Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies

Inclusion Criteria: The following criteria are established to identify subjects with sickle cell disease (SCD) who have a high predicted morbidity and are at risk for early mortality. Subjects with S/S disease, S/C disease, Hemoglobin H disease, Alpha Thalassemia Major, Thalassemia Major (also known as Cooley's anemia) or S/B\* thalassemia and one or more of the following medical complications will be eligible: * History of impaired neurological function and/or findings on Magnetic Resonance Image (MRI)/Magnetic Resonance Angiogram (MRA) that are associated with sickle cell disease * More than 1 episode of acute chest syndrome with stage I or II pulmonary disease * Osteonecrosis involving ≥ 2 joints * Sickle cell nephropathy as evidenced by a glomerular filtration rate of 30% - 50% of the predicted normal * Alloimmunization that is sufficient to interfere with the efficacy of chronic transfusion therapy * Chronic or recurrent priapism * Major visual impairment in one or both eyes with bilateral proliferative retinopathy * Persistent disabling pain (≥ 2 episodes per year) despite trials of chronic transfusion and/or hydroxyurea at recommended doses for at least 6 months duration Additional General Criteria: Subjects must also meet all of the following general inclusion criteria: * Subjects must have a related donor (identical or mismatched for 1, 2 or 3 HLA- A, HLA-B or HLA-DR loci). * Subjects must have adequate cardiopulmonary function as documented by a left ventricular ejection fraction ≥ 50% (or within normal limits per Institutional criteria) or a left ventricular shortening fraction Within normal limits (WNL) per Institutional criteria, without inotropic support. If Ejection fraction is 40-50%, the patient may be considered for participation if cleared by a Cardiologist. * Subjects must have adequate pulmonary function as documented by Diffusing capacity of the lung for carbon monoxide (DLCO) and Forced expiratory volume in 1 second (FEV1) * 50% predicted for age and size. If DLCO and FEV1 are between 40-50%, patient may be considered for participation if cleared by a Pulmonologist. * Subjects must have adequate hepatic function as demonstrated by a serum albumin ≥ 3.0 mg/dL, and serum glutamic pyruvic transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the upper limit of normal. * Subjects must have adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dL. If serum creatinine is ≥ 1.5 mg/dL, then a creatinine clearance test must be done and the result 50% of normal. * Subjects or legal guardians must give written informed consent, and subjects must assent where age and intellectually appropriate. * There are no age limits for this protocol. Exclusion Criteria: * Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate transplantation. * Severe impairment of functional performance as evidenced by a Karnofsky (patients ≥16 years old) or Lansky (children \<16 years old) score \<70% * Stage III or IV sickle cell pulmonary disease * Renal insufficiency (GFR \< 25% of predicted normal for age) * Subjects with a positive human immunodeficiency virus (HIV) antibody test result * Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotrophin (HCG) test * Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site * Subjects must not have had previous radiation therapy that would preclude total body irradiation (as determined by a radiation oncologist).