"Development of Bioengineered Gene Transfer Vectors and Transgenes for the Gene Therapy Treatment of Hemophilia A"
H. Trent Spencer, PhD
Department of Pediatrics
A major focus of the Gene Therapy Program in the Aflac Cancer and Blood Disorders Center is the development of therapeutics for hemophilia A, which is a disease caused by insufficient levels of the blood clotting protein factor VIII (fVIII). We are conducting late stage preclinical testing to support a gene therapy clinical trial incorporating genetically modified hematopoietic stem cells (HSCs) for persons with hemophilia A. In a series of recent studies, we have shown that the transplantation of genetically-engineered HSCs can restore factor VIII (fVIII) activity to curative levels in hemophilia A mice and that human HSCs are readily transduced with recombinant lentiviral vectors encoding a genetically-engineered fVIII transgene. Our gene therapy approach uses a bioengineered fVIII transgene designed at Emory University and contains critical high-expression sequences, which we have shown are necessary and sufficient to achieve therapeutic/curative fVIII expression levels. Using the bioengineered fVIII construct, designated ET-3, in preclinical murine studies we routinely observe normal fVIII activity levels in mice engrafted with only 1 – 5% genetically-modified hematopoietic cells. These engraftment levels are similar to those that have already been achieved in human HSC-based clinical gene therapy trials. We have generated extensive preclinical data using the ET-3 transgene, which demonstrate proof-of-concept that HSCs genetically engineered with ET-3-encoding lentivector, coupled with a non-myeloablative transplant regimen, can be used to treat and possibly cure hemophilia A. In addition, a favorable meeting with the FDA was held that provided the necessary guidance needed to finalize our preclinical data package and vector manufacturing. We are now preparing the necessary regulatory documents to conduct a first in man gene therapy clinical trial for hemophilia A.
Faculty host: Ian Copland