Onco-retroviral and lentiviral vector-based gene therapy for hemophilia: preclinical studies.
Hemophilia A and B gene therapy requires long-term and stable expression of coagulation factor VIII (FVIII) or factor IX (FIX), respectively, and would need to compare favorably with protein replacement therapy. Onco-retroviral and lentiviral vectors are attractive vectors for gene therapy of hemophilia. These vectors have the potential for long-term expression because they integrate stably in the target cell genome. Whereas onco-retroviral vectors can only transduce dividing cells, lentiviral vectors can transduce a broad variety of cell types irrespective of cell division. Several preclinical and clinical studies have explored the use of onco-retroviral and, more recently, lentiviral vectors for gene therapy of hemophilia A or B. Both ex vivo and in vivo gene therapy approaches have been evaluated, resulting in therapeutic FVIII or FIX levels in preclinical animal models. Whereas in vivo gene therapy using onco-retroviral or lentiviral vectors often led to long-term FVIII or FIX expression from transduced hepatocytes, ex vivo approaches were generally hampered by either low or transient expression of FVIII or FIX levels in vivo and/or inefficient engraftment. Furthermore, immune responses against the transgene product remain a major issue that must be resolved before the full potential of these vectors eventually can be exploited clinically. Nevertheless, the continued progress in vector design combined with a better understanding of vector biology may ultimately yield more effective gene therapy approaches using these integrating vectors.
Van Damme
An
A
Center for Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversity Institute for Biotechnology (VIB), University Hospital Gasthuisberg, Leuven, Belgium.
Chuah
Marinee K L
MK
Collen
Désiré
D
VandenDriessche
Thierry
T
D000818:Animals; D004353:Drug Evaluation, Preclinical; D005164:Factor IX / Q000008:administration & dosage; D005169:Factor VIII / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D012190:Retroviridae / Q000235:genetics
D005169:Factor VIII; D005164:Factor IX