PARTICIPANT INCLUSION CRITERIA * Age ≥18 by time of enrollment * Diagnosis of SCD documented by genetic analysis (S/S, S/β-thalassemia-zero) * Must not have medically eligible and available HLA-identical sibling donor or 10/10 allele-matched unrelated donor (within a year prior to harvest) (or refuses to have an allogeneic HSCT) * Inadequate clinical response to hydroxyurea (HU), defined as any one of the following outcomes, while on HU for at least 3 months: * 2 or more acute sickle pain crises requiring hospitalization * no rise in Hb \>1.5 gm/dl from pre-HU baseline or requires transfusion to maintain Hb \> 6.0 gm/dL * Has an episode of acute chest syndrome defined as development of a new pulmonary alveolar consolidation involving at least one complete lung segment associated with acute symptoms including: fever \>38.5, chest pain, tachypnea, intercostal retractions, nasal flaring, use of accessory muscles of respiration, wheezing, rales, or cough not attributable to asthma or bronchiolitis) in the preceding two year period prior to enrollment. The acute chest syndrome event occurred despite adequate supportive care measures. * Or medical decision for other therapy (e.g. chronic transfusion program), or subject refusal to take HU. * The patient must be off HU for at least 30 days (+/- 5 days) before PBSC collection. * Must have one or more of the following clinical complications demonstrating disease severity: * Clinically-significant neurologic event: stroke or any central nervous system deficit lasting \>24 hours. * Abnormal head CT or brain MRI demonstrating previous stroke * Administration of regular RBC transfusions for equal or longer than 1 year to prevent vaso- occlusive crises or other sickle cell disease complications or to maintain Hb \>6. * Pulmonary arterial hypertension with tricuspid regurgitant jet velocity \> 2.5 m/sec within 1 year prior to enrollment * At least one episode of acute chest syndrome that required hospitalization, within the 2 years prior to enrollment * At least 2 acute sickle pain crises requiring hospitalization within the 2 years prior to enrollment * Severe osteonecrosis * History of acute dactylitis during childhood * Recurrent priapism (2 or more episodes) * Karnofsky performance score ≥60% PARTICIPANT EXCLUSION CRITERIA * Patient has a medically eligible and available HLA-identical sibling donor or 10/10 allele-matched unrelated donor (unless they refuse to have an allogeneic HSCT). * Cardiac evaluation: left ventricular ejection fraction (LVEF) \< 40% or LV shortening fraction \< 26% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities. * Poorly controlled hypertension as determined by BP with systolic \>135 or diastolic \>95 mmHg despite treatment. * Pulmonary evaluation: baseline oxygen saturation of \<85% or DLCO\< 40% (corrected for Hb) * Renal evaluation: serum creatinine \>1.5x upper limit of normal for age or GFR\<60 mL/min/1.73 m2 within 90 days prior to PBSC collection. * Hepatic evaluation: serum conjugated (direct) bilirubin \> 2x upper limit of normal for age as per local laboratory or ALT and AST \> 5 times upper limit of normal as per local laboratory within 90 days prior to PBSC collection. * Hematologic evaluation: Leukopenia (WBC\< 3x103/uL) or neutropenia (ANC \< 1.0x103/uL) or thrombocytopenia (platelet count \< 100x103/uL) within 90 days prior to PBSC collection. * PT/INR or PTT \>1.5x upper limit of normal or other clinically significant bleeding disorder to * Liver Iron \>10mg/g by T2\* MRI (within 1 year prior to PBSC collection). * Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR. * Pregnancy * Patient must not have any known cancer or other malignant disease or active infection by CT or MRI of head, chest or ultrasound of abdomen * Abnormal karyotype by cytogenetic or other appropriate tests.