Abstract:
:Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene and is characterized by recurrent and life-threatening bacterial infections. These mutations lead to defective or absent expression of β2 integrins on the leukocyte surface, compromising adhesion and extravasation at sites of infection. Three different lentiviral vectors (LVs) conferring ubiquitous or preferential expression of CD18 in myeloid cells were constructed and tested in human and mouse LAD-I cells. All three hCD18-LVs restored CD18 and CD11a membrane expression in LAD-I patient-derived lymphoblastoid cells. Corrected cells recovered the ability to aggregate and bind to sICAM-1 after stimulation. All vectors induced stable hCD18 expression in hematopoietic cells from mice with a hypomorphic Itgb2 mutation (CD18(HYP)), both in vitro and in vivo after transplantation of corrected cells into primary and secondary CD18(HYP) recipients. hCD18(+) hematopoietic cells from transplanted CD18(HYP) mice also showed restoration of mCD11a surface co-expression. The analysis of in vivo neutrophil migration in CD18(HYP) mice subjected to two different inflammation models demonstrated that the LV-mediated gene therapy completely restored neutrophil extravasation in response to inflammatory stimuli. Finally, these vectors were able to correct the phenotype of human myeloid cells derived from CD34(+) progenitors defective in ITGB2 expression. These results support for the first time the use of hCD18-LVs for the treatment of LAD-I patients in clinical trials.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Leon-Rico D,Aldea M,Sanchez-Baltasar R,Mesa-Nuñez C,Record J,Burns SO,Santilli G,Thrasher AJ,Bueren JA,Almarza Edoi
10.1089/hum.2016.016subject
Has Abstractpub_date
2016-09-01 00:00:00pages
668-78issue
9eissn
1043-0342issn
1557-7422journal_volume
27pub_type
杂志文章abstract::The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial dis...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
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abstract::Adrenomedullin (AM) has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of delayed AM gene transfer in cerebral ischemia. Three days after a 1-hr occlusion of the middle cerebral artery (MCAO), rats w...
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
pub_type: 杂志文章
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更新日期:1997-09-20 00:00:00
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401753153938
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journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
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更新日期:2003-07-20 00:00:00
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
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journal_title:Human gene therapy
pub_type: 杂志文章,评审
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