STRIDE Biorepository

Inclusion Criteria:

• Age at least 15 years old to less than 41 years old
• Severe sickle cell disease [any clinically significant sickle genotype, for example,Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC) or Hemoglobin SBeta thalassemia (Hb Sβ),or Hemoglobin S-OArab genotype] with at least 1 of the following manifestations:

1. Clinically significant neurologic event (stroke) or any neurological deficitlasting > 24 hours;
2. History of two or more episodes of acute chest syndrome (ACS) in the 2-yearperiod preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy);
3. An average of three or more pain crises per year in the 2-year period precedingenrollment or referral (required intravenous pain management in the outpatient orinpatient hospital setting);
4. Administration of regular red blood cell (RBC) transfusion therapy, defined asreceiving 8 or more transfusions per year(in the 12 months before enrollment toprevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chestsyndrome);
5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥ 2.7 m/sec;
6. Ongoing high impact chronic pain on a majority of days per month for at least 6months.

• Adequate physical function as measured by all of the following:

1. Karnofsky/Lansky performance score > or equal to 60
2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LVshortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition (MUGA) Scan
3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% anddiffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected forhemoglobin)
4. Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as perlocal laboratory and creatinine clearance >70 mL/min; or GFR > 70 mL/min/1.73 m2by radionuclide Glomerular Filtration Rate (GFR)
5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normalfor age as per local laboratory; alanine aminotransferase (ALT) and aspartateaminotransferase (AST) < 5 times upper limit of normal as per local laboratory.

Exclusion Criteria:

• Human Leukocyte Antigen (HLA) typing prior to referral (consultation withhematopoietic cell transplantation (HCT) physician). However, if a subject has had HLAtyping with accompanying documentation that relatives were not HLA typed and that asearch of the unrelated donor registry was not performed the subject will beconsidered eligible. Documentation will be reviewed and adjudicated by the ProtocolOfficer or his/her designee.
• Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.
• Seropositivity for HIV
• Previous HCT or solid organ transplant
• Participation in a clinical trial in which the patient received an investigationaldrug or device must be discontinued at enrollment.
• A history of substance abuse as defined by version IV of the Diagnostic & StatisticalManual of Mental Disorders (DSM IV).
• Demonstrated lack of compliance with prior medical care (determined by referringphysician).
• Pregnant or breast feeding females.
• Inability to receive HCT due to alloimmunization, defined as the inability to receivepacked red blood cell (pRBC) transfusion therapy. Additional Eligibility Criteria for Transplant after Biologic Assignment to the Donor Arm: Participants assigned to the Donor Arm at the time of biologic assignment are subject toadditional transplant eligibility criteria as specified below. Additional, repeat clinicalassessments prior to transplant should be obtained in accordance with institutionalpolicies and standards of care in the interest of good clinical practice.
• Participants must have liver magnetic resonance imaging (MRI) (at least 90 days priorto initiation of transplant conditioning) to document hepatic iron content is requiredfor participants who are currently receiving ≥8 packed red blood cell transfusions for ≥1 year or have received ≥20 packed red blood cell transfusions (cumulative).Participants who have hepatic iron content ≥7 mg Fe/g liver dry weight by liver MRImust have a liver biopsy and histological examination/documentation of the absence ofcirrhosis, bridging fibrosis, and active hepatitis (at least 90 days prior toinitiation of transplant conditioning).
• Cerebral MRI/magnetic resonance angiogram (MRA) within 30 days prior to initiation oftransplant conditioning. If there is clinical or radiologic evidence of a recentneurologic event (such as stroke or transient ischemic attack) subjects will bedeferred for at least 6 months with repeat cerebral MRI/MRA to ensure stabilization ofthe neurologic event prior to proceeding to transplantation.
• Documentation of participant's willingness to use approved contraception method untildiscontinuation of all immunosuppressive medications. This is to be documented in themedical record corresponding with the consent conference.
• Have a suitably matched HLA donor
• Willing and able to donate bone marrow
• Absence of anti-donor HLA antibodies