{"id":657,"date":"2025-12-06T04:16:18","date_gmt":"2025-12-06T04:16:18","guid":{"rendered":"http:\/\/www.rischool.org\/?p=657"},"modified":"2025-12-06T04:16:18","modified_gmt":"2025-12-06T04:16:18","slug":"it-expresses-canine-coagulation-factor-ix-cfix-under-control-of-the-liver-specific-human-1-antitrypsin-promoter-haat-including-two-liver-specific-enhancers-hcr-hepatocyte-control-regio","status":"publish","type":"post","link":"https:\/\/www.rischool.org\/?p=657","title":{"rendered":"\ufeffIt expresses canine coagulation factor IX (cFIX) under control of the liver-specific human -1-antitrypsin promoter (hAAT) including two liver-specific enhancers (HCR, hepatocyte control region; ApoE: apolipoprotein E)"},"content":{"rendered":"

\ufeffIt expresses canine coagulation factor IX (cFIX) under control of the liver-specific human -1-antitrypsin promoter (hAAT) including two liver-specific enhancers (HCR, hepatocyte control region; ApoE: apolipoprotein E). liver enzymes. Molecular analysis of liver samples revealed SB-mediated integration and provide evidence that transgene expression was derived mainly from integrated vector forms. Demonstrating that a viral vector system can deliver clinically relevant levels of a therapeutic protein in a large animal model of human disease paves a new path toward the possible cure of genetic diseases. == Introduction U 73122 == Hemophilia B is an X-linked inherited blood clotting disorder caused by mutations in the coagulation factor IX (FIX) gene. This genetic disease has a prevalence of about 1 in 30,000 Caucasian males. Current standard therapies for hemophilia B are based on protein infusion treatments utilizing recombinant proteins or plasma-derived blood components. However, limitations of this treatment option are the potential development of inhibitors, the inconvenience of repeated injections of the coagulation factor concentrates, and the expenses of replacement factor production. As an alternative treatment strategy for hemophilia B, a plethora of liver-based gene therapy methods have been proposed. Preclinical studies in murine and canine models for hemophilia B including gene delivery vehicles based on retrovirus, lentivirus, adeno-associated computer virus (AAV), and recombinant adenovirus were performed. Moloney murine leukemia virus-based retroviral vectors for example, which integrate into the host genome, were utilized in hemophilia dogs.1Furthermore, lentiviral vectors have been shown to be sufficient in mice but efficacy in hemophilia B dogs remains to be shown.2,3To date the longest duration of canine FIX (cFIX) expression (8 years) in hemophilia B dogs was demonstrated after a single liver-directed injection of a recombinant AAV based on serotype 2 vector (AAV2).4In that particular study it is claimed that extrachromosomal AAV vector genomes were responsible for long-term U 73122 expression of cFIX. Regrettably, in the context of a clinical trial in hemophilia patients, this AAV-based approach resulted in transient phenotypic correction (2 weeks) of the bleeding diathesis5most likely due to an adaptive immune response directed against the incoming viral capsid. In the present study, we utilized an integrating adenoviral hybrid-vector system for somatic integration and long-term phenotypic correction of the bleeding disorder. Various generations of recombinant adenoviral vectors were used in the past for the treatment of hemophilia B. The early generation vectors deleted for the early-transcribed adenoviral genesE1andE3resulted in therapeutic cFIX levels in mice and hemophilia B dogs. However, cFIX levels in mouse U 73122 serum although in a therapeutic range significantly decreased over time and plasma cFIX levels of treated animals declined to undetectable levels 2 weeks postinjection.6It became clear that synthesized viral antigens expressed from the early generation recombinant adenoviral genomes induced immune responses that are at least in part responsible for destruction of transduced cells. The primary immune effector cells in this process are major histocompatibility complex class I-restricted cytotoxic T-lymphocytes.7,8,9Further deletion of the E2a, E2b, or E4 regions, while appearing safer, still resulted in some GCN5L<\/a> toxicity.10,11,12 The newest generation of adenoviral vectors is deleted for all those viral coding sequences allowing for packaging of up to 36 kb of foreign DNA.13,14These vectors are commonly referred to as gutted, gene-deleted, helper-dependent, or high-capacity adenoviral vectors (HC-AdVs). It was exhibited that hepatic transduction utilizing HC-AdV is not accompanied by chronic toxicity due to the absence of viral gene expression.15,16However, even HC-AdVs exhibit some dose-dependent toxicity related to the incoming viral particles (vps).17It was shown that systemic cytokines including the early indication of inflammation interleukin-6 as mediators of the innate immune responses were activated17,18and an attenuated adaptive immune response was observed due to an infiltration of adenovirus-specific cytotoxic T-lymphocytes.19 Nonetheless, none of the currently available gene transfer vehicles for gene therapeutic applications is flawless and, to date, HC-AdV still represents one of the most encouraging gene delivery vehicles. This type of vector has been shown to result in long-term transgene expression and phenotypic correction in various species and animal models. We as well as others have shown that after a single injection a HC-AdV can be managed life-long in mice and for up to 2 years in rats.16,20,21,22,23In dogs U 73122<\/a> and nonhuman primates, HC-AdV liver transduction also led to long-term transgene expression.15,16To date, the longest period of transgene expression (up to 964 days) was observed by Brunetti-Pierri and colleagues using a HC-AdV for hepatic transduction of baboons.16,24With respect to canine hemophilia B, there are currently two studies utilizing HC-AdV based on human adenovirus serotype 5. Our previous study exhibited that,.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffIt expresses canine coagulation factor IX (cFIX) under control of the liver-specific human -1-antitrypsin promoter (hAAT) including two liver-specific enhancers…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[23],"tags":[],"class_list":["post-657","post","type-post","status-publish","format-standard","hentry","category-igf-receptors"],"_links":{"self":[{"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/657","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=657"}],"version-history":[{"count":1,"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/657\/revisions"}],"predecessor-version":[{"id":658,"href":"https:\/\/www.rischool.org\/index.php?rest_route=\/wp\/v2\/posts\/657\/revisions\/658"}],"wp:attachment":[{"href":"https:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=657"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=657"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rischool.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=657"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}