Haemophilias: advances towards genetic engineering replacement therapy

Both haemophilia A and B are X-linked recessive disorders and therefore occur almost exclusively in males. The genes for both factors VIII and IX have been mapped to the distal end of the long arm of the X chromosome, bands Xq28 and Xq27.1, respectively. The Factor VIII gene comprises 186 kb DNA with 9 kb of exon of DNA which encodes an mRNA of nearly 9 kb. The Factor IX gene is 34 kb in length and the essential genetic information is present in eight exons which encode 1.6 kb mRNA. In gene therapy, genetic modification of the target cells can be either ex vivo or in vivo. The advantage of the ex vivo approach is that the genetic modification is strictly limited to the isolated cells. In the in vivo approach, the integrity of the target tissue is maintained but the major challenge is to deliver the gene to the target tissue. The use of improved retroviral and adenovirus-based vectors for gene therapy has produced clinically relevant levels of human factor VIII in mice and haemophilic dogs. If further improvements can increase the persistence of expression and decrease the immunological responses, phase I clinical trials in patients can be considered.