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Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model.

ABSTRACT: Adenoviral vector-mediated gene therapy might have potential for long-term correction of the monogenic disease hemophilia A.In this study, we tested the efficacy of administering a helper-dependent adenoviral vector (HDV) designed for maximal liver-restricted canine factor VIII (cFVIII) expression on three out-bred hemophilia A dogs.Three FVIII-deficient animals from the University of North Carolina colony were injected with 1 x 10(12) (Dog A), and 3 x 10(12) (Dog B and C) vp kg(-1) helper-dependent adenoviral vector, and we performed systematic analysis of toxicity, persistence of therapeutic gene expression, and molecular analysis of gene transfer.We observed acute dose-dependent elevation in liver enzymes and thrombocytopenia after injection, although both were transient and resolved within 2 weeks. The whole blood clotting time (WBCT), plasma FVIII concentration, FVIII activity, and activated partial thromboplastin time in all animals improved significantly after treatment, and two animals receiving a higher dose reached near normal WBCT with low-level FVIII activity until terminal sacrifice at 3 months, and 2 years. Importantly, the treated dogs suffered no bleeding events after injection. Moreover, we observed persistent vector-specific DNA and RNA in liver tissue collected from one high-dose animal at days 18 and 79, and could not detect the formation of inhibitory antibodies.Although vector-associated toxicity remains an obstacle, a single injection of HDV led to long-term transgene expression and vector persistence in two FVIII-deficient animals with conversion of their severe phenotype to a moderate one.

SUBMITTER: McCORMACK WM

PROVIDER: S-EPMC3947717 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model.

McCORMACK W M WM Seiler M P MP Bertin T K TK Ubhayakar K K Palmer D J DJ Ng P P Nichols T C TC Lee B B

Journal of thrombosis and haemostasis : JTH 20060601 6

<h4>Background</h4>Adenoviral vector-mediated gene therapy might have potential for long-term correction of the monogenic disease hemophilia A.<h4>Objective</h4>In this study, we tested the efficacy of administering a helper-dependent adenoviral vector (HDV) designed for maximal liver-restricted canine factor VIII (cFVIII) expression on three out-bred hemophilia A dogs.<h4>Methods</h4>Three FVIII-deficient animals from the University of North Carolina colony were injected with 1 x 10(12) (Dog A) ...[more]

PMID: 16706963

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Project description:Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL-1) and some patients with moderate hemophilia (0.01-0.05 IU mL-1) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.

Project description:Background Despite correction of the atrial septal defect (ASD), patients experience atrial fibrillation frequently and have increased morbidity and mortality. We examined physical capacity, cardiac performance, and invasive hemodynamics in patients with corrected ASD. Methods and Results Thirty-eight corrected patients with isolated secundum ASD and 19 age-matched healthy controls underwent right heart catheterization at rest and during exercise with simultaneous expired gas assessment and echocardiography. Maximum oxygen uptake was comparable between groups (ASD 32.7±7.7 mL O2/kg per minute, controls 35.2±7.5 mL O2/kg per minute, P=0.3), as was cardiac index at both rest and peak exercise. In contrast, pulmonary artery wedge v wave pressures were increased at rest and peak exercise (rest: ASD 14±4 mm Hg, controls 10±5 mm Hg, P=0.01; peak: ASD 25±9 mm Hg, controls 14±9 mm Hg, P=0.0001). The right atrial v wave pressures were increased at rest but not at peak exercise. The transmural filling pressure gradient (TMFP) was higher at peak exercise among patients with ASD (10±6 mm Hg, controls 7±3 mm Hg, P=0.03). One third of patients with ASD demonstrated an abnormal hemodynamic exercise response defined as mean pulmonary artery wedge pressure ≥25 mm Hg and/or mean pulmonary artery pressure ≥35 mm Hg at peak exercise. These patients had significantly elevated peak right and left atrial a wave pressures, right atrial v wave pressures, pulmonary artery wedge v wave pressures, and transmural filling pressure compared with both controls and patients with ASD with a normal exercise response. Conclusions Patients with corrected ASD present with elevated right and in particular left atrial pressures at rest and during exercise despite preserved peak exercise capacity. Abnormal atrial compliance and systolic atrial function could predispose to the increased long-term risk of atrial fibrillation. Registration Information clinicaltrials.gov. Identifier: NCT03565471.

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Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model.

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Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model.

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