Inclusion Criteria: 1. Diagnosis of either a) sickle cell disease with genotype HbSS, HbS/B0 thalassemia, HbSD, or HbSO, or b) transfusion-dependent β-thalassemia 2. Age 13-40 years. 3. Clinically severe disease, defined as: For sickle cell disease, the presence of one or more of the following clinical complications: i) Minimum of two episodes of acute chest syndrome (ACS) in the 2 years before study entry. ii) History of three or more episodes of severe pain events requiring a visit to a medical facility and treatment with parenteral opioids in the 2 years before study entry. For β-thalassemia patients: i) At least 100 mL/kg/year or 10 units/year of blood transfusions, on an annualized basis for the two years preceding enrollment. 4. Adequate hematologic parameters including: 1. White blood cell (WBC) count within the range of 2.5 - 25.0 x 109 /L 2. Platelet count within the range of 150 - 700 x 109 /L 5. Adequate organ function and performance status: 1. Karnofsky performance status ≥70% 2. Serum creatinine \</=1.5 times the upper limit of normal for age, and calculated creatinine clearance or GFR \</= 60 mL/min/1.73 m2. 3. Direct bilirubin ≤ 2.0 mg/dL 4. DLCO (corrected for hemoglobin), FEV1, FVC \>50% of predicted 5. Left ventricular ejection fraction \>40% or shortening fraction \>25% 6. For sickle cell patients: Failure of hydroxyurea therapy due to lack of clinical improvement, inability to tolerate due to side effects (e.g., myelosuppression, gastrointestinal symptoms, or hepatic enzyme elevations) or not clinically indicated (such as in a patient on a chronic transfusion regimen). Clinical criteria (per above) must be met despite taking hydroxyurea for greater than or equal to 6 months, unless not indicated or not tolerated. Patients taking hydroxyurea who still meet all inclusion criteria are eligible for the trial. Hydroxyurea should be discontinued when transfusions prior to gene therapy begin. 7. Confirmed sickle cell disease or β-thalassemia diagnosis by molecular genetic testing. 8. No HLA genotypically-identical related appropriate bone marrow donor available. 9. Parental/guardian/patient signed informed consent. 10. Willingness to return for follow-up for 15 years. Exclusion Criteria: 1. Subjects who have concomitant condition or illness including, but not limited to: 1. Uncontrolled infection, such as current febrile illness, infection requiring parenteral antibiotics, or systemic fungal infection. 2. Active malignancy. 3. Active complication of underlying hemoglobinopathy that would place the patient at unacceptable risk for participation, in the judgment of the Investigators. 4. Major surgery in the past 30 days. 5. Medical/psychiatric illness/social situations that would limit compliance with study requirements as determined by the treating physician. 2. Contraindication to administration of conditioning medication (busulfan). 3. Subjects who have undergone allogeneic or autologous hematopoietic stem cell transplant previously. 4. Either or both of the following findings on screening bone marrow aspirate/biopsy: a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) or b) pathogenic mutation in any gene on the Rapid Heme Panel (RHP), a next-generation targeted sequencing clinical assay for hematologic malignancy associated mutations. 5. For SCD patients: 1. Severe cerebral vasculopathy (defined by occlusion or stenosis in the circle of Willis; or presence of Moyamoya disease) 2. Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal transcranial Doppler (TCD) who have transitioned from transfusions to hydroxyurea for stroke prophylaxis are also not eligible for the study. Most recent TCD must be within one year of screening for patients up to 16 years old.) 3. History of overt stroke or any neurologic event lasting \> 24 hours. (Note: patients with imaging evidence of silent stroke but not on a chronic transfusion regimen are not excluded.) 6. Severe iron overload that is deemed to be grounds for exclusion based on the opinion of the Principal Investigator. 7. Known positive HIV serology or HIV nucleic acid testing, or positive serology for HCV, HBV, or HTLV. 8. Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on prior biopsy. 9. Receipt of an investigational study drug or procedure within 90 days of study enrollment. 10. Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception for fertile subjects. Females of child-bearing potential must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from Screening through at least 6 months after drug product infusion. Male subjects must agree to use effective contraception (including condoms) from Screening through at least 6 months after drug product infusion. 11. An assessment by the Investigators that the subject will not comply with the study procedures outlined in the study protocol, or that, as determined by the investigators and/or transplant physician, the subject has any other condition rendering the subject ineligible for HSCT or other study procedures. 12. Patients carrying at least one cytosine (C) alternate allele at the SNP site rs114518452, chr2:210530659-210530659 (GRCh38/hg38), where guanine (G) is the reference allele.