Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens

Ide, Lucienne M.; Gangadharan, Bagirath; Chiang, Kuang‐Yueh; Doering, Christopher B.; Spencer, H. Trent

doi:10.1182/blood-2007-04-082602

Cited by 88 publications

(108 citation statements)

References 33 publications

(40 reference statements)

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“…Several laboratories have investigated different protocols to prevent inhibitor formation in hemophilia. Induction of immune tolerance has been achieved using the following approaches: mucosal (nasal or oral) antigen administration, 32 transient blockade of the inducible co-stimulator pathway by an anti-ICOS monoclonal antibody, 33 hematopoietic stem cell gene IDO modulates inhibitor formation L Liu et al therapy following low-toxicity pretransplantation conditioning and targeted immunosuppression, 34 hepatic gene transfer of naked DNA with transient immunosuppression, 35 hepatic transfer with viral vectors of FIX, 36 or the transient administration of a multidrug cocktail consisting of a specific peptide antigen, an immune suppressive drug (rapamycin) and the cytokine (interleukin 10, IL-10) (R Herzog, personal communication). Each of these approaches involves slightly different mechanisms of immune modulation and may be dependent on the route of antigen administration.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Liu

Mah

et al. 2009

Gene Ther

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A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were codelivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

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Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Liu

Mah

et al. 2009

Gene Ther

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“…There has been substantial progress in gene therapy of hemophilia A in preclinical trials. [18][19][20][21][22][23][24][25][26][27][28][29] Gene therapy of hemophilia A with preexisting FVIII immunity is especially challenging because circulating inhibitory antibodies in plasma may inactivate functional FVIII if it is constitutively secreted into plasma. Therefore, developing a mechanism for secure cellular delivery to sequester and protect FVIII from inhibitor inactivation is a more promising approach than plasma delivery of FVIII to the site of injury when inhibitory antibodies are present in the plasma.…”

mentioning

confidence: 99%

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

Shi

Fahs

Wilcox

et al. 2008

Blood

122

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Although genetic induction of factor VIII (FVIII) expression in platelets can restore hemostasis in hemophilia A mice, this approach has not been studied in the clinical setting of preexisting FVIII inhibitory antibodies to determine whether such antibodies would affect therapeutic engraftment. We generated a line of transgenic mice (2bF8) that express FVIII only in platelets using the platelet-specific ␣IIb promoter and bred this 2bF8 transgene into a FVIII null background. Bone marrow (BM) from heterozygous 2bF8 transgenic (2bF8 tg؉/؊ ) mice was transplanted into immunized FVIII null mice after lethal or sublethal irradiation. After BM reconstitution, 85% of recipients survived tail clipping when the 1100-cGy (myeloablative) regimen was used, 85.7% of recipients survived when 660-cGy (nonmyeloablative) regimens were used, and 60% of recipients survived when the recipients were conditioned with 440 cGy. Our further studies showed that transplantation with 1% to 5% 2bF8 tg؉/؊ BM cells still improved hemostasis in hemophilia A mice with inhibitors. These results demonstrate that the presence of FVIII-specific immunity in recipients does not negate engraftment of 2bF8 genetically modified hematopoietic stem cells, and transplantation of these hematopoietic stem cells can efficiently restore hemostasis to hemophilic mice with preexisting inhibitory antibodies under either myeloablative or nonmyeloablative regimens. IntroductionHemophilia A is a severe congenital bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). 1 Currently, hemophilia is treated with protein replacement therapy using either plasmaderived or recombinant FVIII. 2 Although FVIII replacement markedly improves the life expectancy of patients with hemophilia, up to 30% of patients with severe hemophilia A develop antibodies after FVIII replacement therapy. [3][4][5][6][7] These antibodies cause the clinical failure of treatment in response to routine replacement therapy for bleeding episodes and therefore are referred to as FVIII inhibitors. [8][9][10] Clinically, inhibitor titers greater than 5 Bethesda units (BU)/mL are considered untreatable using routine FVIII replacement. 11 Induction of immune tolerance to the FVIII protein is a treatment option for the eradication of anti-FVIII inhibitors, but it is very expensive and may not always be effective. [12][13][14] Infusion of NovoSeven (FVIIa) may also restore hemostasis in patients with inhibitors, but it is more costly because of its short half life and may result in thrombotic complications. [15][16][17] Gene therapy could be an alternative treatment for hemophilia A. There has been substantial progress in gene therapy of hemophilia A in preclinical trials. [18][19][20][21][22][23][24][25][26][27][28][29] Gene therapy of hemophilia A with preexisting FVIII immunity is especially challenging because circulating inhibitory antibodies in plasma may inactivate functional FVIII if it is constitutively secreted into plasma. Therefore, developing a mechanism for secure cellular del...

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“…A B domain deleted porcine FVIII transgene was also evaluated revealing a 10 -14 fold increase in expression compared to a human FVIII transgene (Doering et al, 2002). Its subsequent transfer within hemophilia A mice resulted in high-level FVIII expression that could be sustained even after low-toxicity pretransplantation conditioning (Ide et al, 2007). Together, these studies demonstrated the ability of a high-expressing porcine FVIII construct to function in vivo.…”

Section: Gene Transfer Of Fviii With Lentiviral Vectorsmentioning

confidence: 98%

Gene Therapy Strategies Incorporating Large Transgenes

Johnston¹,

Doering²,

Spencer³

2011

Gene Therapy - Developments and Future Perspectives

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Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens

Cited by 88 publications

References 33 publications

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

Gene Therapy Strategies Incorporating Large Transgenes

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