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 have now initiated a clinical trial for adults with sickle cell anemia and thalassemia, and have screened over 120 potential subjects and accrued 11 with homozygous sickle cell disease. All 10 patients have thus far undergone transplantation with early donor hematopoietic chimerism resulting in reversion of the phenotype. Nine of 10 patients are free of sickle cell disease with complete replacement of peripheral red blood cells by donor type. There has been no acute or chronic graft versus host disease, and the mixed hematopoietic chimerism observed suggests operational tolerance. We have reported these results and are continuing accrual to better determine the success rate of our regimen. We have also moved on to test this approach in the haplo-idendtical setting.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$1,378,152
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
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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
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
Uchida, Naoya; Fujita, Atsushi; Hsieh, Matthew M et al. (2017) Bone Marrow as a Hematopoietic Stem Cell Source for Gene Therapy in Sickle Cell Disease: Evidence from Rhesus and SCD Patients. Hum Gene Ther Clin Dev :
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

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