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1.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32843442

RESUMO

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.


Assuntos
Terapia Genética/métodos , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/terapia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Adenovírus Humanos , Fatores Etários , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Terapia Genética/efeitos adversos , Vetores Genéticos/administração & dosagem , Glucocorticoides/administração & dosagem , Humanos , Lactente , Ohio , Avaliação de Resultados em Cuidados de Saúde , Prednisolona/administração & dosagem , gama-Glutamiltransferase/metabolismo
2.
Nat Commun ; 11(1): 3929, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764559

RESUMO

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.


Assuntos
Terapia Genética/métodos , Vetores Genéticos , Parvovirinae/genética , Proteinose Alveolar Pulmonar/congênito , Proteína B Associada a Surfactante Pulmonar/deficiência , Animais , Animais Recém-Nascidos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Precursores de Proteínas/genética , Proteolipídeos/genética , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Proteinose Alveolar Pulmonar/terapia , Proteína B Associada a Surfactante Pulmonar/genética , Proteína B Associada a Surfactante Pulmonar/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/genética , Transdução Genética
3.
Med Sci (Paris) ; 36(8-9): 725-734, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32821049

RESUMO

The prognosis for phenylketonuria (PKU) has been improved by neonatal screening and dietary management via a low-phenylalanine diet. This treatment must be followed throughout life, which induces severe compliance problems. Drug treatment with sapropterin (or BH4) has come to help a reduced percentage of patients who respond to this drug. A subcutaneous enzyme therapy is available in the USA and has obtained European marketing authorization, but generates significant side effects, which limits its effectiveness. New therapeutic options for PKU are currently being developed, in particular gene therapy. The purpose of this article is to take stock of the pathophysiology and the various new therapeutic modalities currently in development.


Assuntos
Dieta , Terapia Genética , Fenilcetonúrias/terapia , Biopterina/análogos & derivados , Biopterina/uso terapêutico , Dieta/efeitos adversos , Dieta/métodos , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Recém-Nascido , Triagem Neonatal , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/dietoterapia , Prognóstico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
4.
PLoS One ; 15(8): e0237156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780756

RESUMO

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.


Assuntos
Terapia Genética/métodos , Fator de Crescimento de Hepatócito/genética , Neuralgia/terapia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Hiperalgesia/metabolismo , Lipossomos/metabolismo , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Vírus Sendai/genética , Resultado do Tratamento
5.
Gene ; 763: 145066, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827686

RESUMO

Diabetes is characterized by changed homeostasis of blood glucose levels, which is associated with various complications, including cardiomyopathy, atherosclerosis, endothelial dysfunction, nephropathy, retinopathy and neuropathy. In recent years, accumulative evidence has demonstrated that circular RNAs are identified as a novel type of noncoding RNAs (ncRNAs) involving in the regulation of various physiological processes and pathologic conditions. Specifically, the emergence of complications response to diabetes is finely controlled by a complex gene regulatory network in which circular RNAs play a critical role. Recently, circular RNAs are emerging as messengers that could influence cellular functions under diabetic conditions. Dysregulation of circular RNAs has been closely linked to the pathophysiology of diabetes-related complications. In this review, we aimed to summarize the current progression and underlying mechanisms of circular RNA in the development of diabetes-related complications. We will also provide an overview of circular RNA-regulated cell communications in different types of cells that have been linked to diabetic complications. We anticipated that the completion of this review will provide potential clues for developing novel circular RNAs-based biomarkers or therapeutic targets for diabetes and its associated complications.


Assuntos
Angiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Neuropatias Diabéticas/metabolismo , RNA Circular/metabolismo , Animais , Biomarcadores/metabolismo , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/terapia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/terapia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/terapia , Terapia Genética/métodos , Humanos , Ilhotas Pancreáticas/metabolismo , RNA Circular/genética
6.
Life Sci ; 259: 118165, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735884

RESUMO

CRISPR (clustered regularly interspaced short palindromic Repeats)/Cas9 is a new genetic editing technology that can be a beneficial method to advance gene therapy. CRISPR technology is a defense system of some bacteria against invading viruses. Genome editing based on the CRISPR/Cas9 system is an efficient and potential technology that can be a viable alternative to traditional methods. This system is a compound of a short guide RNAs (gRNAs) for identifying the target DNA sequence and Cas9 protein as nuclease for breaking and cutting of DNA. In this review, recent advances in the CRISPR/Cas9-mediated genome editing tools are presented as well as their use in gene therapy strategies for the treatment of neurological disorders including Parkinson's disease, Alzheimer's disease, and Huntington's disease.


Assuntos
Sistemas CRISPR-Cas , Terapia Genética/métodos , Doenças Neurodegenerativas/terapia , Animais , Humanos
7.
Nat Rev Drug Discov ; 19(7): 463-479, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612263

RESUMO

Naturally occurring stem cells isolated from humans have been used therapeutically for decades. This has primarily involved the transplantation of primary cells such as haematopoietic and mesenchymal stem cells and, more recently, derivatives of pluripotent stem cells. However, the advent of cell-engineering approaches is ushering in a new generation of stem cell-based therapies, greatly expanding their therapeutic utility. These next-generation stem cells are being used as 'Trojan horses' to improve the delivery of drugs and oncolytic viruses to intractable tumours and are also being engineered with angiogenic, neurotrophic and anti-inflammatory molecules to accelerate the repair of injured or diseased tissues. Moreover, gene therapy and gene editing technologies are being used to create stem cell derivatives with improved functionality, specificity and responsiveness compared with their natural counterparts. Here, we review these engineering approaches and areas in which they will help broaden the utility and clinical applicability of stem cells.


Assuntos
Engenharia Celular/métodos , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Animais , Sistemas de Liberação de Medicamentos , Edição de Genes , Terapia Genética/métodos , Humanos , Terapia Viral Oncolítica/métodos
8.
PLoS One ; 15(7): e0236175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697798

RESUMO

Adenoviruses cause upper respiratory infections, conjunctivitis, keratitis, and gastrointestinal illness. These can be fatal in immunocompromised individuals. Adenoviruses have also been engineered into viral vectors to deliver therapeutic genes or induce immunity as vaccine carriers. The success of ocular gene therapy is driven partly by the immunologic and biochemical influences of the intraocular environment. We have shown that versican and hyaluronan modulate adenoviral vector transgene expression through CD44 signaling. Herein we explored the role of these pathways on virus replication and viral protein expression of wild type adenovirus. We report that the addition of vitreous humor (which contains both versican and hyaluronan) increases viral hexon protein levels. Vitreous humor also increased wild type adenovirus DNA replication in vitro. Metalloproteinase and γ-secretase inhibitors, which inhibit CD44 proteolytic activation, blocked adenoviral replication in vitro. Similarly, protein kinase C and RhoA kinase inhibitors, both proteins associated with CD44 mediated pathways, also inhibited wild type adenoviral replication in vitro. Application of metalloproteinase and γ-secretase inhibitors to human conjunctival explants sharply decreased adenoviral vector gene expression. Our results demonstrate that pharmacologic delivery of these inhibitors is easily achievable. The inhibition of these enzymes should be explored as potential therapies of wild type adenoviral infections.


Assuntos
Infecções por Adenoviridae/tratamento farmacológico , Adenoviridae/efeitos dos fármacos , Antivirais/farmacologia , Vetores Genéticos/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adenoviridae/fisiologia , Infecções por Adenoviridae/virologia , Administração Oftálmica , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/uso terapêutico , Túnica Conjuntiva/metabolismo , DNA Viral/genética , DNA Viral/isolamento & purificação , Diaminas/farmacologia , Diaminas/uso terapêutico , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/fisiologia , Células HeLa , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Maleimidas/farmacologia , Maleimidas/uso terapêutico , Metaloproteases/antagonistas & inibidores , Metaloproteases/metabolismo , Permeabilidade , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteólise/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Versicanas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Corpo Vítreo/metabolismo , Quinases Associadas a rho/metabolismo
10.
Med Sci (Paris) ; 36(6-7): 607-615, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32614312

RESUMO

Retinitis pigmentosa is the most common blinding inherited retinal dystrophy. Gene therapy is a burgeoning revolutionary approach that paves the way to treatment of previously incurable diseases. At the end of 2017 and 2018, a gene therapy, Luxturna®, obtained a marketing authorization by respectively the FDA (Food and Drug Administration) and the EMA (European Medicines Agency). This treatment, with proven efficacy, is available to patients with Leber congenital amaurosis and retinitis pigmentosa associated with bi-allelic mutations of the RPE 65 gene. In this paper, we present the current advances in gene therapy for retinitis pigmentosa and discuss the technological, economic and ethical challenges to overcome for gene therapy to improve medical practices.


Assuntos
Terapia Genética , Retinite Pigmentosa/terapia , Estudos de Associação Genética , Terapia Genética/economia , Terapia Genética/ética , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Mutação , Padrões de Prática Médica/normas , Padrões de Prática Médica/tendências , Melhoria de Qualidade , Retinite Pigmentosa/genética
11.
Cardiovasc Pathol ; 49: 107243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32629211

RESUMO

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of cases of heart failure, which is the most common cause of hospitalization in US patients over the age of 65. HFpEF pathogenesis is increasingly believed to be due to pathological hypertrophy and fibrosis of the myocardium that may be a result of systemic inflammation from comorbid conditions such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, anemia, chronic kidney disease and others. It is believed that oxidative stress triggers a process of pathological hypertrophy and fibrosis in cardiac endothelial cells, which leads to increased left ventricle filling pressures and, eventually, symptoms of heart failure. Numerous recent major clinical trials that have examined various therapies aimed at improving mortality in HFpEF have emerged empty-handed and thus the search for effective management strategies continues. Over the last several years, there have been many new developments in the field of antisense oligonucleotide-based therapeutics, which involves using noncoding nucleic acid particles such as microRNA and small interfering RNA to repress the expression of specific messenger RNA. In this article, we review the concept of using oligonucleotide-based therapeutics to prevent or treat HFpEF by targeting a specific microRNA that has been implicated in the pathogenesis of myocardial fibrosis and hypertrophy, microRNA-21 (miR-21). We review the various evidence that implicates miR-21 in the process of myocardial fibrosis and discuss recent attempts to use antimiR-21 compounds to prevent fibrosis. We also discuss proposed methods for screening patients at high risk for HFpEF for diastolic dysfunction in order to determine which patients.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/terapia , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Volume Sistólico , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Resultado do Tratamento , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
12.
Am J Hum Genet ; 107(2): 278-292, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707085

RESUMO

Dominantly inherited disorders are not typically considered to be therapeutic candidates for gene augmentation. Here, we utilized induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation to treat Best disease, a dominant macular dystrophy caused by over 200 missense mutations in BEST1. Gene augmentation in iPSC-RPE fully restored BEST1 calcium-activated chloride channel activity and improved rhodopsin degradation in an iPSC-RPE model of recessive bestrophinopathy as well as in two models of dominant Best disease caused by different mutations in regions encoding ion-binding domains. A third dominant Best disease iPSC-RPE model did not respond to gene augmentation, but showed normalization of BEST1 channel activity following CRISPR-Cas9 editing of the mutant allele. We then subjected all three dominant Best disease iPSC-RPE models to gene editing, which produced premature stop codons specifically within the mutant BEST1 alleles. Single-cell profiling demonstrated no adverse perturbation of retinal pigment epithelium (RPE) transcriptional programs in any model, although off-target analysis detected a silent genomic alteration in one model. These results suggest that gene augmentation is a viable first-line approach for some individuals with dominant Best disease and that non-responders are candidates for alternate approaches such as gene editing. However, testing gene editing strategies for on-target efficiency and off-target events using personalized iPSC-RPE model systems is warranted. In summary, personalized iPSC-RPE models can be used to select among a growing list of gene therapy options to maximize safety and efficacy while minimizing time and cost. Similar scenarios likely exist for other genotypically diverse channelopathies, expanding the therapeutic landscape for affected individuals.


Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Degeneração Macular/genética , Mutação/genética , Alelos , Bestrofinas/genética , Cálcio/metabolismo , Linhagem Celular , Canalopatias/genética , Proteínas do Olho/genética , Edição de Genes/métodos , Terapia Genética/métodos , Genótipo , Células HEK293 , Humanos , Epitélio Pigmentado da Retina/fisiologia
13.
Protein Cell ; 11(10): 707-722, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32519302

RESUMO

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Transplante de Células-Tronco Mesenquimais , Pandemias , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/terapia , Transferência Adotiva , Células Epiteliais Alveolares/patologia , Animais , Apoptose , Líquidos Corporais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Ensaios Clínicos como Assunto , Coinfecção/prevenção & controle , Coinfecção/terapia , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Oxigenação por Membrana Extracorpórea , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/uso terapêutico , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Pesquisa Médica Translacional
15.
Yakugaku Zasshi ; 140(5): 651-655, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378666

RESUMO

Advances in genomic medicine have enabled the development of precise cancer therapies (precision cancer medicine) through multigene testing. Toward this end, we have developed a novel clinical sequencing system called PleSSision (Pathologist edited, Mitsubishi Space Software supervised clinical sequence system for personalized medicine) that performs amplicon exome sequencing targeting 160 cancer genes. Using this system, we have examined more than 600 cases over 3 years, and have identified druggable gene alteration in approximately 60% of the cases. Performing such clinical sequencing requires management of the sample quality and sequencing by pathologists and laboratory technicians; bioinformatics analysis by biomedical scientists; and patient care by nurses and pharmacists, all based on specific skills and knowledge of genomics. In addition, patients diagnosed with a hereditary cancer syndrome based on clinical sequencing results must receive care from a genetic counselor and a medical doctor with expertise in genetics. Recently, poly(ADP-ribose)polymerase (PARP) inhibitors and immune checkpoint inhibitors have been used in the treatment of patients with hereditary cancer syndromes, so collaboration involving other medical staff, especially genomic pharmacists, is also required. In this session, we provide an overview of cancer genomic medicine and emphasize the role that genomic pharmacists play in cancer precision medicine.


Assuntos
Testes Genéticos/métodos , Terapia Genética/métodos , Genoma Humano , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Equipe de Assistência ao Paciente , Farmacêuticos , Medicina de Precisão , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
16.
Yakugaku Zasshi ; 140(5): 657-661, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378667

RESUMO

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.


Assuntos
Ciência de Dados/educação , Terapia Genética/métodos , Genoma Humano , Genômica , Corpo Clínico/educação , Neoplasias/genética , Neoplasias/terapia , Equipe de Assistência ao Paciente , Competência Clínica , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Mutação
17.
Yakugaku Zasshi ; 140(5): 663-666, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378668

RESUMO

The development of cancer genomic medicine has been embraced as an important new policy issue in "The 3rd Basic Plan to Promote Cancer Control Programs" formulated by the Japanese government. Cancer-associated gene panel testing has been recognized by the public health insurance system since July 2019, and is a critical component of the clinical implementation of genomic science. Because of this dynamic change in cancer medicine, pharmacists are now expected to acquire knowledge about genomic science, and to apply it to individualized and appropriate pharmacotherapies. This review outlines the roles of pharmacists in cancer genomic medicine.


Assuntos
Terapia Genética/métodos , Genômica , Neoplasias/genética , Neoplasias/terapia , Farmacêuticos , Papel Profissional , Humanos , Conhecimento , Neoplasias/diagnóstico , Medicina de Precisão
18.
Proc Natl Acad Sci U S A ; 117(20): 10976-10982, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358194

RESUMO

Advances in gene editing are leading to new medical interventions where patients' own cells are used for stem cell therapies and immunotherapies. One of the key limitations to translating these treatments to the clinic is the need for scalable technologies for engineering cells efficiently and safely. Toward this goal, microfluidic strategies to induce membrane pores and permeability have emerged as promising techniques to deliver biomolecular cargo into cells. As these technologies continue to mature, there is a need to achieve efficient, safe, nontoxic, fast, and economical processing of clinically relevant cell types. We demonstrate an acoustofluidic sonoporation method to deliver plasmids to immortalized and primary human cell types, based on pore formation and permeabilization of cell membranes with acoustic waves. This acoustofluidic-mediated approach achieves fast and efficient intracellular delivery of an enhanced green fluorescent protein-expressing plasmid to cells at a scalable throughput of 200,000 cells/min in a single channel. Analyses of intracellular delivery and nuclear membrane rupture revealed mechanisms underlying acoustofluidic delivery and successful gene expression. Our studies show that acoustofluidic technologies are promising platforms for gene delivery and a useful tool for investigating membrane repair.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Sistema Hematopoético , Células-Tronco , Sobrevivência Celular , Citoplasma , Expressão Gênica , Técnicas de Transferência de Genes/instrumentação , Terapia Genética/instrumentação , Proteínas de Fluorescência Verde/genética , Humanos , Células Jurkat , Plasmídeos , Som
19.
Expert Rev Anti Infect Ther ; 18(8): 799-805, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32366131

RESUMO

INTRODUCTION: Clustered regularly interspaced short palindromic repeats (CRISPR) are segments of nucleic acid that play a role in prokaryotic defense and form the basis of a genome editing technology that allows permanent alteration of genetic material. This methodology, known as CRISPR-Cas9, is poised to revolutionize molecular biology, but no literature yet exists on how these advances will affect hospitalists. AREAS COVERED: These specialists in inpatient medicine care for a wide variety of hospitalized patients, including those with infectious disease, cancer, cardiovascular disease, autoimmune disease, hematologic disease, and a variety of other conditions that may soon be impacted by advances in gene-modifying technology provided by CRISPR-Cas9. A Literature search was performed using PubMed [1 December 2019-17 April 2020]. EXPERT OPINION: This paper reviews the remarkable diagnostic and therapeutic potential of the CRISPR-Cas9 platform and concludes with a look at ethical issues and technical hurdles pertaining to the implementation of permanent gene modification in the practice of Hospital Medicine.


Assuntos
Sistemas CRISPR-Cas , Terapia Genética/métodos , Medicina Hospitalar , Betacoronavirus , Infecções por Coronavirus/terapia , Edição de Genes/métodos , Humanos , Pandemias , Pneumonia Viral/terapia
20.
Invest Ophthalmol Vis Sci ; 61(5): 30, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32428231

RESUMO

Purpose: To determine the therapeutic window for gene augmentation for Leber congenital amaurosis (LCA) associated with mutations in LCA5. Methods: Five patients (ages 6-31) with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5gt/gt mouse model and the efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal day 5 (P5) (early, n = 11 eyes), P15 (mid, n = 14), and P30 (late, n = 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease. Results: Patients with LCA5-LCA showed a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted sensitivity loss. The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became nondetectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue. Conclusions: LCA5-LCA is a particularly severe form of LCA that was recapitulated in the Lca5gt/gt mouse. Gene augmentation resulted in structural and functional rescue in the Lca5gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all patients with LCA5-LCA, at a level equivalent to that observed in rescued Lca5gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA.


Assuntos
Dependovirus/genética , Proteínas do Olho/genética , Terapia Genética , Amaurose Congênita de Leber/terapia , Proteínas Associadas aos Microtúbulos/genética , Retina/fisiopatologia , Adulto , Animais , Criança , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Terapia Genética/métodos , Vetores Genéticos , Humanos , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Imagem Óptica , Fenótipo , Pupila/fisiologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia , Adulto Jovem
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