Haemophilia (07/08/19). Peyvandi, Flora; Garagiola, Isabella
Italian clinical researchers review various clinical advances using gene therapy for the treatment of hemophilia A and B. After animal models in the 1990s demonstrated that adeno-associated virus (AAV) vectors showed an efficient expression of factor IX (FIX), the researchers note that the first clinical trial of patients with hemophilia B documented therapeutic levels of FIX, although the effect only lasted a few weeks. With improvements in vector design, circulating FIX levels rose to 2%-5% for a longer period of time. In more recent developments, investigators were able to improve the expression of FIX to more than 30% by inserting the Padua FIX variant into the F9 cDNA. This led to a discontinuation of infusions and reduced bleeding events. For hemophilia A, patients treated with an AAV vector containing a codon-optimized, B-domain deleted F8 cDNA saw transgene expression last for 3 years and circulating FVIII activity levels of 52.3%. Elevated liver enzymes were reported for some patients in clinical trials of AAV-liver directed gene therapy for hemophilia A and B. While steroid treatment resolved the issue in a large group of patients, the researchers note that the pathophysiological mechanism behind the liver toxicity is still not clear, and a subject of ongoing investigation.