Gene therapy using adeno-associated viral (AAV) vectors has been successfully used to treat patients with hemophilia B. Gene therapy for hemophilia A has been more difficult since the coding region of factor VIII is too large for AAV vectors. As described in The New England Journal of Medicine, researchers circumvented the problem by using the AAV serotype 5 (AAV5) vector, which has been optimized to express a compact version of the SQ variant of the human factor VIII with the B-domain depleted (AAV5-hfVIII-SQ). A single intravenous dose of AAV5-hfVIII-SQ was infused into 9 male hemophilia patients broken into three dose cohorts and followed for one year. Six of the seven men who received a higher dose of AAV5-hfVIII-SQ had normal levels of factor VIII activity (77 IU per dl, range 19-164) after one year; the remaining patient who also received a high dose had elevated levels of factor VIII activity (12-32 IU per dl) compared to average patients with hemophilia A. The two men who received low and medium doses had minimal factor VIII activity. No serious adverse events except progression of a preexisting arthropathy were observed. In addition, neutralizing antibodies to factor VIII were not detected. Future studies are needed to optimize this treatment strategy and ensure its safety.
