A Gene Transfer Study Inducing Fetal Hemoglobin in Sickle Cell Disease (GRASP, BMT CTN 2001)

Inclusion Criteria:

1. A diagnosis of sickle cell disease with genotype HbSS or HbS/β0 thalassemia.

2. Between the age of 13-40 years.

3. Clinically severe disease, defined as at least 4 vaso-occlusive events (VOEs) withinthe past 24 months prior to consent.

4. Adequate hematologic parameters (regardless of therapy) including white blood cell (WBC) count within the range of 2.5 - 25.0 x 10^9 /L, hemoglobin within the range of 5 - 11 g/dL, and platelet count above 150 x 10^9 /L

5. Adequate organ function and performance status:

6. Karnofsky/Lansky performance status ≥80%.

7. Serum creatinine </= 1.5 times the upper limit of normal for age, andcalculated creatinine clearance or GFR >/= 60 mL/min/1.73 m2.

8. Persistent aspartate transaminase, alanine transaminase, or direct bilirubinvalue <3× the upper limit of normal (ULN).

9. DLCO, FEV1, and FVC >50% of predicted

10. Left ventricular ejection fraction >40% or shortening fraction >25%

11. No HLA-genotypically identical related bone marrow donor available.

12. Parental/guardian/patient signed informed consent.

Exclusion Criteria: Subjects who have:

1. Concomitant condition or illness including: ongoing or active infection, activemalignancy, major surgery in the past 30 days, medical/psychiatric illness/socialsituations that would limit compliance with study requirements as determined by thetreating physician.

2. Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal TCD who have transitioned fromtransfusions to hydroxyurea for stroke prophylaxis are also not eligible for thestudy.)

3. Patients with history of abnormal TCD (measured with a timed average maximum meanvelocity of ≥200 cm/second in the terminal portion of the internal carotid orproximal portion of middle cerebral artery or if the imaging TCD method is used, >185 cm/second plus evidence of intracranial vasculopathy) who were ever ontransfusions and subsequently transitioned to hydroxyurea.

4. History of overt stroke or any neurologic event lasting >24 hours. (Note: patientswith imaging evidence of silent stroke but not on a chronic transfusion regimen arenot excluded.)

5. Isolated recurrent priapism unresponsive to medical and surgical therapies in theabsence of other qualifying VOE complications that meet inclusion criteria.

6. Contraindication to administration of conditioning medication (busulfan)

7. Prior allogeneic hematopoietic stem cell transplant

8. Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics

9. Severe cerebral vasculopathy

10. Liver MRI (≤ 180 days prior to initiation of BU conditioning) to document hepaticiron content is required for participants who have received ≥20 packed red bloodcell transfusions (cumulative); participants who have hepatic iron content ≥ 9 mgFe/g liver dry weight by liver MRI must have a liver biopsy and histologicalexamination/documentation of the absence of cirrhosis, bridging fibrosis, and activehepatitis (≤ 180 days prior to initiation of transplant conditioning); the absenceof bridging fibrosis will be determined using the histological grading and stagingscale as described by Ishak and colleagues (1995) as described in the Manual ofOperations (MOO);

11. Evidence of HIV infection, HTLV infection, active hepatitis B infection or activehepatitis C infection.

12. Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosison prior biopsy

13. Receipt of an investigational study drug or procedure within 90 days of studyenrollment

14. Either or both of the following findings on screening bone marrow aspirate/biopsy:a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/orcytogenetics (based on WHO definitions) OR b) pathogenic mutation in any gene on theRapid Heme Panel (RHP), a next-generation sequencing clinical assay for genemutations associated with hematologic malignancies performed at Brigham and Women'sHospital.

15. Pregnancy or breastfeeding

16. Presence of a genetically-determined hypercoagulable state or personal history ofprior VTE (deep vein thrombosis or pulmonary embolism) that would represent acontraindication to proceed with central line placement and study events.

The Phase 2 trial is not enrolling patients who reside outside the US at this time.