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Journal of Thrombosis and Haemostasis :... Mar 2023Gene therapy is expected to become a promising treatment, and potentially even a cure, for hemophilia. After several years of research, the first gene therapy product... (Review)
Review
Gene therapy is expected to become a promising treatment, and potentially even a cure, for hemophilia. After several years of research, the first gene therapy product has been granted conditional market authorization by the European Union in August 2022. The recent progress in the field also has implications on the ethical aspects of hemophilia gene therapy. Reviews conducted in the 2000s mainly identified questions on the ethics of conducting early-phase clinical trials. However, since then, the knowledge on safety and efficacy has improved, and the field has moved toward clinical application, a phase that has its own ethical aspects. Therefore, we conducted a narrative review to take stock of the ethical aspects of hemophilia gene therapy. Based on our analysis of the literature, we identified 3 ethical themes. The theme Living up to expectations describes the existing hopes for gene therapy and the unlikelihood of the currently approved product becoming a permanent cure. In the theme Psychosocial impacts, we discuss the fear that gene therapy will impact the identity of people with hemophilia and their need for psychosocial support. The theme Costs and access discusses the expected cost-effectiveness of gene therapy and its implications on accessibility worldwide. We conclude that it may be necessary to change the narratives surrounding gene therapy, from describing it as a cure to describing it as one of the many treatments that temporarily relieve symptoms and that there is a need to reevaluate the desirability of gene therapy for hemophilia, given the availability of other treatments.
Topics: Humans; Hemophilia A; Genetic Therapy; Genetic Vectors; Hemophilia B
PubMed: 36696181
DOI: 10.1016/j.jtha.2022.12.027 -
Blood Advances Apr 2021Hemophilia B is a rare congenital blood disorder characterized by factor IX deficiency. Clinical profiles of hemophilia B range from mild to severe forms of the disease....
Hemophilia B is a rare congenital blood disorder characterized by factor IX deficiency. Clinical profiles of hemophilia B range from mild to severe forms of the disease. The objective of this study was to characterize the economic burden associated with differing clinical profiles of hemophilia B from a US health system perspective. Using the IBM MarketScan database (June 2011-February 2019), a claims-based algorithm was developed to identify 4 distinct profiles (mild, moderate, moderate-severe, and severe) in adult males with hemophilia B based on the frequency of hemorrhage events and factor IX replacement claims. Mean annual health care resource use (HRU) and costs were statistically compared between patients with hemophilia B (N = 454) and 1:1 demographic-matched controls (N = 454), both overall and with stratification by clinical profile. Compared with matched controls, patients with hemophilia B had a significantly higher comorbidity burden (Charlson Comorbidity Index, mean ± standard deviation [SD]: 0.9 ± 1.7 vs 0.3 ± 0.9, P < .001). Across all clinical profiles, patients with hemophilia B had significantly higher HRU vs matched controls (mean ± SD: 0.3 ± 0.6 vs 0.1 ± 0.3 inpatient admissions; 0.6 ± 1.2 vs 0.2 ± 0.6 emergency department visits; 17.7 ± 22.9 vs 8.0 ± 11.0 outpatient visits; all P < .001). Annual total health care costs per patient among patients with hemophilia B were more than 25-fold higher vs matched controls (mean ± SD: $201 635 ± $411 530 vs $7879 ± $29 040, respectively, P < .001). Annual total health care costs per patient increased with increasing severity (mean ± SD: mild, $80 811 ± $284 313; moderate, $137 455 ± $222 021; moderate-severe, $251 619 ± $576 886; severe, $632 088 ± $501 270). The findings of this study highlight the substantial burden of illness associated with hemophilia B.
Topics: Adult; Cost of Illness; Health Care Costs; Hemophilia B; Hospitalization; Humans; Male; Patient Acceptance of Health Care; United States
PubMed: 33830206
DOI: 10.1182/bloodadvances.2020003424 -
Proceedings. Biological Sciences Dec 2015The first clinical gene delivery, which involved insertion of a marker gene into lymphocytes from cancer patients, was published 25 years ago. In this review, we... (Review)
Review
The first clinical gene delivery, which involved insertion of a marker gene into lymphocytes from cancer patients, was published 25 years ago. In this review, we describe progress since then in gene therapy. Patients with some inherited single-gene defects can now be treated with their own bone marrow stem cells that have been engineered with a viral vector carrying the missing gene. Patients with inherited retinopathies and haemophilia B can also be treated by local or systemic injection of viral vectors. There are also a number of promising gene therapy approaches for cancer and infectious disease. We predict that the next 25 years will see improvements in safety, efficacy and manufacture of gene delivery vectors and introduction of gene-editing technologies to the clinic. Gene delivery may also prove a cost-effective method for the delivery of biological medicines.
Topics: Bone Marrow Transplantation; Communicable Diseases; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hemophilia B; Humans; Neoplasms; Retinal Degeneration; Viruses
PubMed: 26702034
DOI: 10.1098/rspb.2014.3003 -
Blood Jan 2019In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a... (Review)
Review
In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a lasting cure with a single drug administration. Near-to-complete correction of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) have now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral vectors with different viral capsids that have been engineered to express high-level, and in some cases hyperactive, coagulation factors were employed. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors (or alternative drugs that promote coagulation), and may therefore ultimately also reduce treatment costs. However, mild liver toxicities have been observed in some patients receiving high vector doses. In some but not all instances, the toxicities correlated with a T-cell response directed against the viral capsid, prompting use of immune suppression. In addition, not all patients can be treated because of preexisting immunity to viral capsids. Nonetheless, studies in animal models of hemophilia suggest that the approach can also be used for immune tolerance induction to prevent or eliminate inhibitory antibodies against coagulation factors. These can form in traditional protein replacement therapy and represent a major complication of treatment. The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development.
Topics: Animals; Blood Coagulation Factors; Dependovirus; Genetic Therapy; Genetic Vectors; Hemophilia A; Hemophilia B; Humans
PubMed: 30559260
DOI: 10.1182/blood-2018-07-820720 -
Drugs Jun 2023Eftrenonacog alfa (Alprolix) is an extended half-life recombinant factor IX (rFIX)-Fc fusion protein (hereafter referred to as rFIXFc). Administered as an intravenous... (Review)
Review
Eftrenonacog alfa (Alprolix) is an extended half-life recombinant factor IX (rFIX)-Fc fusion protein (hereafter referred to as rFIXFc). Administered as an intravenous bolus, it is approved for prophylactic use and the treatment of bleeding in patients with haemophilia B in various countries worldwide, including those of the EU, as well as the USA. In multinational, phase III trials, rFIXFc was effective for the prophylaxis, perioperative management or on-demand treatment of bleeding in male patients with severe haemophilia B regardless of age and irrespective of whether or not they had been previously treated with FIX replacement products. Prophylactic efficacy was maintained over the longer term (up to 5 years) in previously treated patients. rFIXFc effectiveness in the real-world setting is supported by results of prospective studies, as well as the outcomes of several retrospective trials. rFIXFc was well tolerated in clinical trials in previously treated and untreated children, adolescents and/or adults with severe haemophilia B. Thus, rFIXFc continues to represent a useful treatment option among the haemophilia B patient population.
Topics: Adult; Child; Adolescent; Humans; Male; Factor IX; Hemophilia B; Prospective Studies; Retrospective Studies; Recombinant Fusion Proteins; Hemorrhage; Hemophilia A
PubMed: 37081241
DOI: 10.1007/s40265-023-01868-7 -
Nature Communications Nov 2022AAV-delivered CRISPR/Cas9 (AAV-CRISPR) has shown promising potentials in preclinical models to efficiently insert therapeutic gene sequences in somatic tissues. However,...
AAV-delivered CRISPR/Cas9 (AAV-CRISPR) has shown promising potentials in preclinical models to efficiently insert therapeutic gene sequences in somatic tissues. However, the AAV input doses required were prohibitively high and posed serious risk of toxicity. Here, we performed AAV-CRISPR mediated homology-independent knock-in at a new target site in mAlb 3'UTR and demonstrated that single dose of AAVs enabled long-term integration and expression of hF9 transgene in both adult and neonatal hemophilia B mice (mF9 -/-), yielding high levels of circulating human Factor IX (hFIX) and stable hemostasis restoration during entire 48-week observation period. Furthermore, we achieved hemostasis correction with a significantly lower AAV dose (2 × 10 vg/neonate and 1 × 10 vg/adult mouse) through liver-specific gene knock-in using hyperactive hF9 variant. The plasma antibodies against Cas9 and AAV in the neonatal mice receiving low-dose AAV-CRISPR were negligible, which lent support to the development of AAV-CRISPR mediated somatic knock-in for treating inherited diseases.
Topics: Mice; Animals; Humans; Hemophilia B; Gene Editing; CRISPR-Cas Systems; Antibody Formation; Genetic Vectors; Hemostasis; Liver
PubMed: 36434000
DOI: 10.1038/s41467-022-34898-y -
Journal of Thrombosis and Haemostasis :... Jun 2020The advent of extended half-life (EHL) recombinant clotting factors and innovative non-factor replacement therapeutics, such as emicizumab, offers several advantages... (Review)
Review
The advent of extended half-life (EHL) recombinant clotting factors and innovative non-factor replacement therapeutics, such as emicizumab, offers several advantages over existing products for the prophylactic treatment of people living with hemophilia (PwH). These include low annual bleeding rates with less frequent dosing, higher trough plasma concentrations, and a more convenient route of administration. However, increasing use of these therapies poses challenges to clinicians and coagulation laboratories due to the lack of standardized assays for monitoring of hemostatic parameters, and the potential for misinterpretation of test results, which may jeopardize patient safety. Definitive diagnosis of hemophilia and treatment monitoring is reliant on demonstrating factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B) deficiency using a functional coagulation assay. The most frequently used assays are based on activated partial thromboplastin time, using a one-stage or two-stage process. While one-stage and chromogenic assays have performed well with human-derived FVIII and FIX and full-length recombinant products, EHL recombinant factors are heterogeneous in structure and mode of action and therefore show wide variation in activity levels between different one-stage assays, and between one-stage and chromogenic assays. In the context of the recommended stepwise approach for laboratory diagnosis of hemophilia, we examine the diagnostic challenges associated with the use of EHL factors and novel non-factor therapeutics and consider the optimal diagnostic approach in PwH who are receiving these treatments. Ultimately, accurate diagnostic solutions are a prerequisite for personalized therapy to minimize treatment burden and improve quality of life in PwH.
Topics: Clinical Laboratory Techniques; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Humans; Quality of Life
PubMed: 32115865
DOI: 10.1111/jth.14784 -
Molecular Therapy : the Journal of the... Nov 2019
Topics: Animals; Clinical Trials as Topic; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hemophilia A; Hemophilia B; Humans; Liver; Transgenes; Treatment Outcome
PubMed: 31630963
DOI: 10.1016/j.ymthe.2019.10.005 -
Journal of Internal Medicine Jan 2015Congenital haemophilia A and B are genetic disorders affecting factor VIII and factor IX production, respectively. Factor replacement is the only effective treatment for... (Review)
Review
Congenital haemophilia A and B are genetic disorders affecting factor VIII and factor IX production, respectively. Factor replacement is the only effective treatment for these deficiencies, but a patient's immune system can develop inhibitory antibodies which bind and interfere with the function of the replaced factor in a variety of ways. The main treatment goal for patients with inhibitors is to induce immune tolerance to the injected factor. If not successful, a different treatment termed bypass therapy is needed to treat bleeds. The goal of this review is to demonstrate the usefulness of haemophilia registries as information sources to supplement available evidence regarding predictors of inhibitor development and immune tolerance induction (ITI) outcomes. In this systematic review, relevant keywords were used to search online academic databases during February 2014. Inclusion criteria were original publication and data obtained from a haemophilia or ITI registry with a minimum of 30 patients. A data collection form was created to extract information from selected manuscripts. Titles, abstracts and then full texts were screened to determine the eligibility of reports for this review. Eleven manuscripts from nine registries were determined eligible and included in the study. Registries have reported on some core variables, but are inconsistent in reporting less practiced predicting variables. Variables that may affect inhibitor and ITI outcomes were each divided into two categories: patient characteristics (such as age and family history) and treatment-related variables (including exposure days, treatment duration and dose). It is recommended that, in addition to exploratory hypothesis testing, a minimum set of variables should be collected and reported by registries. International collaboration and well-designed prospective registries are of major importance to advance this field in order to determine inhibitor risks and ITI outcomes and facilitate the development of new treatments.
Topics: Age Factors; Child; Evidence-Based Medicine; Factor VIII; Female; Follow-Up Studies; Hemophilia A; Hemophilia B; Humans; Immune Tolerance; Infant; Infant, Newborn; International Cooperation; Male; Registries; Risk Assessment; Severity of Illness Index; Sex Factors; Time Factors; Treatment Outcome
PubMed: 25169114
DOI: 10.1111/joim.12301 -
Cell Reports May 2018Hemophilia B is an ideal target for gene- and cell-based therapies because of its monogenic nature and broad therapeutic index. Here, we demonstrate the use of cell...
Hemophilia B is an ideal target for gene- and cell-based therapies because of its monogenic nature and broad therapeutic index. Here, we demonstrate the use of cell therapy as a potential long-term cure for hemophilia B in our FIX-deficient mouse model. We show that transplanted, cryopreserved, cadaveric human hepatocytes remain functional for more than a year and secrete FIX at therapeutic levels. Hepatocytes from different sources (companies and donors) perform comparably in curing the bleeding defect. We also generated induced pluripotent stem cells (iPSCs) from two hemophilia B patients and corrected the disease-causing mutations in them by two different approaches (mutation specific and universal). These corrected iPSCs were differentiated into hepatocyte-like cells (HLCs) and transplanted into hemophilic mice. We demonstrate these iPSC-HLCs to be viable and functional in mouse models for 9-12 months. This study aims to establish the use of cells from autologous and heterologous sources to treat hemophilia B.
Topics: Animals; Cell Transplantation; Disease Models, Animal; Factor IX; Hemophilia B; Hepatocytes; Heterografts; Induced Pluripotent Stem Cells; Mice; Mice, Knockout
PubMed: 29719266
DOI: 10.1016/j.celrep.2018.03.121