Inclusion Criteria:
* Participants with severe sickle cell disease (SCD) who are ≥18 years of age and willing to donate autologous hematopoietic stem cells (HSCs) for advancing future gene therapy for SCD after collection of back-up product. Severe SCD, for the purpose of this study, will be defined as participants who are receiving chronic transfusion therapy due to SCD related complications or are eligible for or currently enrolled on an allogeneic transplant protocol.
* Participant must have a documented diagnosis of SCD with documentation of SCD genotype by medical history
* Participants should either have a central line in place, be able to undergo apheresis without the necessity of the insertion of a central venous catheter, or agree to have a central line placed if IV access is inadequate.
* ECOG performance status/Karnofsky score/Lansky score \>80
* White blood cell (WBC) count \>3.0 x 10\^9/L, absolute neutrophil count (ANC) \>1.0 x 10\^9/L, and platelet count \>150 x 10\^9/L, and hemoglobin \>7.0 gm/dL
* Adequate renal function defined as serum/plasma creatinine \< 1.5 mg/dL and an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m\^2 based on the CKD-Epi equation or the St. Jude equation.
* Adequate liver function defined as direct bilirubin \< 2.5 times the upper limit of normal range; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 5 times the upper limit of normal range.
* Participant's cardiac function (i.e., ejection fraction \>40%) and pulmonary status (i.e., no evidence of pulmonary hypertension) within the last 6 months must be sufficient to undergo apheresis, as assessed by the Principal Investigator or an independent physician evaluating the participant. If an assessment has not been done within the last 6 months, an echocardiogram will be performed.
* Negative serologic tests for syphilis, hepatitis B and C, HIV, and HTLV-1/II
* Feasible manual or automated exchange transfusion plan to achieve hemoglobin S (HbS) near 30% within one week of mobilization
* Female participants of childbearing age should have a negative pregnancy test.
* Participants of childbearing potential should agree to use of a highly effective form of contraception during treatment and for at least 1 month after the last dose of motixafortide. Women of childbearing potential must agree to use 2 methods of effective contraception: One barrier method (e.g. diaphragm, or condom or sponge, each of which are to be combined with a spermicide) and one hormonal method, unless she uses a highly effective method. Highly effective methods of contraception include:
* Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
* Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system (IUS)
* Bilateral tubal occlusion
* Vasectomised partner
* Sexual abstinence.
Exclusion Criteria:
* Active and painful splenomegaly or splenomegaly (size greater than upper limit of normal on examination).
* Participant who, by medical history, requires rare donor registry RBC units for transfusion, or is unable to receive routine transfusion. Eligible study participants must have undergone prior work-up for the presence of red cell alloantibodies and confirmation of available compatible blood product support
* Known allergy to or contraindication for motixafortide administration, or medications routinely administered during apheresis
* Participant who has had a prior autologous or allogeneic transplantation, inclusive of gene therapy
* Active viral, bacterial, fungal, or parasitic infection.
* History of cancer, excluding squamous carcinoma of the skin and cervical carcinoma in situ.
* Participant who has received experimental therapy within 4 weeks prior to providing informed consent
* Poorly controlled diabetes mellitus, as assessed by the Investigator
* Concomitant treatment with alternative investigational agent unable to be held for 30 days
* Unwillingness to use a highly effective method of contraception for 1 month after motixafortide
* Pregnancy
* Inability or unwillingness of research participant or legal guardian/ representative to give written informed consent.
* Inability or unwillingness of research participant to hold hydroxyurea for 30 days prior to first dose of study drug
