Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B

Nichols, Timothy C.; Raymer, Robin A.; Franck, Helen; Merricks, Elizabeth P.; Bellinger, Dwight A.; DeFriess, Natalie; Margaritis, Paris; Arruda, Valder R.; Kay, Mark A.; High, Katherine A.

doi:10.1111/j.1365-2516.2010.02255.x

Cited by 19 publications

(22 citation statements)

References 31 publications

(36 reference statements)

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“…Reduction in the frequency of annualized bleeding events can be used as a metric for judging success of a therapeutic intervention in these dogs. 11 Two hemophilia B dog models with different mutations and immune responses to canine FIX have been used. First, the Chapel Hill strain has a missense mutation, a G-to-A substitution at nucleotide 1477, that results in the substitution of glutamic acid for glycine at position 379 in the catalytic (serine protease) domain of the molecule.…”

Section: Canine Hemophilia Bmentioning

confidence: 99%

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Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

Nichols

Whitford

Arruda

et al. 2015

Human Gene Therapy Clinical Development

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Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches.

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Section: Canine Hemophilia Bmentioning

confidence: 99%

“…[8][9][10][11] Also, most of the dogs that have been used weighed 20 or more kilograms, and thus scaling up to humans is in the range *3-to 10-fold; as opposed to mice, which weigh *25 g, and constitute an *2800-fold scale-up. The size of dogs places demands on manufacturing that can slow progress if vector production is limiting.…”

Section: Introductionmentioning

confidence: 99%

Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

Nichols

Whitford

Arruda

et al. 2015

Human Gene Therapy Clinical Development

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“…However, the underlying F9 mutation, mRNA levels, and risk of inhibitor formation differ. [13][14][15] Submitted July 10, 2014; accepted December 24, 2014. Prepublished online as Blood First Edition paper, January 7, 2015; DOI 10.1182/blood-2014-07-588194.…”

Section: Introductionmentioning

confidence: 99%

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

Crudele

Finn

Siner

et al. 2015

Blood

138

178

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• Liver-restricted expression of FIX-Padua induces immune tolerance to the transgene in hemophilia B inhibitor dog models.• Long-term toxicity studies show no increased risk of thrombogenicity of FIX-Padua in mice and dogs.Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 3 10 12 vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine)in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8-to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. (Blood. 2015;125(10):1553-1561

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“…27,29 Although congenital hemophilia A models in dogs, sheep, rats, and pigs have been reported to develop joint bleeds, it seems difficult to express reproducible joint bleeds in individuals and to efficiently evaluate drug efficacy in a practicable experimental period. [28][29][30][31][32][33][34] Our model stably developed leg-joint damage within 8 weeks, which was possibly produced by the severe acquired hemophilic state and by bodyweight loading due to the bipedal motion of the monkeys. Thus, this model may be particularly useful in testing the efficacy of therapeutic agents from the orthopedic aspect of hemophilia A.…”

Section: Discussionmentioning

confidence: 88%

Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

Muto¹,

Yoshihashi²,

Takeda³

et al. 2014

Blood

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Key Points• A long-term acquired hemophilia A model expressing spontaneous joint bleeds and other bleeds was newly established in nonhuman primates.• Weekly SC dose of the anti-FIXa/X bispecific antibody ACE910 prevented joint bleeds and other bleeds in the primate hemophilia A model.ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. (Blood. 2014;124(20): 3165-3171)

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Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B

Cited by 19 publications

References 31 publications

Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

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