The overall objective of this project is to develop strategies, which will allow the efficient and safe treatment of hematopoietic diseases by hematopoietic stem cell (HSC) gene therapy. Unfortunately neither in vitro studies nor studies in the mouse model have been predictive for safety and efficacy of gene transfer in large animals or humans, thus we will use the dog model which will also allow us to evaluate improved strategies directly in a disease model. While gene transfer efficiencies into HSCs in the dog model and other large animals have improved significantly over the past several years, the development of leukemia in 3 patients in the French X-linked severe combined immunodeficiency (XSCID) gene therapy trial has shifted the emphasis from efficacy to safety. Thus, we will use the dog model to study the safety of 3 commonly used integrating vector systems: gammaretrovirus, lentivirus, and foamy virus vectors. Using these vector systems, we have been able to achieve efficient transduction of canine long-term repopulating cells with stable gene transfer levels >5% in a significant number of dogs. Thus, we now have a unique resource available to study in Specific Aim 1 the safety of HSC gene transfer with these vectors.
In Specific Aim 2, we will further optimize transduction conditions for foamy and lentiviral vectors to minimize risks from insertional mutagenesis. We will focus on lentivirus and foamy virus vectors since, in contrast to gammaretroviral vectors, these vector systems allow for efficient transduction using short transduction cultures. This is particularly important for stem cell gene therapy in a nonmyeloablative transplant setting where maintenance of stem cells is crucial for the ability to compete with surviving endogenous stem cells. Thus, in Specific Aim 3 we will use these vector systems in a nonmyeloablative setting and also explore whether in vivo selection strategies can improve gene transfer levels after nonmyeloablative conditioning. Finally, in Specific Aim 4 we will test improved gene transfer protocols in a canine genetic disease model. The availability of a clinically relevant large animal model should allow us to quickly translate our findings to clinical HSC gene therapy studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL036444-29
Application #
7917286
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
29
Fiscal Year
2009
Total Cost
$710,951
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807
Thakar, M S; Bonfim, C; Walters, M C et al. (2017) Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia. Bone Marrow Transplant 52:570-573
Burroughs, Lauri M; Shimamura, Akiko; Talano, Julie-An et al. (2017) Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. Biol Blood Marrow Transplant 23:1669-1677
Vaughn, J E; Anwer, F; Deeg, H J (2016) Treatment of refractory ITP and Evans syndrome by haematopoietic cell transplantation: is it indicated, and for whom? Vox Sang 110:5-11
Aki, S Z; Inamoto, Y; Carpenter, P A et al. (2016) Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity. Bone Marrow Transplant 51:1350-1353
Khera, Nandita; Gooley, Ted; Flowers, Mary E D et al. (2016) Association of Distance from Transplantation Center and Place of Residence on Outcomes after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1319-1323
Karoopongse, Ekapun; Marcondes, A Mario; Yeung, Cecilia et al. (2016) Disruption of Iron Regulation after Radiation and Donor Cell Infusion. Biol Blood Marrow Transplant 22:1173-1181
Hoffmeister, P A; Storer, B E; Syrjala, K L et al. (2016) Physician-diagnosed depression and suicides in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. Bone Marrow Transplant 51:153-6
Gallo, S; Woolfrey, A E; Burroughs, L M et al. (2016) Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD? Bone Marrow Transplant 51:1573-1578
Festuccia, Moreno; Deeg, H Joachim; Gooley, Theodore A et al. (2016) Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome. Biol Blood Marrow Transplant 22:1227-1233

Showing the most recent 10 out of 788 publications