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  4. Dual-regulated Lentiviral Vector for Gene Therapy of X-linked Chronic Granulomatosis
 
research article

Dual-regulated Lentiviral Vector for Gene Therapy of X-linked Chronic Granulomatosis

Chiriaco, Maria
•
Farinelli, Giada
•
Capo, Valentina
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2014
Molecular Therapy

Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack of persistent engraftment. Our novel strategy, based on regulated lentiviral vectors (LV), targets gp91(phox) expression to the differentiated myeloid compartment while sparing HSC, to reduce the risk of genotoxicity and potential perturbation of reactive oxygen species levels. Targeting was obtained by a myeloid-specific promoter (MSP) and posttranscriptional, microRNA-mediated regulation. We optimized both components in human bone marrow (BM) HSC and their differentiated progeny in vitro and in a xenotransplantation model, and generated therapeutic gp91(phox) expressing LVs for CGD gene therapy. All vectors restored gp91(phox) expression and function in human X-CGD myeloid cell lines, primary monocytes, and differentiated myeloid cells. While unregulated LVs ectopically expressed gp91(phox) in CD34(+) cells, transcriptionally and post-transcriptionally regulated LVs substantially reduced this off-target expression. X-CGD mice transplanted with transduced HSC restored gp91(phox) expression, and MSP-driven vectors maintained regulation during BM development. Combining transcriptional (SP146.gp91-driven) and posttranscriptional (miR-126-restricted) targeting, we achieved high levels of myeloid-specific transgene expression, entirely sparing the CD34+ HSC compartment. This dual-targeted LV construct represents a promising candidate for further clinical development.

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Type
research article
DOI
10.1038/mt.2014.87
Web of Science ID

WOS:000339780000012

Author(s)
Chiriaco, Maria
Farinelli, Giada
Capo, Valentina
Zonari, Erika
Scaramuzza, Samantha
Di Matteo, Gigliola
Sergi, Lucia Sergi
Migliavacca, Maddalena
Hernandez, Raisa Jofra
Bombelli, Ferdinando
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Date Issued

2014

Publisher

Elsevier

Published in
Molecular Therapy
Volume

22

Issue

8

Start page

1472

End page

1483

Editorial or Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
LVG  
Available on Infoscience
August 29, 2014
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/106226
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