Abstract
Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.
Highlights
Hemophilia A (HA) and hemophilia B (HB) are X-linked hereditary hemorrhagic disorders arising from mutations in the genes encoding coagulation factors VIII (FVIII) in HA and IX (FIX) in HB [1]
The severity of HA and HB is contingent on the functional levels of the corresponding circulating factors, with levels of FVIII or FIX below 1% considered diagnostic of severe hemophilia, levels between 1 and 5% diagnostic of moderate hemophilia and those between 5% and 40% of mild hemophilia
Other educational programs geared at patients and healthcare providers include more specific training on matters such as the use of associated virus (AAV), whose application in patients with hemophilia is becoming increasingly common. These programs require the participation of academically experienced specialists [43]. They are often based on an information handbook that includes information on AAV-mediated gene transfer, the eligibility criteria for participation in clinical trials, the possibility of anticipating the adverse events that could occur in the course of a clinical trial following gene therapy, the parameters that should be monitored during the clinical trial and the long-term effects of the therapy
Summary
Hemophilia A (HA) and hemophilia B (HB) are X-linked hereditary hemorrhagic disorders arising from mutations in the genes encoding coagulation factors VIII (FVIII) in HA and IX (FIX) in HB [1]. Pre-existing antibodies against AAVs significantly affect the use of AAV vectors even in the presence of relatively low levels of neutralizing antibodies from natural parvovirus infections Such capsid-targeted antibodies have been shown to be capable of inhibiting transduction of the intravenously administered vector in animal models and have been associated with limited effectiveness in clinical trials in humans [37]. This is important to determine the primary eligibility of patients for AAV-based gene therapy clinical trials. This makes it possible to translate the biological efficacy observed in animal studies to clinical trials in humans, which provides a rational basis to determine the initial dose of the new in vivo virus-mediated gene therapy products
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
