Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

Dinauer, Mary C.; Gifford, Mary; Pech, Nancy; Li, Ling Lin; Emshwiller, Patricia

doi:10.1182/blood.v97.12.3738

Cited by 66 publications

(51 citation statements)

References 37 publications

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“…Notably, the mouse model of respiratory infection, induced by intratracheal injection and used in our work, differs from the models generated previously that reproduced the systemic infection with S. aureus introduced by an intraperitoneal injection. 30 In our model of acute pneumonia, it should be pointed out that mice with DHR activity as low as 20% or with a low vector copy number of 0.3 were protected from death and inflammation. These results would suggest that a reduced-intensity conditioning, such as the one adopted for previous CGD trials or other diseases, could be used.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies described an enhanced susceptibility to infection of A. fumigatus, B. cepacia, or S. aureus in XCGD mice but to date none of these models has been used to study protection against acute respiratory infection after LVs gene therapy. [28][29][30][31][32] Dinauer's group first showed that XCGD mice treated with retroviral vectors (RVs) were able to control the acute inflammation and the development of chronic granulomatous lesions of CGD, induced by intradermal injection of Aspergillus fumigatus (AF) hyphae. 33 We found that mice treated with gene therapy using regulated LVs were protected from the lethal disease and, similarly to WT mice, had no further consequences.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…11 Although animal mouse models have shown promise of long-term cure using retroviral vectors, phase 1 clinical studies have yet to produce a sufficient number of functioning neutrophils for an extended period of time. 12 Allogeneic BMT from an HLA-matched related donor remains the only curative treatment for CGD.…”

Section: Discussionmentioning

confidence: 99%

Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease

Bhattacharya

Slatter

Curtis

et al. 2003

Bone Marrow Transplant

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Summary:Chronic granulomatous disease (CGD) causes growth failure, inflammatory lung damage and often early death. Prophylactic cotrimoxazole improves medium-term survival, but cannot prevent inflammatory sequelae. We report the first patient with CGD who underwent successful HLA identical sibling umbilical cord stem cell transplantation (UCSCT) after myeloablative conditioning. The patient presented with colitis, confirmed as CGD at 2 years of age. Following BU16/CY200 conditioning, he had UCSCT from his unaffected HLA identical sister. A year post-transplant, his colitis had resolved clinically and on radioisotope scan growth has improved. Neutrophil oxidative burst was 92% normal with full donor lymphocyte reconstitution.

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“…At first sight CGD seems a good candidate for such an approach, as the genes encoding the relevant subunits of the NADPH oxidase complex are metabolic genes not involved in cell proliferation. Furthermore functional correction of as few as 10% of neutrophils should be sufficient to alleviate the symptoms of the disease based on the experience in X-linked CGD carriers (Mills et al, 1980) and on gene therapy studies in murine CGD (Dinauer et al, 2001). In addition, the expression of small amounts of gp91phox can lead to considerable reconstitution of superoxide generation (Bjorgvinsdottir et al, 1997).A major obstacle however remains: the lack of a selective growth advantage of gene transduced cells, e.g.…”

Section: Stem Cell Gene Therapymentioning

confidence: 99%

Modern management of chronic granulomatous disease

2008

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SummaryChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and in defective degradation of inflammatory mediators with concomitant granuloma formation. Current prophylaxis with trimethoprim-sulfamethoxazole, itraconazole and in selected cases additional interferon gamma is efficient, but imperfect. A significant recent progress towards new antibiotic (e.g. linezolid) and antifungal (e.g. voriconazole and posaconazole) therapy will allow survival of most patients into adulthood. Adolescent and adult CGD is increasingly characterized by inflammatory complications, such as granulomatous lung and inflammatory bowel disease, requiring immunosupressive therapy. Allogeneic haematopoietic stem cell transplantation from a human leucocyte antigen identical donor is currently the only proven curative treatment for CGD and can be offered to the selected patients. Gene-replacement therapy for patients lacking a suitable stem cell donor is still experimental and faces major obstacles and risks. However, it may offer some transitory benefits and has helped in a few cases to overcome life-threatening infections.

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Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

Cited by 66 publications

References 37 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

Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease

Modern management of chronic granulomatous disease

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