largest Argentine national pediatric tertiary care referral center. Limited studies on pediatric HV from Latin American countries have been published. OBJECTIVE: This study describes and analyzes the cohort of children admitted to the HVP during an 11 years period. METHODS: Longitudinal study. POPULATION: all patients (pts) admitted to the HVP between 2007 and 2018. We analyzed demographic and clinical variables, sleep study results, ventilation setting, and start manner collected in a prospective data base. RESULTS: A total of 244 pts were admitted. Median age at ventilation start was 9.41 (3.47-14.08) years, 84% of pts had health insurance. The most frequent underlying diseases were neuromuscular disease (43%) and genetic syndromes (23%). Home-hospital distance was 100-500 km in 16% of cases and greater than 500 km in 34%. Seventy percent of pts had sleep studies before ventilation initiation. Ventilation was started in our general pediatric ward in 83.6%. Noninvasive ventilation was used in 86.1%. The actual number of pts still on follow up is 133 of 244 (54.5%), 16.8% dropped out, 16.4% were transitioned to adult care, 5.32% resolved their sleep-disordered breathing, and 5.32% died. CONCLUSIONS: The HVP admitted pts from all the country. Ventilation was started on the basis of clinical and objective sleep measures. This long-term experience underlines the feasibility of a HVP in an emergent country.


Assuntos
Serviços de Assistência Domiciliar , Respiração Artificial , Adolescente , Argentina , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Doenças Genéticas Inatas/terapia , Humanos , Estudos Longitudinais , Masculino , Doenças Neuromusculares/terapia
11.
Int J Mol Sci ; 21(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991730

RESUMO

RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.


Assuntos
Edição de Genes , Terapia Genética , Edição de RNA , Retina/metabolismo , Transgenes , Adenosina Desaminase/metabolismo , Animais , Sistemas CRISPR-Cas , Imunofluorescência , Marcação de Genes , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Humanos , Proteínas de Ligação a RNA/metabolismo , Retina/patologia , Doenças Retinianas/genética , Doenças Retinianas/terapia
13.
J Pathol ; 250(1): 9-18, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31579936

RESUMO

Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doenças Genéticas Inatas/genética , Chaperonas Moleculares/genética , Mutação , Animais , Chaperonina 60/genética , Chaperonina 60/metabolismo , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/metabolismo , Fenótipo , Prognóstico , Processamento de Proteína Pós-Traducional , Fatores de Risco , Transdução de Sinais
14.
Esc. Anna Nery Rev. Enferm ; 24(1): e20190128, 2020.
Artigo em Inglês | LILACS, BDENF - Enfermagem | ID: biblio-1039817

RESUMO

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.


Assuntos
Humanos , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Adulto Jovem , Serviços Públicos de Saúde , Acesso aos Serviços de Saúde , Doenças Genéticas Inatas/terapia , Brasil , Família , Cuidadores , Pesquisa Qualitativa , Necessidades e Demandas de Serviços de Saúde/organização & administração , Doenças Genéticas Inatas/diagnóstico
15.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801211

RESUMO

The gene editing tool CRISPR-Cas has become the foundation for developing numerous molecular systems used in research and, increasingly, in medical practice. In particular, Cas proteins devoid of nucleolytic activity (dead Cas proteins; dCas) can be used to deliver functional cargo to programmed sites in the genome. In this review, we describe current CRISPR systems used for developing different dCas-based molecular approaches and summarize their most significant applications. We conclude with comments on the state-of-art in the CRISPR field and future directions.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas , Doenças Transmissíveis/terapia , Edição de Genes/métodos , Doenças Genéticas Inatas/terapia , Inflamação/terapia , Neoplasias/terapia , Proteína 9 Associada à CRISPR/metabolismo , Cromatina/química , Cromatina/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Doenças Transmissíveis/genética , Doenças Transmissíveis/metabolismo , Doenças Transmissíveis/patologia , Metilação de DNA , Epigênese Genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Genoma Humano , Histonas/genética , Histonas/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , RNA Guia/genética , RNA Guia/metabolismo
17.
AMA J Ethics ; 21(12): E1029-1035, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31876465

RESUMO

As patients with genetic diseases seek to have healthy biologically connected children, they will undoubtedly turn to trusted health care professionals for guidance. "Doctor, should I enter a clinical trial to edit my embryos?" is likely to become a query posed by patients with genetic illnesses. Physicians need both empathic communication skills and a framework for responding to this question. Applying the 4-S framework to gene editing can guide clinicians' responses to patients' CRISPR queries by facilitating discussion of (1) safety, (2) significance of harm to be averted, (3) impact on succeeding generations, and (4) social consequences.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/ética , Terapia Genética/ética , Educação de Pacientes como Assunto/ética , Relações Médico-Paciente/ética , Aconselhamento/ética , Doenças Genéticas Inatas/terapia , Terapia Genética/efeitos adversos , Humanos , Educação de Pacientes como Assunto/métodos , Fatores de Risco
19.
Artigo em Russo | MEDLINE | ID: mdl-31765538

RESUMO

In order to optimize economic and organizational technologies for the provision of medical care to the population and to increase the effectiveness of preventive programs, an analysis of the accumulated morbidity and prevalence of monogenic hereditary diseases (MHDs) has been carried out in 13 federal subjects of the Russian Federation representing 11 ethnic groups: Russians of 6 regions, Tatars, Maris, Chuvashs, Bashkirs, Udmurts, Abazins, Adygeans, Nogays, Circassians and Karachays. The study of the population was carried out according to the developed protocol of complex genetic and epidemiological studies in the Research Center for Medical Genetics, which remains unchanged throughout the study. Here we have studied the structure of the genetic load and diversity of MHDs depending on the prevalence of diseases and in accordance with the classification by organ and system types of disease: neurological, ophthalmological, genodermatosis, skeletal, hereditary syndromes, and other hereditary pathology (metabolic hereditary diseases, disorders of blood, hearing, etc.). It is shown that the maximum number of patients (61.81%) falls in the group of frequent forms of MHDs, which differ by federal subjects / ethnic groups of the Russian Federation. There are frequent forms of MHDs for all populations, and "specific" forms for particular federal subjects of the Russian Federation/ethnic groups. Only for a small group of hereditary diseases there is treatment. Most of the detected diseases-psychiatric, neurological, hematological, and hereditary syndromes-significantly reduce life expectancy. Hereditary diseases of the skeleton, eyes, ears and metabolism affect the quality of life, adaptation in society and public health. On average, 65% of patients are diagnosed with MHDs for the first time. This situation implies changes in medical thinking, changes in education and development of both common for all regions and specific prevention programs. Thus, fundamental research in medicine can improve the quality of medical services and contribute to the improvement of public health.


Assuntos
Doenças Genéticas Inatas , Serviços Preventivos de Saúde , Qualidade de Vida , Doenças Genéticas Inatas/prevenção & controle , Doenças Genéticas Inatas/terapia , Humanos , Prevalência , Federação Russa
20.
Cell ; 179(4): 813-827, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31675495

RESUMO

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.


Assuntos
Envelhecimento/genética , Biomarcadores , Senescência Celular/genética , Doenças Genéticas Inatas/genética , Pontos de Checagem do Ciclo Celular/genética , Cromatina/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/terapia , Humanos
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