Gene therapy for hemophilia

Hemophilia A and B are X-chromosome linked recessive bleeding disorders tha t result from a deficiency in factor Vm (MII) and factor IX (FIX) respectiv ely. Though factor substitution therapy has greatly improved the lives of h emophiliac patients, there are still limitations to the current treatment t hat have triggered interest in alternative treatments by gene therapy. Sign ificant progress has recently been made in the development of gene therapy for the treatment of hemophilia A and B. These advances parallel the techni cal improvements of existing vector systems including MoMLV-based retrovira l, adenoviral and AAV vectors, and the development of new delivery methods such as lentiviral vectors, helper-dependent adenoviral vectors and improve d non-viral gene delivery methods. Therapeutic and physiologic levels of FV III and FIX could be achieved in FVII- and FIX-deficient mice and hemophili a dogs by different gene therapy approaches. Long-term correction of the bl eeding disorders and in some cases a permanent cure has been realized in th ese preclinical studies. However, the induction of neutralizing antibodies often precludes stable phenotypic correction. Another complication is that certain promoters are prone to transcriptional inactivation in vivo, preclu ding long-term FVIII or FIX expression. Several gene therapy phase I clinic al trials are currently ongoing in patients suffering from severe hemophili a A or B. No significant adverse side-effects were reported, and semen samp les were negative for vector sequences by sensitive PCR assays. Most import antly, some subjects report fewer bleeding episodes and occasionally have v ery low levels of clotting factor activity detected. The results from the e xtensive preclinical studies in normal and hemophilic animal models and enc ouraging preliminary clinical data indicate that the simultaneous developme nt of different strategies is likely to bring a permanent cure for hemophil ia one step closer to reality. Copyright (C) 2001 John Wiley & Sons, Ltd.