Supervisors info:
Αργυρή Γιαλεράκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Όλγα Κατσαρού, Διευθύντρια, Κέντρο Αιμοδοσίας και Μονάδα Αιμορροφιλικών, Γενικό Νοσοκομείο Αθηνών «Λαϊκό»
Ευφροσύνη Νομικού, Διευθύντρια Νοσοκομειακής Υπηρεσίας, Τμήμα Αιμοδοσίας, Γενικό Νοσοκομείο Αθηνών «Ιπποκράτειο»
Summary:
Hemophilia encompasses a group of rare bleeding disorders caused by the lack/deficiency of a clotting factor. Hereditary hemophilia A is inherited as an X-linked recessive disorder and is characterized by the lack of FVIII. It is classified as severe, moderate, or mild, according to a patient’s FVIII activity plasma levels. Clinical manifestations consist of spontaneous or traumatic bleeding events. In severe hemophilia, the most frequent sites of bleeding are the joints (hemarthroses), mainly the knee joints, leading to hemophilic arthropathy if repetitive bleedings occur in a joint.
The therapeutic management of hereditary hemophilia A includes supportive measures used in the case of bleeding episodes or pain, and pharmaceutical measures like the administration of factor replacement therapy, by the use of human or recombinant FVIII, and monoclonal antibodies. This kind of treatments does not offer cure, which can be achieved by the administration of gene therapy.
Gene therapy for hemophilia A is based on the development of viral vectors that carry the
transgene encoding FVIII and transfer it into the hepatocytes. A variety of pharmaceutical
products has been and continues being used in clinical trials for severe hemophilia A, whilst only Valoctocogene roxaparvovec (Roctavian) has been approved in Europe and the U.S.A. Gene therapy is given as a single-dose intravenous injection.
Considering the results of phase 1/2 and phase 3 ongoing clinical trials, it comes out that
gene therapy for hemophilia A provides safety and efficient FVIII activity levels that offer
markedly reduction of the number of bleeding episodes and the need of prophylaxis
treatment. The most frequent adverse effect was a mild, transient and asymptomatic
elevation in ALT serum levels that was not associated with hepatic dysfunction, as well as
no one of the participants presented with liver fibrosis or malignancy. In the majority of
patients occurred a conversion of severe to mild hemophilia A, leading to cessation or
reduction of the use of prophylaxis. There was no development of FVIII inhibitors, however,in some individuals, immune response against vector capsids had been detected. Due to the frequent lowering pattern of the FVIII activity levels over the years, it is very possible that the patients who received gene therapy for hemophilia A, will need an additional dose of the drug in the future.
Keywords:
Hemophilia A, Gene therapy, Adeno-associated viral vectors, Ongoing clinical trials, Safety and efficacy of gene therapy for Hemophilia A
