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Dennis D Hickstein - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of foamy viral vector mediated gene therapy for canine Leukocyte Adhesion Deficiency
Molecular Therapy, 2013Co-Authors: Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, David W Russell, Katherine R Calvo, Heather R Shive, Eleanor Karlsson, Robert R West, Dennis D HicksteinAbstract:The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunoDeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4–7 years) of four dogs with canine Leukocyte Adhesion Deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34+ hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18+ Leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with Leukocyte Adhesion Deficiency type 1 (LAD-1) in a human gene therapy clinical trial.
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lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
Gene Therapy, 2010Co-Authors: E J R Nelson, Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, Michael J Hunter, Dennis D HicksteinAbstract:Lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
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Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and Leukocyte Adhesion Deficiency
Current opinion in hematology, 2007Co-Authors: Harry L. Malech, Dennis D HicksteinAbstract:PURPOSE OF REVIEW Chronic granulomatous disease and Leukocyte Adhesion Deficiency are the major primary immune deficiencies affecting phagocytic blood cells. Major advances in clinical diagnosis and development of novel treatments for these disorders merit review. RECENT FINDINGS Clinically beneficial gene therapy correction of X-linked chronic granulomatous disease in two adult patients was reported. Nonmyeloablative busulfan conditioning before administration of gene corrected autologous hematopoietic stem cells was likely an essential maneuver to achieve successful gene therapy. There is an increased association of autoimmune disorders with chronic granulomatous disease. Preimplantation genetic diagnosis of Leukocyte Adhesion Deficiency-I led to the birth of a normal child. A canine model of Leukocyte Adhesion Deficiency-I facilitated development of new nonmyeloablative hematopoietic stem cell transplant and gene therapy approaches to Leukocyte Adhesion Deficiency. Nonmyeloablative transplantation may provide an effective, but less toxic approach for Leukocyte Adhesion Deficiency in children. There have been advances in understanding the basis of Leukocyte Adhesion Deficiency-II and III. SUMMARY The most important subjects reviewed in this chapter include new advances in development of gene therapy for chronic granulomatous disease and Leukocyte Adhesion Deficiency-I; transplantation for Leukocyte Adhesion Deficiency-I; prenatal diagnosis of Leukocyte Adhesion Deficiency-I; and association of autoimmune diseases with chronic granulomatous disease.
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correction of the disease phenotype in canine Leukocyte Adhesion Deficiency using ex vivo hematopoietic stem cell gene therapy
Blood, 2006Co-Authors: Thomas R Bauer, Laura M Tuschong, Robert A Sokolic, Tanya H Burkholder, Mehreen Hai, Cole J Ferguson, Cynthia E Dunbar, Dennis D HicksteinAbstract:Canine Leukocyte Adhesion Deficiency (CLAD) represents the canine counter-part of the human disease Leukocyte Adhesion Deficiency (LAD). Defects in the Leukocyte integrin CD18 Adhesion molecule in both CLAD and LAD lead to recurrent, life-threatening bacterial infections. We evaluated ex vivo retroviral-mediated gene therapy in CLAD using 2 nonmyeloablative conditioning regimens—200 cGy total body irradiation (TBI) or 10 mg/kg busulfan—with or without posttransplantation immunosuppression. In 6 of 11 treated CLAD dogs, therapeutic levels of CD18+ Leukocytes were achieved. Conditioning with either TBI or busulfan allowed long-term engraftment, and immunosuppression was not required for efficacy. The percentage of CD18+ Leukocytes in the peripheral blood progressively increased over 6 to 8 months after infusion to levels ranging from 1.26% to 8.37% at 1-year follow-up in the 6 dogs. These levels resulted in reversal or moderation of the severe CLAD phenotype. Linear amplification–mediated polymerase chain reaction assays indicated polyclonality of insertion sites. These results describe ex vivo hematopoietic stem cell gene transfer in a disease-specific, large animal model using 2 clinically applicable conditioning regimens, and they provide support for the use of nonmyeloablative conditioning regimens in preclinical protocols of retroviral-mediated gene transfer for nonmalignant hematopoietic diseases such as LAD.
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nonmyeloablative hematopoietic stem cell transplantation corrects the disease phenotype in the canine model of Leukocyte Adhesion Deficiency
Experimental Hematology, 2005Co-Authors: Thomas R Bauer, Laura M Tuschong, Robert A Sokolic, Tanya H Burkholder, Matthew F. Starost, John Bacher, Robert E Donahue, Dennis D HicksteinAbstract:Objective The aim of this study was to test a nonmyeloablative hematopoietic stem cell transplant regimen applicable to children with Leukocyte Adhesion Deficiency (LAD) who have a histocompatible sibling donor by using the canine model of LAD, namely canine Leukocyte Adhesion Deficiency or CLAD. Methods Thirteen CLAD pups received a hematopoietic stem cell transplant from a dog Leukocyte antigen (DLA)-matched littermate donor after pretransplant nonmyeloablative conditioning with 200 cGy total-body irradiation and posttransplant immunosuppression with cyclosporine and mycophenolate mofetil. Donor chimerism following transplant was assessed by flow cytometry for the presence of donor CD18 peripheral blood Leukocytes and Leukocyte subsets. Results Eleven of the 13 transplanted animals achieved stable mixed donor chimerism and reversal of the severe CLAD phenotype without graft-vs-host disease. The level of donor chimerism ranged from 3.9 to 95.5% at 1 year following transplant. There was one early death 3 weeks after transplant from thrombocytopenia and hemorrhage, and one dog with donor microchimerism (0.5% CD18 + donor Leukocytes) who had attenuation of the CLAD phenotype. Conclusion These results demonstrate that a nonmyeloablative transplant regimen from a DLA-matched littermate donor leads to mixed chimerism and reversal of the severe disease phenotype in dogs with CLAD, and provides support for the use of this approach in children with LAD who possess a histocompatible sibling donor.
Haydar Frangoul - One of the best experts on this subject based on the ideXlab platform.
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Matched unrelated bone marrow transplantation with reduced-intensity conditioning for Leukocyte Adhesion Deficiency
Bone Marrow Transplantation, 2006Co-Authors: Michael E. Engel, T. R. Bauer, C Calder, Becky Manes, Daniel D Hickstein, Haydar FrangoulAbstract:Matched unrelated bone marrow transplantation with reduced-intensity conditioning for Leukocyte Adhesion Deficiency
Jun Okamura - One of the best experts on this subject based on the ideXlab platform.
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Unrelated bone marrow transplantation using a reduced intensity-conditioning regimen in Leukocyte Adhesion Deficiency.
Bone Marrow Transplantation, 2006Co-Authors: Daijiro Takahashi, Yoshihisa Nagatoshi, Yusuke Saito, Jun Nagayama, Yuichi Shinkoda, Jiro Inagaki, Kyoko Fujita, Jun OkamuraAbstract:Unrelated bone marrow transplantation using a reduced intensity-conditioning regimen in Leukocyte Adhesion Deficiency
Thomas R Bauer - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of foamy viral vector mediated gene therapy for canine Leukocyte Adhesion Deficiency
Molecular Therapy, 2013Co-Authors: Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, David W Russell, Katherine R Calvo, Heather R Shive, Eleanor Karlsson, Robert R West, Dennis D HicksteinAbstract:The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunoDeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4–7 years) of four dogs with canine Leukocyte Adhesion Deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34+ hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18+ Leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with Leukocyte Adhesion Deficiency type 1 (LAD-1) in a human gene therapy clinical trial.
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treatment of canine Leukocyte Adhesion Deficiency by foamy virus vectors expressing cd18 from a pgk promoter
Gene Therapy, 2011Co-Authors: Thomas R Bauer, Laura M Tuschong, Erik M Olson, James M Allen, Yi Li, Tanya H Burkholder, David W RussellAbstract:Treatment of canine Leukocyte Adhesion Deficiency by foamy virus vectors expressing CD18 from a PGK promoter
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Feline Leukocyte Adhesion Deficiency.
Blood, 2010Co-Authors: Urs Giger, Suzanne M. Pratt, Christina M. Palena, Doug R Kennedy, Thomas R BauerAbstract:Abstract 3779 Leukocyte Adhesion Deficiency (LAD) caused by CD18 Deficiency is an autosomal recessive immunoDeficiency which has been described in humans, Irish Setter dogs, Holstein cattle, and transgenic mice. We report here on the characterization of the clinical features and Leukocyte function abnormalities of a novel feline model of Leukocyte Adhesion Deficiency. The proband was a 5 year old male domestic longhair cat with a life-long history of infections, inflammation and granulomas. Severe gingivitis was recognized at 8 weeks of age which progressed to peridontitis and loss of all deciduous and adult teeth before 1 year of age. Over the next years this cat experienced recurrent severe upper respiratory infections, gastroenteritis, anterior uveitis, various abscesses, and epidermal sloughing with sepsis secondary to small grooming lacerations. The various illnesses seemed to be responsive to various long-term antibiotic as well as glucocorticoid treatments. Complete blood cell counts revealed a persistent severe leukocytosis (50-91,000/μl) due to mature neutrophilia with few toxic changes, and mild lymphocytosis, monocytosis and eosinophilia. Serum immunoglobulin concentrations were normal. Compared to feline control cells, neutrophils of the proband did not express any CD18 on the cell surface as determined with two monoclonal anti-CD18 antibodies but normal CD45 expression. Adhesion of affected neutrophils with and without PMA activation was severally impaired; the Adhesion of normal feline neutrophils could be completely blocked by the anti-CD18 antibody. In a proliferation assay the proband9s T-cells responded weakly at 1 pg SEA but near normally at 100 pg SEA, suggesting a CD18-independent T-cell response in cats. Sequencing of the feline CD18 β-integrin gene is being completed. In conclusion, this naturally-occurring feline model of CD18 Deficiency exhibits similar features to LAD in other species. However, feline LAD seems clinically milder allowing for a longer life expectancy possibly due to T-cell independent activities. This LAD model may be helpful in developing and assessing novel therapies. Disclosures: No relevant conflicts of interest to declare.
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lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
Gene Therapy, 2010Co-Authors: E J R Nelson, Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, Michael J Hunter, Dennis D HicksteinAbstract:Lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
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correction of the disease phenotype in canine Leukocyte Adhesion Deficiency using ex vivo hematopoietic stem cell gene therapy
Blood, 2006Co-Authors: Thomas R Bauer, Laura M Tuschong, Robert A Sokolic, Tanya H Burkholder, Mehreen Hai, Cole J Ferguson, Cynthia E Dunbar, Dennis D HicksteinAbstract:Canine Leukocyte Adhesion Deficiency (CLAD) represents the canine counter-part of the human disease Leukocyte Adhesion Deficiency (LAD). Defects in the Leukocyte integrin CD18 Adhesion molecule in both CLAD and LAD lead to recurrent, life-threatening bacterial infections. We evaluated ex vivo retroviral-mediated gene therapy in CLAD using 2 nonmyeloablative conditioning regimens—200 cGy total body irradiation (TBI) or 10 mg/kg busulfan—with or without posttransplantation immunosuppression. In 6 of 11 treated CLAD dogs, therapeutic levels of CD18+ Leukocytes were achieved. Conditioning with either TBI or busulfan allowed long-term engraftment, and immunosuppression was not required for efficacy. The percentage of CD18+ Leukocytes in the peripheral blood progressively increased over 6 to 8 months after infusion to levels ranging from 1.26% to 8.37% at 1-year follow-up in the 6 dogs. These levels resulted in reversal or moderation of the severe CLAD phenotype. Linear amplification–mediated polymerase chain reaction assays indicated polyclonality of insertion sites. These results describe ex vivo hematopoietic stem cell gene transfer in a disease-specific, large animal model using 2 clinically applicable conditioning regimens, and they provide support for the use of nonmyeloablative conditioning regimens in preclinical protocols of retroviral-mediated gene transfer for nonmalignant hematopoietic diseases such as LAD.
Laura M Tuschong - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of foamy viral vector mediated gene therapy for canine Leukocyte Adhesion Deficiency
Molecular Therapy, 2013Co-Authors: Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, David W Russell, Katherine R Calvo, Heather R Shive, Eleanor Karlsson, Robert R West, Dennis D HicksteinAbstract:The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunoDeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4–7 years) of four dogs with canine Leukocyte Adhesion Deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34+ hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18+ Leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with Leukocyte Adhesion Deficiency type 1 (LAD-1) in a human gene therapy clinical trial.
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treatment of canine Leukocyte Adhesion Deficiency by foamy virus vectors expressing cd18 from a pgk promoter
Gene Therapy, 2011Co-Authors: Thomas R Bauer, Laura M Tuschong, Erik M Olson, James M Allen, Yi Li, Tanya H Burkholder, David W RussellAbstract:Treatment of canine Leukocyte Adhesion Deficiency by foamy virus vectors expressing CD18 from a PGK promoter
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lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
Gene Therapy, 2010Co-Authors: E J R Nelson, Thomas R Bauer, Laura M Tuschong, Tanya H Burkholder, Michael J Hunter, Dennis D HicksteinAbstract:Lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
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Lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine Leukocyte Adhesion Deficiency
Gene Therapy, 2010Co-Authors: E J R Nelson, T. R. Bauer, Laura M Tuschong, Tanya H Burkholder, Michael J Hunter, D D HicksteinAbstract:Canine Leukocyte Adhesion Deficiency (CLAD) provides a unique large animal model for testing new therapeutic approaches for the treatment of children with Leukocyte Adhesion Deficiency (LAD). In our CLAD model, we examined two different fragments of the human elongation factor 1α (EF1α) promoter (EF1αL, 1189 bp and EF1αS, 233 bp) driving the expression of canine CD18 in a self-inactivating (SIN) lentiviral vector. The EF1αS vector resulted in the highest levels of canine CD18 expression in CLAD CD34^+ cells in vitro . Subsequently, autologous CD34^+ bone marrow cells from four CLAD pups were transduced with the EF1αS vector and infused following a non-myeloablative dose of 200 cGy total-body irradiation. None of the CLAD pups achieved levels of circulating CD18^+ neutrophils sufficient to reverse the CLAD phenotype, and all four animals were euthanized because of infections within 9 weeks of treatment. These results indicate that the EF1αS promoter-driven CD18 expression in the context of a RRLSIN lentiviral vector does not lead to sufficient numbers of CD18^+ neutrophils in vivo to reverse the CLAD phenotype when used in a non-myeloablative transplant regimen in dogs.
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correction of the disease phenotype in canine Leukocyte Adhesion Deficiency using ex vivo hematopoietic stem cell gene therapy
Blood, 2006Co-Authors: Thomas R Bauer, Laura M Tuschong, Robert A Sokolic, Tanya H Burkholder, Mehreen Hai, Cole J Ferguson, Cynthia E Dunbar, Dennis D HicksteinAbstract:Canine Leukocyte Adhesion Deficiency (CLAD) represents the canine counter-part of the human disease Leukocyte Adhesion Deficiency (LAD). Defects in the Leukocyte integrin CD18 Adhesion molecule in both CLAD and LAD lead to recurrent, life-threatening bacterial infections. We evaluated ex vivo retroviral-mediated gene therapy in CLAD using 2 nonmyeloablative conditioning regimens—200 cGy total body irradiation (TBI) or 10 mg/kg busulfan—with or without posttransplantation immunosuppression. In 6 of 11 treated CLAD dogs, therapeutic levels of CD18+ Leukocytes were achieved. Conditioning with either TBI or busulfan allowed long-term engraftment, and immunosuppression was not required for efficacy. The percentage of CD18+ Leukocytes in the peripheral blood progressively increased over 6 to 8 months after infusion to levels ranging from 1.26% to 8.37% at 1-year follow-up in the 6 dogs. These levels resulted in reversal or moderation of the severe CLAD phenotype. Linear amplification–mediated polymerase chain reaction assays indicated polyclonality of insertion sites. These results describe ex vivo hematopoietic stem cell gene transfer in a disease-specific, large animal model using 2 clinically applicable conditioning regimens, and they provide support for the use of nonmyeloablative conditioning regimens in preclinical protocols of retroviral-mediated gene transfer for nonmalignant hematopoietic diseases such as LAD.