Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector

Scallan, Ciaran D.; Lillicrap, David; Jiang, Haiyan; Qian, Xiaobing; Patarroyo-White, Susannah; Parker, Amy; Liu, Tongyao; Vargas, Joseph A.; Nagy, Dea; Powell, Stephen Joseph; Wright, J. Fraser; Turner, Patricia V.; Tinlin, Shawn; Webster, Sandra; McClelland, Alan; Couto, Linda B.

doi:10.1182/blood-2003-01-0292

Cited by 98 publications

(91 citation statements)

References 36 publications

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“…This result is consistent with the hypothesis that neonatal gene therapy results in tolerance to cFVIII in HA dogs; although the small number of animals analyzed (n ϭ 2) and the relatively low incidence of inhibitor formation (0-50%) in dogs with a similar mutation after cFVIII protein (45) or gene (11,(26)(27)(28) therapy to adults make it impossible to be certain that this will be consistently effective. Studies using the vector expressing cFVIII and HA dogs from an inhibitor-prone lineage, or a vector expressing hFVIII in mice and dogs, followed by challenge with hFVIII protein, are needed to demonstrate true tolerance.…”

Section: Neonatal Gene Therapy Did Not Induce Inhibitors In Ha Mice Osupporting

confidence: 67%

“…Both WBCT and aPTT were normalized in the RV-treated HA dogs, and no bleeding episodes have occurred. The FVIII levels achieved in this study are Ͼ20-fold higher than the long-term expression with other vectors for HA in dogs (11,(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 90%

“…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.…”

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confidence: 99%

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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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Section: Neonatal Gene Therapy Did Not Induce Inhibitors In Ha Mice Osupporting

confidence: 67%

Section: Discussionmentioning

confidence: 90%

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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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“…51,52 The prevalence of inhibitor formation in hemophilia A in conventional protein-based therapy is substantially higher than in hemophilia B (20%-30% vs. 3%-4%) and avoiding antibody responses to factor VIII after hepatic gene transfer in murine and canine models has been more challenging than in factor IX gene transfer. [53][54][55] Third, published studies were performed in naïve animals, while human patients (perhaps with the exception of young children) typically have antigen-experienced T cells to the transgene product (and often to the viral vector as well due to natural infection). For example, in contrast to our experience in hemophilia B mice and dogs, expression of factor IX following adeno-associated viral-mediated hepatic gene transfer in patients with severe hemophilia B was not sustained, despite absence of an antibody response to factor IX.…”

Section: Potential Hurdles For Clinical Applicationmentioning

confidence: 99%

Tolerance Induction by Viral In Vivo Gene Transfer

Dobrzynski¹,

Herzog²

2005

Clinical Medicine & Research

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Treatment of genetic disease by protein or gene replacement therapy is hampered by immune responses to the therapeutic protein. An excellent example is formation of inhibitory antibodies to coagulation factors in treatment of the X-linked bleeding disorder hemophilia. Experiments in murine and canine models of hemophilia B (deficiency in factor IX) have demonstrated sustained therapeutic levels of factor IX transgene expression following hepatic adeno-associated viral gene transfer in animals with deletion and nonsense mutations in the factor IX gene. This article reviews experimental evidence for induction of immune tolerance to the factor IX transgene product by hepatic adeno-associated viral gene transfer, which has been shown to limit T helper cell responses and to substantially reduce the risk of antibody responses.Tolerance induction is associated with activation of regulatory CD4 + T cells capable of suppressing antibody formation to factor IX protein. Hepatic administration of adeno-associated viral vector expressing ovalbumin in mice transgenic for a T cell receptor specific for this antigen provided direct evidence for induction of CD4 + T cell tolerance, including T cell anergy and clonal deletion. Taken together, these data indicate the potential for viral in vivo gene transfer not only to provide sustained systemic expression, but moreover to induce immunological hypo-responsiveness to the therapeutic gene product.

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“…Earlier studies have shown that avoiding antibody responses to factor VIII after hepatic factor VIII gene transfer in murine and canine models has been more difficult to obtain than after factor IX gene transfer. 17,20 Restricting expression to hepatocytes by using a human a 1 -antitrypsin promoter was also insufficient to prevent inhibitor formation against factor VIII. 21 Larger antigens, such as human factor VIII or human plasminogen, contain more potentially immunogenic peptides and this number will further increase on knockout backgrounds.…”

mentioning

confidence: 99%

The impact of antigen expression in antigen-presenting cells on humoral immune responses against the transgene product

et al. 2009

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Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector

Cited by 98 publications

References 36 publications

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

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

Tolerance Induction by Viral In Vivo Gene Transfer

The impact of antigen expression in antigen-presenting cells on humoral immune responses against the transgene product

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