• Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of the following:

‣ 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);

⁃ 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.

• Participants must have adequate physical function as measured by all of the following:

‣ Karnofsky performance score ≥60.

⁃ Cardiac function: Left ventricular ejection fraction (LVEF) \>40%; or LV shortening fraction \> 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan.

⁃ Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) \> 40% (corrected for hemoglobin).

⁃ 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.

⁃ 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.

• 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.