Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease

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); ACS is defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms, treated in the hospital with supplemental oxygen at a minimum.

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 via parenteral (PN) route) 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 parenteral analgesics.

3. 2 or more episodes of splenic sequestration, defined as an acute decrease in hemoglobin by at least 2 g/dL accompanied by splenomegaly in the 2 years before enrollment.

4. Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months before enrollment) recalcitrant to medical treatment

5. Any episode of hepatic sequestration defined as right upper quadrant pain, hepatomegaly, and rapidly decreasing hemoglobin level with hepatic dysfunction within the 2 years before enrollment.

6. Leg ulcer recalcitrant to treatment within 2 years prior to enrollment.

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.

3. Baseline prothrombin time or partial thromboplastin time \<1.5 ULN except if receiving a prophylactic anticoagulant which causes an elevated prothrombin or partial thromboplastin time.

4. 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.

What this study is about