Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors

Chuah, Marinee; Schiedner, Gudrun; Thorrez, Lieven; Brown, Brian D.; Johnston, Marion M.; Gillijns, Veerle; Hertel, Sabine; Rooijen, Nico van; Lillicrap, David; Collen, Désiré; VandenDriessche, Thierry; Kochanek, Stefan

doi:10.1182/blood-2002-03-0823

Cited by 132 publications

(130 citation statements)

References 54 publications

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“…In most preclinical experiments using immunocompetent hemophilia A murine and canine models, strong immune responses against FVIII after gene therapy have completely inhibited circulating FVIII activity and thus subverted the effect of gene therapy. [2][3][4][5]8,9,[14][15][16] Recent gene transfer studies 1,5,9,[17][18][19][20] indicate that the risk of transgene-specific immune responses depends on multiple factors, including the type and dose of the vector, the expression cassette and tissue specificity of the promoter, the type and level of transgene expression, route of administration, transduced cell type, and the age and the underlying mutation of the gene therapy model. Some of these factors have been extensively reviewed.…”

Section: Introductionmentioning

confidence: 99%

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

Peng

Blazar

et al. 2008

Blood

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Section: Introductionmentioning

confidence: 99%

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

Peng

Blazar

et al. 2008

Blood

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“…An adeno-associated virus vector resulted in Ϸ3% of normal FVIII activity in HA dogs (26). Adenoviral vectors resulted in high initial expression (Ͼ25% of normal) in HA dogs (11,27,28) and normal primates (29), but expression fell over time. A helper-dependent adenoviral vector had low expression in one patient and the trial was discontinued because of inflammatory responses (9).…”

mentioning

confidence: 99%

“…Stable and therapeutic levels of FVIII have been achieved in HA mice (reviewed in refs. [5][6][7][8][9] by transduction of liver with gamma retroviral vectors (RVs) [Ͼ20% of normal FVIII (10)], adenoviral vectors [Ͼ50% of normal (11)(12)(13)(14)(15)], lentiviral vectors [Ͼ5% of normal (16,17)], hydrodynamic injection of plasmid DNA [Ͼ300% of normal (18)], and adeno-associated virus vectors [2-100% of normal (19)(20)(21)(22)(23)]. Ex vivo gene therapy of endothelial cells (24) or hematopoietic stem cells (25) has also resulted in Ͼ50% of normal FVIII activity.…”

mentioning

confidence: 99%

Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy

Nichols

Sarkar

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) deficiency. FVIII replacement therapy can reduce bleeding but is expensive, inconvenient, and complicated by development of antibodies that inhibit FVIII activity in 30% of patients. Neonatal hepatic gene therapy could result in continuous secretion of FVIII into blood and might reduce immunological responses. Newborn HA mice and dogs that were injected i.v. with a retroviral vector (RV) expressing canine B domain-deleted FVIII (cFVIII) achieved plasma cFVIII activity that was 139 ؎ 22% and 116 ؎ 5% of values found in normal dogs, respectively, which was stable for 1.5 yr. Coagulation tests were normalized, no bleeding had occurred, and no inhibitors were detected. This is a demonstration of long-term fully therapeutic gene therapy for HA in a large animal model. Desmopressin (DDAVP; 1-deamino-[D-Arg 8 ]vasopressin) is a drug that increases FVIII activity by inducing release of FVIII complexed with von Willebrand factor from endothelial cells. It has been unclear, however, if the FVIII is synthesized by endothelial cells or is taken up from blood. Because the plasma cFVIII in these RVtreated dogs derives primarily from transduced hepatocytes, they provided a unique opportunity to study the biology of the DDAVP response. Here we show that DDAVP did not increase plasma cFVIII levels in the RV-treated dogs, although von Willebrand factor was increased appropriately. This result suggests that the increase in FVIII in normal dogs after DDAVP is due to release of FVIII synthesized by endothelial cells.H emophilia A (HA) is an X-linked bleeding disorder with an incidence of 1 in 5,000 males (1). Severe HA patients have Յ1% of normal factor VIII (FVIII) activity (normal levels are 200 ng͞ml) and frequently bleed spontaneously. Patients with 1-5% of normal activity have moderately severe bleeding, and patients with 5-25% of normal activity usually bleed only with surgery or trauma. HA is generally treated with FVIII protein injections, which are expensive and inconvenient. An alternative treatment for mild HA is desmopressin (DDAVP; 1-deamino-[D-Arg 8 ]vasopressin), which releases FVIII complexed with von Willebrand factor (VWF) from endothelial cells (2). It has been unclear, however, as to whether this stored FVIII is synthesized de novo in endothelial cells or taken up from blood, because both endothelial cells and hepatocytes express FVIII mRNA (3).HA is a candidate for gene therapy, which involves transfer of a FVIII gene into cells that secrete functional protein into blood. The 7-kb FVIII cDNA encodes a 2,332-aa protein that is cleaved intracellularly to an N-terminal heavy chain (A1, A2, and B domains) and a C-terminal light chain (A3, C1, and C2 domains) (4). Because the B domain released after FVIII activation is not necessary for function, B domain-deleted (BDD) constructs of only 4.5 kb have been used in most gene therapy approaches. (25) has also resulted in Ͼ50% of normal FVIII activity.Gene therapy for HA has been less effective in lar...

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“…The stoichiometric advantage increases as the age of intervention is reduced, and this may partially offset the apparent difficulty in scaling vector doses from small to large species based on mass alone. For example, compared with mice, disproportionately low concentrations of transgenic clotting factor were measured in the plasma of dogs despite their receipt of equivalent or higher doses of vector per kilogram of helper-dependent adenovirus 21 or AAV2. 22 …”

Section: Vector: Cell Ratiomentioning

confidence: 99%

Fetal and neonatal gene therapy: benefits and pitfalls

et al. 2004

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Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors

Abstract: High-capacity adenoviral (HC-Ad

Cited by 132 publications

References 54 publications

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy

Fetal and neonatal gene therapy: benefits and pitfalls

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