Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response.
Mol Ther
; 24(10): 1873-1880, 2016 10.
Article
em En
| MEDLINE
| ID: mdl-27456061
ABSTRACT
Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
4_TD
/
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Pneumonia Estafilocócica
/
Staphylococcus aureus
/
Glicoproteínas de Membrana
/
Terapia Genética
/
Transplante de Células-Tronco Hematopoéticas
/
NADPH Oxidases
/
Doença Granulomatosa Crônica
Tipo de estudo:
Guideline
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Ther
Ano de publicação:
2016
Tipo de documento:
Article