Gene therapy for hemophilia.
OBJECTIVE
This review will highlight the progress achieved in the past 2 years on using gene therapy to treat hemophilia in animals and humans.


RESULTS
There has been substantial progress in using gene therapy to treat animals with hemophilia. Novel approaches for hemophilia A in mice include expression of Factor VIII in blood cells or platelets derived from ex-vivo transduced hematopoietic stem cells, or in-vivo transfer of transposons expressing Factor VIII into endothelial cells or hepatocytes. Advances in large-animal models include the demonstration that neonatal administration of a retroviral vector expressing canine Factor VIII completely corrected hemophilia A in dogs, and that double-stranded adeno-associated virus vectors resulted in expression of Factor IX that is 28-fold that obtained using single-stranded adeno-associated virus vectors. In humans, one hemophilia B patient achieved 10% of normal activity after liver-directed gene therapy with a single-stranded adeno-associated virus vector expressing human Factor IX. Expression fell at 1 month, however, which was likely due to an immune response to the modified cells.


CONCLUSIONS
Gene therapy has been successful in a patient with hemophilia B, but expression was unstable due to an immune response. Abrogating immune responses is the next major hurdle for achieving long-lasting gene therapy.
Ponder
Katherine P
KP
Departments of Internal Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA. kponder@im.wustl.edu
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology; D006467:Hemophilia A / Q000628:therapy*; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D051379:Mice; D023421:Models, Animal