Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options

Regling, Katherine; Callaghan, Michael U.; Sidonio, Robert F.

doi:10.2147/phmt.s293246

Cited by 6 publications

(6 citation statements)

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“…While PWIBD receiving care at HTCs generally report a high level of satisfaction [ 31 – 33 ], their numbers are increasing [ 19 , 34 ] and the treatment landscape complexity is intensifying [ 35 , 36 ]. HSR examines access to high quality, affordable care, health inequities, and individuals who may encounter more barriers [ 20 , 32 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science

Byams

Baker

Bailey³

et al. 2023

Expert Review of Hematology

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Background: The National Hemophilia Foundation (NHF) conducted extensive all-stakeholder inherited bleeding disorder (BD) community consultations to inform a blueprint for future research. Sustaining and expanding the specialized and comprehensive Hemophilia Treatment Center care model, to better serve all people with inherited BDs (PWIBD), and increasing equitable access to optimal health emerged as top priorities. Research Design and Methods: NHF, with the American Thrombosis and Hemostasis Network (ATHN), convened multidisciplinary expert working groups (WG) to distill priority research initiatives from consultation findings. WG5 was charged with prioritizing health services research (HSR); diversity, equity, and inclusion (DEI); and implementation science (IS) research initiatives to advance community-identified priorities. Results: WG5 identified multiple priority research themes and initiatives essential to capitalizing on this potential. Formative studies using qualitative and mixed methods approaches should be conducted to characterize issues and meaningfully investigate interventions. Investment in HSR, DEI and IS education, training, and workforce development are vital. Conclusions: An enormous amount of work is required in the areas of HSR, DEI, and IS, which have received inadequate attention in inherited BDs. This research has great potential to evolve the experiences of PWIBD, deliver transformational community-based care, and advance health equity.

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Section: Introductionmentioning

confidence: 99%

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science

Byams

Baker

Bailey³

et al. 2023

Expert Review of Hematology

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“…The treatment of patients with hemophilia A has evolved over time, from fresh frozen plasma transfusion, and cryoprecipitate to FVIII concentrates (in the 1970s), purified FVIII (ref. 5,6 ), recombinant FVIII (in the 1990s) and prolonged half-life recombinant FVIII products 5,7 . Among replacement therapies, those bioengineered using XTEN fusion technology seem to be the most promising, according to the results from phase 1/2 studies 8 (the polypeptide XTEN can be produced using E. coli, is less immunogenic, and is potentially biodegradable) (ref.…”

Section: Introductionmentioning

confidence: 99%

“…10 ). Novel non-factor therapies (such as emicizumab -a FVIII mimetic bispecific antibody or Mim8 -a next-generation FVIII mimetic human bispecific antibody) augment or bypass the hemostatic pathway 5 . Emicizumab mimics the function of activated FVIII (ref.…”

Section: Introductionmentioning

confidence: 99%

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From a bispecific monoclonal antibody to gene therapy: A new era in the treatment of hemophilia A

Mihăilă¹

2023

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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The treatment of hemophilia A has progressed amazingly in recent years. Emicizumab, a bispecific-humanized monoclonal antibody, is able to improve coagulation by bridging activated factor IX and factor X. Emicizumab is administered subcutaneously and much less often compared to factor VIII products. It has low immunogenicity, does not require dose adjustment, and can be administered regardless of the presence of factor VIII inhibitors. Thrombin generation assays but not factor VIII activity are indicated to guide and monitor the treatment. Emicizumab has enabled the conversion of patients with severe forms into patients with milder forms of hemophilia A. It has reduced the number of bleeding episodes compared to both on-demand and prophylactic substitution therapy and has an excellent safety profile. Gene therapy can elevate factor VIII plasma levels for many years after a single treatment course, could offer longterm protection from bleeding episodes, and minimize or eliminate the need for substitutive treatment with factor VIII concentrates. Gene therapy can provoke an immune response, manifested by an increase in common liver enzymes, that require immunotherapy. Long term monitoring is necessary to identify possible adverse effects. Future objectives are: the development of an ideal viral vector, the possibility of its re-administration, the use of gene therapy in hemophiliac children, and determining whether it can be successfully used to induce immune tolerance to factor VIII ceteri paribus. The future will determine the place of each type of treatment and group of patients for which it is indicated.

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“…The use of viral vectors delivering FVIII, such as adeno-associated viral vectors 1 and, more recently, lentiviral vectors (LVs), has been experimentally tested in an attempt to permanently correct HA. 2 Adeno-associated viral vector–mediated correction of liver hepatocytes was successful, reaching phase 3 clinical trials of gene therapy (GT) ( www.clinicaltrials.gov , # NCT04370054 and # NCT04323098 ). However, several limitations, mainly related to preexisting immunity and chronic liver disease, narrow the inclusion criteria of patients with HA eligible for this therapy.…”

Section: Introductionmentioning

confidence: 99%

CD14+/CD31+ monocytes expanded by UM171 correct hemophilia A in zebrafish upon lentiviral gene transfer of factor VIII

et al. 2023

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Emerging gene therapy (GT) clinical trials test the correction of hemophilia A (HA) by replacing factor VIII (FVIII) in autologous hematopoietic stem cells (HSC). Although it is known that platelets, monocyte/macrophages, and mesenchymal stromal cells can secrete transgenic FVIII, a systematic examination of blood lineages as extrahepatic sources of FVIII has not yet been performed. In this study, we sought to provide a comprehensive map of native and lentivirus-based transgenic FVIII production from HSC stage to mature blood cells, through a flow cytometry analysis. In addition, we generated a model of transient HA in zebrafish based on antisense RNA, to assess the corrective potential of the FVIII-transduced HSCs. We discovered that FVIII production begins at the CD34+ progenitor stage after cytokine stimulation in culture. Among all mature white blood cells, monocytes are the largest producers of native FVIII, and can maintain protein overexpression during differentiation from HSCs, when transduced by a FVIII lentiviral vector. Moreover, the addition of the HSC self-renewal agonist UM171 to CD34+ cells during transduction expanded a subpopulation of CD14+/CD31+ monocytes with excellent ability to carry the FVIII transgene, allowing the correction of HA phenotype in zebrafish. Finally, the HA zebrafish model showed that f8 RNA is predominantly localized in the hematopoietic system at the larval stage, which indicates a potential contributory role of FVIII in hematopoiesis that warrants further investigation. We believe that our study may be of broad interest to hematologists and researchers striving to advance knowledge and permanent treatments for patients with HA.

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Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options

Cited by 6 publications

References 50 publications

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science

From a bispecific monoclonal antibody to gene therapy: A new era in the treatment of hemophilia A

CD14+/CD31+ monocytes expanded by UM171 correct hemophilia A in zebrafish upon lentiviral gene transfer of factor VIII

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