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Hemophilia B

G N Nguyen, L A George, J I Siner, R J Davidson, C B Zander, X L Zheng, V R Arruda, R M Camire, D E Sabatino
BACKGROUND: The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a Paired basic Amino acid Cleaving Enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
Julie Ann Smith
Hemophilia will be encountered in the oral and maxillofacial surgeon's office. A thorough understanding of hemophilia is necessary to safely care for these patients. One must understand the severity of the patient's hemophilia as well as whether or not inhibitors are present. The patient's surgical management will be influenced by these two factors. In addition to the possible need to transfuse factors or desmopressin, special care must be taken perioperatively to avoid bleeding complications. This article reviews the overall management of hemophilia A and B as well as the specific perioperative management of these patients...
November 2016: Oral and Maxillofacial Surgery Clinics of North America
Amy M Lange, Ekaterina S Altynova, Giang N Nguyen, Denise E Sabatino
Factor VIII (FVIII) is a large glycoprotein that is challenging to express both in vitro and in vivo. Several studies suggest that high levels of FVIII expression can lead to cellular stress. After gene transfer, transgene expression is restricted to a subset of cells and the increased FVIII load per cell may impact activation of the unfolded protein response. We sought to determine whether increased FVIII expression in mice after adeno-associated viral liver gene transfer would affect the unfolded protein response and/or immune response to the transgene...
2016: Molecular Therapy. Methods & Clinical Development
Irene Zolotukhin, David M Markusic, Brett Palaschak, Brad E Hoffman, Meera A Srikanthan, Roland W Herzog
Hemophilia A and B are coagulation disorders resulting from the loss of functional coagulation factor VIII (FVIII) or factor IX proteins, respectively. Gene therapy for hemophilia with adeno-associated virus vectors has shown efficacy in hemophilia B patients. Although hemophilia A patients are more prevalent, the development of therapeutic adeno-associated virus vectors has been impeded by the size of the F8 cDNA and impaired secretion of FVIII protein. Further, it has been reported that over-expression of the FVIII protein induces endoplasmic reticulum stress and activates the unfolded protein response pathway both in vitro and in hepatocytes in vivo, presumably due to retention of misfolded FVIII protein within the endoplasmic reticulum...
2016: Molecular Therapy. Methods & Clinical Development
(no author information available yet)
No abstract text is available yet for this article.
October 13, 2016: Blood
Joshua I Siner, Benjamin J Samelson-Jones, Julie M Crudele, Robert A French, Benjamin J Lee, Shanzhen Zhou, Elizabeth Merricks, Robin Raymer, Timothy C Nichols, Rodney M Camire, Valder R Arruda
Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645-1648) in the design of B-domain-deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity...
October 6, 2016: JCI Insight
Slawomir Gajda, Tomasz Szopiński, Andrzej B Szczepanik, Roman Sosnowski, Anna M Szczepanik
Surgery in patients with hemophilia is a serious challenge. It requires a comprehensive approach, as well as careful postoperative monitoring. We present here the first case of a transperitoneal laparoscopic radical nephrectomy (TLRN) for renal cell carcinoma, of the clear-cell type, performed in a hemophilia B patient. The level of factor IX clotting activity before surgery and on postoperative days 1-6 was maintained at 65-130% and at 30-40% on subsequent days until healing of the post-operative wound was achieved...
2016: Central European Journal of Urology
Anirban Basu, Prasun Subedi, Sachin Kamal-Bahl
BACKGROUND: Financing medical breakthroughs or cures is becoming increasingly challenging in the current fiscal environment. OBJECTIVES: In this paper, we develop the precise conditions needed for a financing mechanism, HealthCoin, to work between a private payer and Medicare, to incentivize the former to invest in breakthrough therapies or cures in the US. METHODS: We illustrate the valuation of such a currency for a cure of Type 2 diabetes...
September 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Dario Balestra, Daniela Scalet, Franco Pagani, Malgorzata Ewa Rogalska, Rosella Mari, Francesco Bernardi, Mirko Pinotti
In cellular models we have demonstrated that a unique U1snRNA targeting an intronic region downstream of a defective exon (Exon-specific U1snRNA, ExSpeU1) can rescue multiple exon-skipping mutations, a relevant cause of genetic disease. Here, we explored in mice the ExSpeU1 U1fix9 toward two model Hemophilia B-causing mutations at the 5' (c.519A > G) or 3' (c.392-8T > G) splice sites of F9 exon 5. Hydrodynamic injection of wt-BALB/C mice with plasmids expressing the wt and mutant (hFIX-2G(5'ss) and hFIX-8G(3'ss)) splicing-competent human factor IX (hFIX) cassettes resulted in the expression of hFIX transcripts lacking exon 5 in liver, and in low plasma levels of inactive hFIX...
October 4, 2016: Molecular Therapy. Nucleic Acids
Jérémie Martinet, Gwladys Bourdenet, Amine Meliani, Laetitia Jean, Sahil Adriouch, Jose L Cohen, Federico Mingozzi, Olivier Boyer
BACKGROUND: Gene therapy is a promising treatment option for hemophilia and other protein deficiencies. However, immune responses against the transgene product represent an obstacle to safe and effective gene therapy, urging for the implementation of tolerization strategies. Induction of a hematopoietic chimerism via bone marrow transplantation (BMT) is a potent means for inducing immunological tolerance in solid organ transplantation. OBJECTIVES: We reasoned, here, that the same viral vector could be used, first, to transduce BM cells for inducing chimerism-associated transgene-specific immune tolerance and, second, for correcting protein deficiencies by vector-mediated systemic production of the deficient coagulation factor...
2016: Frontiers in Immunology
C Levy, F Fusil, F Amirache, C Costa, A Girard, D Negre, O Bernadin, G Garaulet, A Rodriguez, N Nair, T Vandendriessche, M Chuah, F-L Cosset, E Verhoeyen
BACKGROUND: B cells are attractive targets for gene therapy of diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen presenting cells. OBJECTIVE: Evaluation of human B cells for secretion of clotting factors such as factor IX (IX) as possible treatment for hemophilia. METHODS: We tested here for the first time our newly developed baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) for human (h) B-cell transduction followed their adaptive transfer into NSG mouse...
September 29, 2016: Journal of Thrombosis and Haemostasis: JTH
T Manon-Jensen, M A Karsdal, L N Nielsen, M Kjelgaard-Hansen, B Vandahl, E H N Olsen, M Enoksson, K Roepstorff
BACKGROUND: Hemophilic arthropathy is a severe complication of hemophilia. It is caused by recurrent bleeding into joint cavities, which leads to synovial inflammation, fibrosis, cartilage degradation, and bone remodeling. Extracellular matrix remodeling of affected tissues is a hallmark of these pathological processes. OBJECTIVES: The aim of this study was to use serological biomarkers of collagen turnover to evaluate extracellular matrix remodeling in a factor VIII-deficient rat model of hemophilic arthropathy...
September 28, 2016: Journal of Thrombosis and Haemostasis: JTH
Massimo Morfini
Replacement therapy for FVIII/IX in hemophilia A/B is more than 50 years old following the discovery of cryoprecipitate by Judith Pool in 1964. On-demand therapy and prophylaxis to treat or prevent bleedings is very demanding owing to the short half-life (HL) of factor concentrates (no more than 12-14 h for FVIII or 16-18 h for FIX). Patients are very eager to prolong the intervals between bolus. The enhanced HL of long-acting recombinant FIX (rFIX) concentrates seems to fulfill this expectance. Areas covered: Great improvements have been achieved in the bio-engineering of new rFIX concentrates...
October 2, 2016: Expert Opinion on Drug Metabolism & Toxicology
Kevin J O'Brien, Jay Lozier, Andrew R Cullinane, Brigitte Osorio, Khanh Nghiem, Vladislav Speransky, Wadih M Zein, James C Mullikin, Anne T Neff, Karen L Simon, May Christine V Malicdan, William A Gahl, Lisa R Young, Bernadette R Gochuico
PURPOSE: Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. RESULTS: The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism...
September 3, 2016: Molecular Genetics and Metabolism
Danielle Nance, Robert A Campbell, Jesse W Rowley, Jonathan M Downie, Lynn B Jorde, Walter H Kahr, Sarah A Mereby, Neal D Tolley, Guy A Zimmerman, Andrew S Weyrich, Matthew T Rondina
BACKGROUND: Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. OBJECTIVE: We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. PATIENTS/METHODS: Platelet number, size, and light transmission aggregometry to multiple agonists were evaluated in pedigree members...
September 14, 2016: Journal of Thrombosis and Haemostasis: JTH
Sorcha Allen, Craig B Reeder, Mark J Kransdorf, Christopher P Beauchamp, Matthew A Zarka, Farouk Mookadam
INTRODUCTION: Hemophilic pseudotumor is a rare but well documented complication seen in approximately 1-2% of patients with hemophilia. The incidence continues to decrease, likely because of increasingly sophisticated techniques in managing factor deficiency. We present a case of hemophilic pseudotumor in a patient without hemophilia, an exceptionally rare entity, and outline a hybrid approach to treatment. PRESENTATION OF CASE: The patient presented with a left sided iliopsoas mass and associated radiculopathy, with a history of a poorly characterized bleeding diathesis and Noonan's syndrome...
2016: International Journal of Surgery Case Reports
Flora Peyvandi, Isabella Garagiola, Eugenia Biguzzi
Historically, the bleeding episodes in subjects with coagulation disorders were treated by substitution therapy, initially using whole blood and fresh frozen plasma and more recently with specific factor concentrate. Nowadays, patients with hemophilia have the possibility to choose different effective and safe treatments including novel extended half-life and alternative hemostatic drugs. The availability of novel extended half-life products could probably overcome current prophylaxis limitations particularly in hemophilia B by reducing frequency of injections, achieving a higher trough level and improving the quality of life of the patients...
September 2, 2016: Journal of Thrombosis and Haemostasis: JTH
Asim Azhar, Ejaj Ahmad, Qamar Zia, Mohammad Owais, Ghulam Md Ashraf
Therapeutic proteins are engineered proteins produced in the laboratory for pharmaceutical use. With the advent of recombinant DNA technology, the proteins can be generated in specific host cells under defined conditions. In the process of production of genetically engineered animals, the gene of interest can be added at a single cell stage to produce a cloned animal from genetically engineered cells. Several recombinant cytokines, clotting factors etc have been licensed and are currently being utilized for the treatment of cancer, infectious diseases, hemophilia, anemia, multiple sclerosis, and hepatitis B/C...
September 1, 2016: Current Protein & Peptide Science
D L Li, B L Li, Z D Zhao, W Cao
No abstract text is available yet for this article.
August 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
C Reimann, M van Buiren, J Schelling, S Halimeh, T Niehues, B Strahm, B Zieger
No abstract text is available yet for this article.
August 29, 2016: Klinische Pädiatrie
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