Key Inclusion Criteria: Diagnosis of severe sickle cell disease as defined by: * Documented SCD genotype (βS/βS, βS/β0, βS/β+, or others) and * History of at least two severe vaso-occlusive events per year requiring medical attention despite hydroxyurea or other supportive care measures in the two year-period prior to provision of informed consent or assent, as applicable Karnofsky (for subjects \>16 years of age) or Lansky (for subjects ≤ 16 years of age) Performance Status ≥ 80% Normal transcranial doppler velocity in subjects 16 years of age or younger Key Exclusion Criteria: * Available 10/10 HLA-matched related donor * Prior HSCT or contraindications to autologous HSCT * Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells (HSCs) and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients * Unable to receive red blood cell (RBC) transfusion for any reason * Unable or unwilling to comply with standard of care changes in background medical treatment in preparation of, during, or following HSCT, including and not limited to discontinuation of hydroxyurea, voxelotor, crizanlizumab, or L-glutamine * Any history of severe cerebral vasculopathy * Inadequate end organ function * Advanced liver disease * Any prior or current malignancy or immunodeficiency disorder * Immediate family member with a known or suspected Familial Cancer Syndrome * Clinically significant and active bacterial, viral, fungal, or parasitic infection Other protocol defined inclusion/exclusion criteria may apply