Browsing by Subject "hemophilia"

Now showing 1 - 3 of 3
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    Experimental Variables that Affect Human Hepatocyte AAV Transduction in Liver Chimeric Mice
    (Elsevier, 2020-09-11) Zou, Chenhui; Vercauteren, Koen O. A.; Michailidis, Eleftherios; Kabbani, Mohammad; Zoluthkin, Irene; Quirk, Corrine; Chiriboga, Luis; Yazicioglu, Mustafa; Anguela, Xavier M.; Meuleman, Philip; High, Katherine A.; Herzog, Roland W.; Jong, Ype P. de; Pediatrics, School of Medicine
    Adeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene expression in such models remain poorly defined. Here, we aimed to test whether three experimental conditions influence AAV transgene expression in immunodeficient, fumaryl-acetoactetate-hydrolase-deficient (Fah−/−) chimeric mice repopulated with primary human hepatocytes. We examined the effects of the murine liver injury cycle, human donor variability, and vector doses on hepatocyte transduction with various AAV serotypes expressing a green fluorescent protein (GFP). We determined that the timing of AAV vector challenge in the liver injury cycle resulted in up to 7-fold differences in the percentage of GFP expressing human hepatocytes. The GFP+ hepatocyte frequency varied 7-fold between human donors without, however, changing the relative transduction efficiency between serotypes for an individual donor. There was also a clear relationship between AAV vector doses and human hepatocyte transduction and transgene expression. We conclude that several experimental variables substantially affect human hepatocyte transduction in the Fah−/− chimera model, attention to which may improve reproducibility between findings from different laboratories.
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    A Molecular Revolution in the Treatment of Hemophilia
    (Elsevier, 2019) Butterfield, John S. S.; Hege, Kerry M.; Herzog, Roland W.; Kaczmarek, Radoslaw; Pediatrics, School of Medicine
    For decades, the monogenetic bleeding disorders hemophilia A and B (coagulation factor VIII and IX deficiency) have been treated with systemic protein replacement therapy. Now, diverse molecular medicines, ranging from antibody to gene to RNA therapy, are transforming treatment. Traditional replacement therapy requires twice to thrice weekly intravenous infusions of factor. While extended half-life products may reduce the frequency of injections, patients continue to face a lifelong burden of the therapy, suboptimal protection from bleeding and joint damage, and potential development of neutralizing anti-drug antibodies (inhibitors) that require less efficacious bypassing agents and further reduce quality of life. Novel non-replacement and gene therapies aim to address these remaining issues. A recently approved factor VIII-mimetic antibody accomplishes hemostatic correction in patients both with and without inhibitors. Antibodies against tissue factor pathway inhibitor (TFPI) and antithrombin-specific small interfering RNA (siRNA) target natural anticoagulant pathways to rebalance hemostasis. Adeno-associated virus (AAV) gene therapy provides lasting clotting factor replacement and can also be used to induce immune tolerance. Multiple gene-editing techniques are under clinical or preclinical investigation. Here, we provide a comprehensive overview of these approaches, explain how they differ from standard therapies, and predict how the hemophilia treatment landscape will be reshaped.
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    Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies
    (Elsevier, 2022-12) Rana, Jyoti; Muñoz, Maite Melero; Biswas , Moanaro; Pediatrics, School of Medicine
    Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance.