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1.
Mol Ther ; 25(9): 2093-2103, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28760668

RESUMO

Influenza A virus infection causes substantial morbidity and mortality in seasonal epidemic outbreaks, and more efficient treatments are urgently needed. Innate immune sensing of viral nucleic acids stimulates antiviral immunity, including cell-autonomous antiviral defense mechanisms that restrict viral replication. RNA oligonucleotide ligands that potently activate the cytoplasmic helicase retinoic-acid-inducible gene I (RIG-I) are promising candidates for the development of new antiviral therapies. Here, we demonstrate in an Mx1-expressing mouse model of influenza A virus infection that a single intravenous injection of low-dose RIG-I ligand 5'-triphosphate RNA (3pRNA) completely protected mice from a lethal challenge with influenza A virus for at least 7 days. Furthermore, systemic administration of 3pRNA rescued mice with pre-established fulminant influenza infection and prevented the fatal effects of a streptococcal superinfection. Type I interferon, but not interferon-λ, was required for the therapeutic effect. Our results suggest that the use of RIG-I activating oligonucleotide ligands has the clinical potential to confine influenza epidemics when a strain-specific vaccine is not yet available and to reduce lethality of influenza in severely infected patients.


Assuntos
Infecções Bacterianas , Vírus da Influenza A , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Superinfecção , Animais , Quimiocina CXCL10/metabolismo , Vírus da Influenza A/imunologia , Interferon Tipo I/metabolismo , Ligantes , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Proteínas de Membrana/agonistas , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/agonistas , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/genética , Infecções por Orthomyxoviridae/mortalidade , Substâncias Protetoras/administração & dosagem , RNA/administração & dosagem , RNA/genética , Receptores de Superfície Celular , Análise de Sobrevida , Receptores Toll-Like/metabolismo
2.
Br J Haematol ; 176(5): 796-804, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28198996

RESUMO

Inhibitor formation in non-severe haemophilia A is a life-long risk and associated with morbidity and mortality. There is a paucity of data to understand real-world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non-severe haemophilia A in seven London haemophilia centres. In the 2-year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy-nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had 'high-risk' F8 genotypes. In patients with 'standard-risk' F8 genotypes treated on-demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after 'high-risk' treatment episodes. In patients with 'standard-risk' F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of 'high-risk' F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non-severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism.


Assuntos
Fator VIII/genética , Genótipo , Hemofilia A/imunologia , Hemofilia A/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Hemofilia A/genética , Hemostáticos/uso terapêutico , Humanos , Lactente , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
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