Inclusion Criteria: 1. Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of the following: 1. History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea); 2. History of at least 4 severe vaso-occlusive pain events in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to or any sickle-related acute event are acceptable; a severe painful vaso-occlusive event is defined as receiving analgesic treatment (opioid or other analgesic) for longer than 24 -hours in a hospital or emergency room (ER) observation unit visit or at least 2 visits in a day unit or ER over 72 hours with both visits requiring intravenous analgesics. 2. Participants must have adequate physical function as measured by all of the following: 1. Karnofsky performance score ≥60. 2. Cardiac function: Left ventricular ejection fraction (LVEF) \>40%; or LV shortening fraction \> 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan. 3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) \> 40% (corrected for hemoglobin). 4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2. 5. Hepatic function: i. Serum conjugated (direct) bilirubin \< 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded. ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS \< 5 times upper limit of normal as per local laboratory. f. Liver MRI using a validated methodology per institutional preference (T2\* or R2\* or by ferriscan \[R2 MRI\]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 8 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis\[1\], and active hepatitis. 3. Written informed consent or assent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. Exclusion Criteria: 1. Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings). 2. Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C. 3. Participants who have received a Hematopoietic Cell Transplant (HCT) 4. Participants who have received a solid organ transplant. 5. Participants who have participated in another clinical trial in which the participant received an investigational or off-label use of a drug or device within 3 months prior to enrollment. 6. Females who are pregnant or breast feeding. 7. Females of child bearing potential (to include all female participants \> 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized) who do not agree to practice two (2) effective methods of contraception at the same time, or who do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-stem cell infusion. 8. Males (even if surgically sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-stem cell infusion. 9. Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction. 10. Patients who have a human leukocyte antigen identical (HLA-ID) sibling donor 11. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. 12. Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD