Preclinical Safety and Efficacy of Human CD34+ Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome

Scaramuzza, Samantha; Biasco, Luca; Ripamonti, Anna; Castiello, Maria Carmina; Loperfido, Mariana; Drăghici, Elena; Hernández, Raisa Jofra; Benedicenti, Fabrizio; Radrizzani, Marina; Salomoni, Monica; Ranzani, Marco; Bartholomae, Cynthia C.; Vicenzi, Elisa; Finocchi, Andrea; Bredius, Robbert G. M.; Bosticardo, Marita; Schmidt, Manfred; Kalle, Christof von; Montini, Eugenio; Biffi, Alessandra; Roncarolo, Maria Grazia; Naldini, Luigi; Villa, Anna; Aiuti, Alessandro

doi:10.1038/mt.2012.23

Cited by 73 publications

(80 citation statements)

References 43 publications

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“…Gene correction of autologous cells is currently being tested as an alternative to allogeneic bone marrow transplantation in WAS patients. 4,6,7,25 Our results show that WASp-deficient cells can be mobilized with G-CSF and transduced effectively without preventing their engraftment capacity. WAS patients may develop splenomegaly, as was observed in WKO mice.…”

Section: Discussionmentioning

confidence: 65%

“…4 Gene therapy is based on the infusion of gene-modified autologous hematopoietic stem cells (HSC) using retroviral or lentiviral vectors. [5][6][7] Current gene therapy protocols rely on the use of either bone marrow cells or mobilized peripheral blood cells to obtain CD34 + HSC that will be used for ex vivo gene transfer. Several procedures can be used to mobilize peripheral CD34 + HSC.…”

Section: Introductionmentioning

confidence: 99%

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Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor

Charrier

Blundell²,

Cédrone

et al. 2013

Haematologica

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor

Charrier

Blundell²,

Cédrone

et al. 2013

Haematologica

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“…Thus, the complexity of myogenic process require a fine-tune regulation of miR669 family expression in consideration of potential ex-vivo cell therapy protocols. Lentiviral vectors have been largely used in gene therapy applications [41][42][43][44][45] and in the last decade many studies focused on the identification of retroviral integration sites (RIS) to monitor vector-host interaction in long-term follow-up of patients [46]. However, integration site analysis has now considered critical in gene therapy protocols considering the adverse effects occurred in SCID clinical trials during the early 2000s.…”

Section: Discussionmentioning

confidence: 99%

miRNA Lentiviral Vector Integration and Gene Targeting Efficacy in Cardiac Progenitors

Loperfido¹,

Crippa²,

Sampaolesi³

2012

J Stem Cell Res Ther

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Stem and progenitor cardiac cells are challenging for possible cell therapy application. Several research laboratories are exploiting the feasibility of autologous cell therapy approach to get rid of immunosuppressive treatments responsible for undesirable side effects. Recently, we showed that cardiac progenitors isolated from Sgcb null mice, animal model of limb-girdle muscular dystrophy type 2E, undergo an aberrant differentiation in vitro and in vivo due to the dysregulation of miR669. This miRNA family is able to inhibit the skeletal myogenic program directly targeting MyoD 3' UTR. Using lentiviral technology we provided evidence that it is possible to rescue the dystrophic aberrant phenotype by miRNA669 overexpression without gene correction. However, how the viruses carrying the miRNAs were positioned in the genome upon transduction and how their localization site could influence the rescue potential was not analysed. Here we investigate the integration profile of lentiviral vector carrying the pre-miR669 in infected polyclonal and clonal populations derived from Sgcb cardiac progenitors. Our study reveals that the retroviral insertion sites (RIS) are largely restricted to coding genes (65%). Although with the limitation of our analysis, we found no hits for cancer-related genes and several sequenced RIS brought to light genes mainly involved in muscle function. Thus our data show that lentiviral vector insertional profile is cell-specific, however, the chromatin state of target cells positively influences the viral integrations.

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“…46,47 The vector lots were produced and purified by MolMed s.p.a. (Milan, Italy) using a large-scale validated process following GMP protocols.…”

Section: Lentiviral Vectors Productionmentioning

confidence: 99%

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

Farinelli

Hernández

Rossi³

et al. 2016

Molecular Therapy

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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 therapytreated 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.

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Preclinical Safety and Efficacy of Human CD34+ Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome

Cited by 73 publications

References 43 publications

Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor

Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor

miRNA Lentiviral Vector Integration and Gene Targeting Efficacy in Cardiac Progenitors

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

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