Inclusion Criteria

• Ages 18 to 40
• Confirmation of sickle cell disease (SCD) diagnosis (HbSS or HbS[beta]0 genotype)
• Severe SCD, defined as having 1 or more of the following manifestations: Clinically significant neurologic event (example [e.g.], stroke) or any neurological deficit lasting more than 24 hours; History of 2 or more episodes or Acute Chest Syndrome (ACS) in 2 years prior to informed consent (despite adequate supportive therapies such as asthma therapy); Six or more pain crises per year in 2 years prior to informed consent (requiring intravenous [IV] pain management in the outpatient or inpatient hospital setting); History of 2 or more cases or priapism with participant seeking medical care in the 2-years prior to informed consent; Regular RBC transfusion therapy in the year prior to informed consent (having received 8 or more transfusions to prevent vaso-occlusive clinical complications); and Echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity of greater than or equal to 2.5 meter per second (m/s)
• Clinically stable to undergo stem cell mobilization and myeloablative hematopoietic stem cell transplantation (HSCT)
• Adequate physiological function, defined as the following: Karnofsky/Lansky Performance of greater than or equal to 60; Acceptable cardiac function as defined in protocol; Acceptable pulmonary function as defined in protocol; Acceptable renal function as defined in protocol; and Acceptable hepatic function as defined in protocol
• Ability to understand purpose and risks of study, provide Informed Consent Form (ICF) and authorization to use protected health information
• Completion of age-appropriate cancer screening
• Willingness to use double-barrier method of contraception through entire study period (for participants of childbearing potential)
• Willingness to receive blood transfusions
• Willingness to discontinue hydroxyurea (HU) at least 30 days prior to stem cell mobilization through Day 100 post-transplantation

Exclusion Criteria:

• Previous receipt of an autologous or allogeneic HSCT or solid organ transplantation
• Previous treatment with gene therapy
• Current enrollment in an interventional study or having received an investigational drug within 30 days of study enrollment
• Pregnant or breastfeeding female
• Female or male who plans to become pregnant or impregnate a partner, respectively, during the anticipated study period
• Contraindication to plerixafor, apheresis, or busulfan
• Treatment with prohibited medication in previous 30 days
• Known allergy or hypersensitivity to plerixafor, busulfan, or investigational product excipients
• History of active malignancy within past 5 years, any history of hematologic malignancy, or a family history of a cancer predisposition syndrome (without negative result of candidate)
• Current diagnosis of uncontrolled seizures
• History of significant bleeding disorder
• Clinically significant infection
• Any major organ dysfunction involving brain, kidney, liver, lung, or heart (e.g., congestive heart failure, pulmonary hypertension)
• Corrected QT interval of more than 500 millisecond (ms) based on screening electrocardiogram (ECG)
• Positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• Known to have a gamma-globin variant associated with altered oxygen affinity
• Hereditary persistence of fetal hemoglobin (HPFH) or HbF concentration of more than or equal to 20 percent (%) at screening
• Absolute Neutrophil Count (ANC) of less than or equal to 1,000 per microliter
• Platelet count of less than 100,000 per microliter
• History of platelet alloimmunization (precluding ability to provide transfusion support)
• Extensive Red Blood Cell (RBC) alloimmunization (precluding ability to provide transfusion support)
• Judged unsuitable for participation by investigator and/or sponsor