Platelet-Targeted Hyperfunctional Factor IX (FIX) Gene Therapy for Hemophilia B Mice with Pre-Existing Anti-FIX Immunity

Hemophilia B (HB) is a prime model for gene therapy. While data from current clinical trials using AAV-mediated liver-targeted FIX gene therapy are very encouraging, this protocol can only be applied to adults without liver disease or anti-AAV antibodies. Thus, developing another gene therapy protocol is desired. Our previous studies have demonstrated that platelet-targeted FIX expression driven by the platelet-specific αIIb promoter (2bF9) restores hemostasis and induces immune tolerance in HB mice (Chen et al. Mol Ther 2014). To improve the efficacy, we used a codon-optimized hyperfunctional FIX Padua (2bCoF9R338L) to replace the normal FIX expression cassette. We showed a 5.8-fold higher platelet-FIX antigen (plt-F9:Ag) and a 28-fold activity (plt-F9:C) levels in HB mice (the non-inhibitor model), respectively, in the 2bCoF9R338L group compared to the 2bF9 group. Here we evaluate 2bCoF9R338L gene therapy in HB mice with preexisting anti-F9 immunity (the inhibitor model). Both donor and recipient HB mice were immunized with rhF9 in the presence of Incomplete Freund's Adjuvant to induce inhibitor development. Plt-F9 expression was introduced by 2bCoF9R338L lentivirus transduction of Sca-1+ cells followed by syngeneic transplantation into primed recipients preconditioned with either a lethal 11Gy or a sub-lethal 6.6Gy total body irradiation. Animals were analyzed starting at 4 weeks after transplantation.FACS analysis showed that there was 21.4 ± 11.4% (n = 6) tr...
Source: Blood - Category: Hematology Authors: Tags: 321. Blood Coagulation and Fibrinolytic Factors: Animal Models and Therapeutic Targets in Thrombosis and Hemostasis Source Type: research

Related Links:

Researchers from Case Western Reserve University in Ohio found those who lived in areas with high pollution levels were 26 per cent more likely to die within 4.8 years of the operation.
Source: the Mail online | Health - Category: Consumer Health News Source Type: news
In only the third documented such procedure, an international team of surgeons met in Belgrade, Serbia, to transplant a testicle from one twin to the other, restoring testosterone.
Source: the Mail online | Health - Category: Consumer Health News Source Type: news
Conclusion: Sirolimus-eluting Stentys stent may represent a potential solution for specific coronary anatomies such as bifurcation, ectasic, or tapered vessels. Risk of stent thrombosis appears related to clinical presentation with STEMI and to anatomic features, stressing the importance of the use of intracoronary imaging for self-expandable stents implantation.
Source: Coronary Artery Disease - Category: Cardiology Tags: Myocardial Infarction/Cardiogenic Shock Source Type: research
Conclusions DCB angioplasty for de novo small coronary lesions in the real-world environment in Japan is effective with acceptable 12-month outcomes.
Source: Coronary Artery Disease - Category: Cardiology Tags: Myocardial Infarction/Cardiogenic Shock Source Type: research
We examined the proportions of use of TRA, the influence on in-hospital outcomes, and adjusted long-term effects. Results The rate of TRA rose from 15.9% in period 1 to 69.1% in period 2, including in specific situations such as acute coronary syndrome, chronic total occlusion, bifurcation, calcified lesions, and unprotected left main PCI. In-hospital rates of bleeding were lower for TRA versus transfemoral artery (1.8 vs. 5.1%, overall, P 
Source: Coronary Artery Disease - Category: Cardiology Tags: Myocardial Infarction/Cardiogenic Shock Source Type: research
Background We hypothesized that the transition from bare-metal stents (BMS) to newer generation drug-eluting stents (n-DES) in clinical practice may have reduced the risk also in patients with kidney dysfunction. Methods: Observational study in the national SWEDEHEART registry, that compared the 1-year risk of in-stent restenosis (RS) and stent thrombosis (ST) in all percutaneous coronary intervention treated patients(n = 92 994) during 2007–2013. Results: N-DES patients were younger than BMS, but had more often diabetes, previous myocardial infarction, previous revascularization and were more often treated w...
Source: Coronary Artery Disease - Category: Cardiology Tags: Myocardial Infarction/Cardiogenic Shock Source Type: research
Conclusion Compared with heparin plus GPI or bivalirudin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding at 30 days among patients with NSTE-ACS and positive biomarkers.
Source: Coronary Artery Disease - Category: Cardiology Tags: Adjunctive Pharmacology Source Type: research
Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM) Issue: Ahead of print
Source: Clinical Chemistry and Laboratory Medicine - Category: Laboratory Medicine Source Type: research
Multidisciplinary, cancer-specific geriatric assessment to create an individualized optimization plan appears to improve outcomes in older patients undergoing hematopoietic cell transplantation (HCT), researchers report.Reuters Health Information
Source: Medscape Medical News Headlines - Category: Consumer Health News Tags: Transplantation News Source Type: news
X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease is caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4–CD8–B220–TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) recept...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
More News: Anaphylactic Shock | Bleeding | Clinical Trials | Gene Therapy | Genetics | Haemophilia | Hemophilia | Liver | Liver Disease | Liver Transplant | Study | Thrombosis | Transplants | Urology & Nephrology