Inclusion Criteria: 1. A diagnosis of sickle cell disease with genotype HbSS or HbS/β0 thalassemia. 2. Between the age of 13-40 years. 3. Clinically severe disease, defined as at least 4 vaso-occlusive events (VOEs) within the past 24 months prior to consent. 4. Adequate hematologic parameters (regardless of therapy) including white blood cell (WBC) count within the range of 2.5 - 25.0 x 10\^9 /L, hemoglobin within the range of 5 - 11 g/dL, and platelet count above 150 x 10\^9 /L 5. Adequate organ function and performance status: 1. Karnofsky/Lansky performance status ≥80%. 2. Serum creatinine \</= 1.5 times the upper limit of normal for age, and calculated creatinine clearance or GFR \>/= 60 mL/min/1.73 m2. 3. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value \<3× the upper limit of normal (ULN). 4. DLCO, FEV1, and FVC \>50% of predicted 5. Left ventricular ejection fraction \>40% or shortening fraction \>25% 6. No HLA-genotypically identical related bone marrow donor available. 7. Parental/guardian/patient signed informed consent. Exclusion Criteria: Subjects who have: 1. Concomitant condition or illness including: ongoing or active infection, active malignancy, major surgery in the past 30 days, medical/psychiatric illness/social situations that would limit compliance with study requirements as determined by the treating physician. 2. Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal TCD who have transitioned from transfusions to hydroxyurea for stroke prophylaxis are also not eligible for the study.) 3. Patients with history of abnormal TCD (measured with a timed average maximum mean velocity of ≥200 cm/second in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used, \>185 cm/second plus evidence of intracranial vasculopathy) who were ever on transfusions and subsequently transitioned to hydroxyurea. 4. History of overt stroke or any neurologic event lasting \>24 hours. (Note: patients with imaging evidence of silent stroke but not on a chronic transfusion regimen are not excluded.) 5. Isolated recurrent priapism unresponsive to medical and surgical therapies in the absence of other qualifying VOE complications that meet inclusion criteria. 6. Contraindication to administration of conditioning medication (busulfan) 7. Prior allogeneic hematopoietic stem cell transplant 8. Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics 9. Severe cerebral vasculopathy 10. Liver MRI (≤ 180 days prior to initiation of BU conditioning) to document hepatic iron content is required for participants who have received ≥20 packed red blood cell transfusions (cumulative); participants who have hepatic iron content ≥ 9 mg Fe/g liver dry weight by liver MRI must have a liver biopsy and histological examination/documentation of the absence of cirrhosis, bridging fibrosis, and active hepatitis (≤ 180 days prior to initiation of transplant conditioning); the absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995) as described in the Manual of Operations (MOO); 11. Evidence of HIV infection, HTLV infection, active hepatitis B infection or active hepatitis C infection. 12. Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on prior biopsy 13. Receipt of an investigational study drug or procedure within 90 days of study enrollment 14. Either or both of the following findings on screening bone marrow aspirate/biopsy: a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) OR b) pathogenic mutation in any gene on the Rapid Heme Panel (RHP), a next-generation sequencing clinical assay for gene mutations associated with hematologic malignancies performed at Brigham and Women's Hospital. 15. Pregnancy or breastfeeding 16. Presence of a genetically-determined hypercoagulable state or personal history of prior VTE (deep vein thrombosis or pulmonary embolism) that would represent a contraindication to proceed with central line placement and study events. The Phase 2 trial is not enrolling patients who reside outside the US at this time.