Hematologic disorders such as the thalassemias and hemoglobinopathies, resulting from absent/reduced or abnormal production of one or more of the globin-molecule subunits, respectively, together constitute the most prevalent group of human monogenic diseases. Strategies which aim to replace the absent or defective globin gene have long been envisioned as potentially curative, and gene transfer strategies targeting hematopoietic stem cells have been central to this goal. Certainly, allogeneic bone marrow transplantation, a form of hematopoietic stem cell based gene transfer accomplished by replacement of the entire diseased organ with that from a donor with a normal genotype, has proven curative, yet procedural toxicities limit application. In order to expand application, we have explored nonmyeloablative transplant regimens which are designed to allow engraftment of allogeneic hematopoietic stem cells without the toxicity of conventional marrow ablative conditioning. Using mobilized peripheral blood stem cells as the source, we demonstrated reliable engraftment in the absence of marrow ablation in patients with metastatic cancer and extended these observations to patients ineligible for conventional myeloablative transplantation due to comorbidities. While clearly establishing the ability to achieve hematopoietic engraftment in humans without marrow ablation, procedural toxicity, mainly in the form of graft-versus-host disease, remained too high for application to nonmalignant disorders. We therefore returned to animal models and have recently developed a low intensity conditioning regimen designed to promote tolerance to the allograft. Based upon a unique mechanism for tolerance induction, we compared the use of immunosuppression with rapamycin to that with conventional immunosuppression with cyclosporine after low dose irradiation in a murine model of mobilized peripheral blood allograft rejection. Only mice treated with rapamycin demonstrated long-term hematopoietic chimerism, and the levels achieved exceeded 75% at greater than 4 months of follow up. In anticipation of moving these observations toward clinical application for adults with sickle cell anemia, we established the safety and feasibility of peripheral blood stem cell mobilization in individuals with sickle cell trait, as these heterozygotes represent approximately half of the sibling donor pool. We initiated a clinical trial for adults with sickle cell anemia and thalassemia and recently reported our results in the first 10 patients. Since that report, accrual has reached 30, and results are similar with an 86% disease free survival. The protocol has been amended to accrue up to 50, with a number of secondary endpoints such as neurocognitive functioning measured before and yearly with their sibling donor as the control, pain, quality of life, kidney function, lung function, heart function. Additionally, we have begun a planned immunosuppression taper in individuals with >50% CD3+ T cell chimerism, and 15 subjects are now off immunosuppression with stable mixed chimerism. There has been no acute or chronic graft versus host disease, and the mixed hematopoietic chimerism observed in the absence of long term immunosuppression demonstrates operational tolerance. These results have also now been reported. Given the limited number of patients with an available HLA-matched sibling donor, we have also moved on to test this approach in the haplo-idendtical setting in a protocol testing escalating doses of post-graft cyclophosphamide. Accrual to the protocol is now active, and we have reached the third dosing cohort in which patients receive 2 doses of post-graft cyclophosphamide. Though follow up is relatively short, the first 4 patients at this dosing level have engrafted and are outpatients. Accrual is ongoing.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Heart Lung and Blood Inst
Zip Code
Luethy, Paul M; Murphy, Sean C; Seilie, Annette M et al. (2018) Diagnostic challenges of prolonged post-treatment clearance of Plasmodium nucleic acids in a pre-transplant autosplenectomized patient with sickle cell disease. Malar J 17:23
Darbari, Deepika S; Liljencrantz, Jaquette; Ikechi, Austin et al. (2018) Pain and opioid use after reversal of sickle cell disease following HLA-matched sibling haematopoietic stem cell transplant. Br J Haematol :
Leonard, Alexis; Tisdale, John F (2018) Stem cell transplantation in sickle cell disease: therapeutic potential and challenges faced. Expert Rev Hematol 11:547-565
Pittman, C; Hsieh, M M; Coles, W et al. (2017) Reversal of pre-capillary pulmonary hypertension in a patient with sickle cell anemia who underwent haploidentical peripheral blood stem cell transplantation. Bone Marrow Transplant 52:641-642
Connor Jr, Joseph L; Minniti, Caterina P; Tisdale, John F et al. (2017) Sickle Cell Anemia and Comorbid Leg Ulcer Treated With Curative Peripheral Blood Stem Cell Transplantation. Int J Low Extrem Wounds 16:56-59
Uchida, Naoya; Haro-Mora, Juan J; Fujita, Atsushi et al. (2017) Efficient Generation of ?-Globin-Expressing Erythroid Cells Using Stromal Cell-Derived Induced Pluripotent Stem Cells from Patients with Sickle Cell Disease. Stem Cells 35:586-596
Abraham, Allistair; Hsieh, Matthew; Eapen, Mary et al. (2017) Relationship between Mixed Donor-Recipient Chimerism and Disease Recurrence after Hematopoietic Cell Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant 23:2178-2183
Fitzhugh, Courtney D; Hsieh, Matthew M; Taylor, Tiffani et al. (2017) Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Blood Adv 1:652-661
Fitzhugh, Courtney D; Cordes, Stefan; Taylor, Tiffani et al. (2017) At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT. Blood 130:1946-1948
Allen, Elizabeth S; Srivastava, Kshitij; Hsieh, Matthew M et al. (2017) Immunohaematological complications in patients with sickle cell disease after haemopoietic progenitor cell transplantation: a prospective, single-centre, observational study. Lancet Haematol 4:e553-e561

Showing the most recent 10 out of 30 publications