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

Chiriaco, Maria; Farinelli, Giada; Capo, Valentina; Zonari, Erika; Scaramuzza, Samantha; Matteo, Gigliola Di; Sergi, Lucia Sergi; Migliavacca, Maddalena; Hernández, Raisa Jofra; Bombelli, F.; Giorda, Ezio; Kajaste‐Rudnitski, Anna; Trono, Didier; Grez, Manuel; Rossi, Paolo; Finocchi, Andrea; Naldini, Luigi; Gentner, Bernhard; Aiuti, Alessandro

doi:10.1038/mt.2014.87

Cited by 59 publications

(79 citation statements)

References 45 publications

(67 reference statements)

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“…34 Our study included a wide distribution of VCN (ranging from 0.3 to 9.8). While these VCNs are in line with previous studies from our group and others [36][37][38] it is expected that lower VCNs would be observed in the clinical application based on our previous studies in human CD34+ cells, 23 and clinical trials in other therapeutic areas. 34,39 Unfortunately, no published data is available regarding the protection from the infections in clinical trials with lentiviral vectors encoding for gp91phox.…”

Section: Discussionsupporting

confidence: 91%

“…45 Finally, our data further validate the use of regulated vectors based on transcriptional or post-transcriptional regulators that allow the adequate expression of a functional transgene while preventing ectopic expression in undifferentiated HSCs. 23 Taken together, our results provide a useful and manageable model that mimics the hallmarks of human disease and demonstrates robust preclinical evidence of efficacy and supports the progression to the clinical settings of gene therapy with regulated lentiviral vectors.…”

Section: Discussionsupporting

confidence: 61%

“…To test the efficacy of gene therapy in vivo, 8-week-old XCGD mice were initially treated with HSPC transduced with regulated lentiviral vectors in which the transgene gp91phox is driven by a myeloid-specific promoter 23,26 (MSP) with (MSP.gp91_126T (2), n = 9) or without (MSP.gp91, n = 5) a miRNA126 detargeting element. 23 Consequently, Lineage negative (Lin−) cells harvested from bone marrow (BM) of XCGD mice were transduced with the therapeutic vectors and transplanted into lethally irradiated recipients.…”

Section: Gene Therapy With Regulated Vectors Effectively Clears S Aumentioning

confidence: 99%

“…23 Consequently, Lineage negative (Lin−) cells harvested from bone marrow (BM) of XCGD mice were transduced with the therapeutic vectors and transplanted into lethally irradiated recipients.…”

Section: Gene Therapy With Regulated Vectors Effectively Clears S Aumentioning

confidence: 99%

“…[19][20][21] With these vectors, gp91phox expression is targeted to the differentiated myeloid cells to reduce the risk of genotoxicity and perturbation of reactive oxygen species levels in HSCs. [22][23][24][25] Those vectors showed a restored gp91phox in differentiated human or mouse cells; however, the preclinical efficacy of gene therapy, in terms of protection against infections and inflammatory responses, has not been studied yet. We established a model of S. aureus airways infection in XCGD mice to evaluate the in vivo antimicrobial efficacy and beneficial effect on the inflammatory response of gene therapy.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 61%

Section: Gene Therapy With Regulated Vectors Effectively Clears S Aumentioning

confidence: 99%

Section: Gene Therapy With Regulated Vectors Effectively Clears S Aumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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CRISPR genome engineering and viral gene delivery: A case of mutual attraction

Schmidt

Grimm

2015

Biotechnology Journal

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The adaptation of the CRISPR/Cas9 DNA engineering machinery for mammalian cells has revolutionized our approaches to low- or high-throughput genome annotation and paved the way for conceptually novel therapeutic strategies. A large part of the attraction of CRISPR stems from the small size of its two core components--Cas9 and gRNA--and hence its compatibility with virtually any available viral vector delivery system. As a result, over the past two years, four major classes of viral vectors have already been engineered and applied as CRISPR delivery tools--retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses (AAVs). The juxtaposition of these two technologies reflects a case of tremendous mutual attraction and holds unprecedented promises for biology and medicine. Here, we provide an overview of the state-of-the-art of this rapidly emerging field, from a comparative description of the principal vector designs, to a synopsis of some of the most exciting applications that were reported to date, including the use of viral CRISPR vectors for genome-wide loss-of-function screens, multiplexed gene editing or disease modeling in animals. Once specificity and safety have been improved further, viral vector-mediated in vitro/in vivo CRISPR delivery and expression promise to radically transform basic and applied biomedical research.

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Definitive Treatments for Chronic Granulomatous Disease with a Focus on Gene Therapy

Santilli

Thrasher

2023

NADPH Oxidases Revisited: From Function to Structure

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

Cited by 59 publications

References 45 publications

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

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

CRISPR genome engineering and viral gene delivery: A case of mutual attraction

Definitive Treatments for Chronic Granulomatous Disease with a Focus on Gene Therapy

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