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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003ETreatment of hemophilia A is benefiting from extended half-life recombinant factor VIII compounds that maintain higher trough levels of drug with less frequent dosing. A variety of pegylated recombinant factor VIII compounds are available. A promising avenue of treatment is the targeted use of liver mesenchymal stem cells that produce factor VIII.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Ehemophilia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Erecombinant factor VIII\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eextended half-life\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epegylation\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emesenchymal stem cells\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eother diseases of blood \u0026amp; blood-forming organs\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003EAbout 60% of people with hemophilia A have the severe form of the disease, which is characterized by factor VIII (FVIII) levels \u0026lt;\u20051%. Intracranial hemorrhage and spontaneous bleeding require urgent intravenous administration of FVIII; however, this can cause complications including infection and thrombosis.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EIn an era of different recombinant FVIII treatment options, with the prospect of extended FVIII half-life, getting a better understanding of the product(s) that provide the maximum advantage for individual patients is important. Even incremental lengthening of the time of higher FVIII trough levels provides more protection from spontaneous bleeding. The goal in the treatment of hemophilia A, therefore, according to Jerry S. Powell, MD, CSL Behring, King of Prussia, Pennsylvania, USA, is to use a factor that is retained in the body longer and at higher levels than is the case now.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIn hemophilia A about 30% of patients will, when exposed to normal factor VIII recognize it as foreign by the immune system. Treatment involving factor administration can help damp down the production of immune inhibitors [Nakar C et al. \u003Cem\u003EHaemophilia\u003C\/em\u003E. 2015].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn hemophilia B, recombinant factor IX modified by pegylation has displayed a markedly extended half-life in phase 3 trials [Negrier C et al. \u003Cem\u003EBlood\u003C\/em\u003E. 2011]. Another factor IX recombinant product fuses albumin, which is cleaved at the site of coagulation to deliver the native factor IX. A similar strategy involving recombinant FVIII (rFVIII) has been explored for the treatment of hemophilia A. Various products have been developed that feature pegylation and a recombinant fusion protein incorporating FVIII and a carboxy-terminal bound fragment crystallizable (Fc) domain of immunoglobulin G.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ErFVIII-Fc features a longer half-life and decreased rate of clearance compared with the current recombinant FVIII products, independent of the level of von Willebrand Factor (vWF) [Powell JS et al. \u003Cem\u003EBlood\u003C\/em\u003E. 2012].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EAlternatives to factor replacement include FVIIIa mimetic-specific antibody, antibody to tissue factor pathway inhibitor, and the use of RNA interference technology to block antithrombin production. As with the extended half-life strategy, these alternate strategies aim for better and less frequent prophylactic treatment of hemophilia A, according to Andreas Tiede, MD, PhD, Hannover Medical School, Hannover, Germany.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe area of most robust research and development has been pegylation. The attachment of polyethylene glycol changes the physiochemical properties of the target compound and lengthens its residency in the body.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EPegylated products are approved for use with a variety of diseases, including leukemia, hepatitis C, age-related macular degeneration, rheumatoid arthritis, and Crohn disease. All feature a half-life that is extended compared with the native compound, with appreciable retention of activity [Fishburn CS. \u003Cem\u003EJ Pharm Sci\u003C\/em\u003E. 2008].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EPegylated products for hemophilia A include the B domain deleted FVIII compounds N8-GP, BAY 94-9027, and CSL 627, and the full-length FVIII backbone product BAX 855. With all, the pegylated region is removed during thrombin activation. All feature longer half-lives (about 1.5-fold increase, translating to about 18 hours for N8-GP, BAY 94-9027, and BAX 855 and about 13 hours for CSL 627) compared with recombinant FVIII [Tiede A et al. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E. 2013].\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ECompared with FVIII, N8-GP displays reduced binding to lipoprotein receptor\u2013related protein (LRP), similar potency and efficacy, and better protection from bleeding. vWF does affect the activity of N8-GP; the consequences, if any, are unknown. The compound is currently being evaluated in a phase 3 trial. BAX 855 has a similar thrombin-mediated activation rate as rFVIII but reduced binding to LRP. The reduced binding to LRP of these 2 compounds likely influences their extended half-lives. BAY 94-9027 can be monitored in serum using the one-stage activated partial thromboplastin time FVIII assay [Gu JM et al. \u003Cem\u003EHaemophilia\u003C\/em\u003E. 2014], which could be exploited in phase 3 trials to monitor FVIII activity in patients treated with the compound. CSL 627 is similar to rFVIII in the rate of blood coagulation and performance in a mouse model of hemophilia. The compound also displays relatively increased binding to vWF. Its performance in a phase 1 assay has been promising [Coyle TE et al. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003ENo safety issues have been evident with any of the compounds. Larger PEGs can accumulate in the body without any apparent adverse effects. Although immune response to PEG has been documented for other pegylated molecules, this has not been observed so far in vivo for the pegylated FVIII compounds.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EAside from the use of extended activity rFVIII compounds, researchers including Etienne Sokal, MD, PhD, Universit\u00e9 Catholique de Louvain, Brussels, Belgium, are exploring stem cell therapy for relief of hemophilia. The research is grounded in the knowledge that the liver is a repository for thousands of enzymes that catalyze a wide variety of reactions. So, supplying progenitors of these cells could replace the enzyme-mediated defect of interest [Sokal EM. \u003Cem\u003EJ Inherit Metab Dis\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ELiver mesenchymal stem cells (MSCs) can be differentiated in vitro and used therapeutically [Khuu DN et al. \u003Cem\u003ECell Transplant\u003C\/em\u003E. 2013, 2011; Najimi M et al. \u003Cem\u003ECell Transplant\u003C\/em\u003E. 2007]. Intra-portal infusion facilitates the targeted delivery of liver MSCs to the liver [Defresne F et al. \u003Cem\u003ENucl Med Biol\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EA phase 1\/2 study [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01765283\u0026amp;atom=%2Fspmdc%2F15%2F21%2F12.atom\u0022\u003ENCT01765283\u003C\/a\u003E] involving 20 pediatric patients (14 with urea cycle disorders and 6 Crigler-Najjar patients) with 3 doses of liver MSCs has indicated the safety and preliminary efficacy of treatment in restoring liver function in terms of urea production. These results have prompted studies assessing whether stem cell\u2013mediated functional restoration can be applied to clotting factor deficiencies. The capacity of MSCs to produce FVIII has been demonstrated in vitro [Sanada C et al. \u003Cem\u003EJ Cell Physiol\u003C\/em\u003E. 2013], with correction of hemophilia and joint bleeding shown in animal models [Follenzi A et al. \u003Cem\u003EBlood\u003C\/em\u003E. 2012; Porada CD et al. \u003Cem\u003EExp Hematol\u003C\/em\u003E. 2011]. Other examinations have indicated the potential of liver stem cells to target joints affected in hemophilia.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EThe emerging data indicate the therapeutic safety of adult liver MSCs and their capability as a vector for delivery of enzymes or proteins to affected tissues. The hope is that MSCs that express FVIII can be delivered where needed in patients with hemophilia.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/15\/21\/12.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlglq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}