Gene therapy 1·0 in haemophilia: effective and safe, but with many uncertainties

Publication date: March 2020Source: The Lancet Haematology, Volume 7, Issue 3Author(s): Michael Makris
Source: The Lancet Haematology - Category: Hematology Source Type: research

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Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Authors: Lillicrap D, Fijnvandraat K, Young G, Mancuso ME Abstract Introduction: Novel non-replacement therapies (e.g. emicizumab) have improved the management of patients with hemophilia A with and without inhibitors while introducing new challenges and increasing the complexity of clinical decision-making.Areas covered: Use of emicizumab can substantially delay initial exposure to FVIII thereby altering the natural history of inhibitor development, but it remains unclear whether later exposure to FVIII might modify the incidence of inhibitor development. Moreover, decisions regarding initiation of immune toleranc...
Source: Expert Review of Hematology - Category: Hematology Tags: Expert Rev Hematol Source Type: research
CONCLUSIONS: after 12 weeks of observation, both approaches significantly reduced bleeds per animal and increased the proportion of bleed-free animals compared to controls (43% vs. 0%, respectively [AAV]; 75% vs. 8%, respectively [injection]). Both approaches resulted in an anti-FVIII inhibitory response in 20-37% of treated animals, similar to HA patients. Inhibitory antibodies were refractory to clinical improvement (reduction of bleeds) only in the AAV-based prophylaxis. An integrated model-based analysis of data on FVIII exposure and bleeding events was performed. This predicted the bleeding risk at any given circulati...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
Abstract Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for ...
Source: J Appl Genet - Category: Genetics & Stem Cells Authors: Tags: J Appl Genet Source Type: research
Human Gene Therapy, Ahead of Print.
Source: Human Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research
Human Gene Therapy,Volume 31, Issue 5-6, Page 283-285, March 2020.
Source: Human Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research
Abstract The success story of hemophilia care first materialized in the 1970s, when the availability of plasma-derived concentrates of coagulation factor VIII (FVIII) and factor IX (FIX) made possible the effective treatment of bleeding in patients with hemophilia A and B. This positive scenario consolidated in terms of safety and availability in the 1990s, when recombinant coagulation factors were first produced and allowed to start regimens of prophylaxis of bleeding instead of their episodic treatment. Prophylaxis became evidence-based standard of care following the demonstration of its superiority in the frame...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
An experimental gene therapy for hemophilia A remained effective up to 3 years after a single infusion, researchers recently reported in the New England Journal of Medicine. BioMarin Pharmaceutical ’s valoctocogene roxaparvovec encodes factor VIII, the blood-clotting protein that’s missing or low in people with hemophilia A, the most common form of the disease.
Source: JAMA - Category: General Medicine Source Type: research
Abstract Adeno-associated virus serotype 8 (AAV8) gene therapy has shown efficacy in several clinical trials and is considered a highly promising technology to treat monogenic diseases such as hemophilia A and B. However, a major drawback of AAV8 gene therapy is that it can be applied only once because anti-AAV8 immunity develops after the first treatment. Readministration may be required in patients who are expected to need redosing, e.g. due to organ growth, or to boost suboptimal expression levels, but no redosing-protocol has been established. We have developed a preventive immune-suppressive protocol for a hu...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
Conclusions: Valoctocogene roxaparvovec was found to be cost-saving-on average by about $6.8 million per patient-and more effective than prophylactic therapy for treatment of hemophilia A. The comparative benefit of gene therapy was observed across a broad range of simulated patients that were representative of the real-world severe hemophilia A population. PMID: 31971453 [PubMed - as supplied by publisher]
Source: Journal of Medical Economics - Category: Health Management Tags: J Med Econ Source Type: research
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