Inclusion Criteria:
* Age ≥18 years and ≤24.9 years.
* Patients with SCD (Hb SS, Hb SB0 and Hb SB+ genotype) who have experienced EITHER (a) 2 or more SCD-related vaso-occlusive events (acute pain events, acute chest syndrome, priapism and splenic sequestration) per year in the 2-year period before screening, OR (b) administration of regular red blood cell (RBC) transfusions (≥8 transfusions in the 12 months preceding enrollment) EXCEPT if the RBC transfusions are being administered for primary or secondary stroke prevention and, in the opinion of the treating hematologist, cannot be safely discontinued after infusion of the gene modified drug product.
* Failure, intolerance, or refusal of hydroxyurea therapy.
* Patients must be eligible for autologous stem cell transplant as per investigator's judgment.
* Females of childbearing potential (i.e., those who are post-menarchal with an intact uterus and at least 1 ovary, and those who are less than 1 year postmenopausal) must agree to use acceptable method(s) of contraception from start of mobilization through at least 6 months post-infusion.
* Males must agree to use effective contraception from start of mobilization through at least 6 months post-infusion.
* Patients should be willing to participate in an additional long-term follow-up study after completion of this trial.
Exclusion Criteria:
* Availability of an human leukocyte antigen (HLA)-matched sibling who is willing and able to donate an appropriate graft for hematopoietic cell transplantation (HCT).
* Karnofsky or Lansky performance score \< 80.
* Pregnant, as confirmed by positive serum or urine pregnancy test within 14 days before enrollment (if female).
* Breastfeeding.
* Uncontrolled (undergoing appropriate treatment and with progression of clinical symptoms) or clinically significant bacterial, viral, or fungal infections within 1 month before enrollment.
* Patients with confirmed Hepatitis B or Hepatitis C infections.
* Patients with confirmed seropositivity or positive nucleic acid amplification test (NAAT) for human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV).
* Patients with a history of stroke.
* Serum conjugated (direct) bilirubin \> 2× the upper limit of normal for age, or serum alanine transaminase (ALT) \> 3× the upper limit of normal for age as per the local laboratory. Participants with hyperbilirubinemia or elevated aspartate aminotransferase (AST) as the result of hyperhemolysis, or with a severe drop in hemoglobin post blood transfusion, are not excluded as long as these values downtrend and return to acceptable limits subsequently.
* Left ventricular shortening fraction \< 25% or ejection fraction \< 45% by echocardiogram.
* Estimated creatinine clearance less than 60 mL/min/1.73m\^2.
* Diffusion capacity of carbon monoxide (DLCO) \< 50% (adjusted for hemoglobin) OR baseline oxygen saturation \< 85% in patients unable to perform pulmonary function tests.
* Prior HCT or gene therapy.
* Known hepatic cirrhosis, bridging hepatic fibrosis, or active hepatitis. Appropriate ultrasound or magnetic resonance (MR) imaging may be used to define the presence and degree of cirrhosis. Liver biopsy may be performed at the discretion of the attending physician or principal investigator if there are concerns regarding the presence of severe hepatic fibrosis or cirrhosis such that participation in this trial will not be in the patient's best interest.
* Active known malignancy, myelodysplasia, abnormal cytogenetics, or immunodeficiency.
* Patients with history of a significant bleeding disorder.
* Cerebrovascular procedure within 6 months, including pial synangiosis for moyamoya.
* Patients with history of untreated moyamoya disease or presence of moyamoya disease at screening that in the opinion of the investigator puts the subjects at the risk of bleeding.
* Evidence of a pathogenic clonal variant in any candidate gene detected by a standard, licensed next-generation sequencing clinical assay for gene mutations associated hematological malignancies.
* Patients with history of intolerance, contraindication, or known sensitivity to plerixafor or motixafortide or busulfan. Prior anaphylactic reaction with excipients of the proposed product.
* Patients with participation in another clinical study with an investigational drug/product within 30 days of screening or fewer than 5 half-lives of the investigational agent whichever is longer from screening.
* Patients with history of alloimmunization to RBC antigens and for whom the investigator anticipates that there will be insufficient RBC units available for the duration of the study.
