Hematopoietic stem cell (HSC)-based gene therapies now offer curative potential for patients with sickle cell disease (SCD), with decreased toxicity compared to allogeneic hematopoietic cell transplantation. However, effective HSC-based gene therapy depends on collecting sufficient HSCs to generate the therapeutic product, and currently available mobilization regimens carry unacceptable risk for patients with SCD or do not reliably yield optimal numbers of HSCs for gene therapy.

The investigators hypothesize that HSC mobilization with motixafortide (CXCR4i) alone and the combination of motixafortide plus natalizumab (VLA-4i) will be safe and tolerable in SCD patients. In addition, the investigators hypothesize that combined CXCR4 and VLA-4 blockade with motixafortide plus natalizumab will result in a rapid, robust, and synergistic increase in HSC mobilization to peripheral blood (PB) in patients with SCD, when compared to motixafortide alone.

Inclusion Criteria:

• Adult patients at least 18 years old

• Diagnosis of sickle cell disease (hemoglobin SS or Sβ0 genotype)

• Receiving automated RBC exchanges via apheresis-capable central venous access or willing to have apheresis-capable venous access placed.

• Able to hold hydroxyurea, voxelotor, and/or crizanlizumab for at least 60 days prior to mobilization

• Able to hold iron chelation for at least 7 days prior to mobilization

• ECOG performance status ≤ 1

• Normal bone marrow and organ function at screening as defined below:

  • Leukocytes ≥ 2,000/uL
  • Absolute neutrophil count ≥ 1,500/uL
  • Platelets ≥ 75,000/uL
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN at time of screening
  • Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
  • Baseline oxygen saturation ≥ 92% on room air
  • Left ventricular ejection fraction (LVEF) ≥ 45% (Of note, transthoracic echocardiogram (TTE) will not be required for study. However, if the treating physician has clinical concerns for active cardiac disease for which a TTE is clinically warranted as standard of care, then an EF of ≥ 45% will be required).

• The effects of motixafortide and natalizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, and 3 months after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 3 months after completion of the study.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Patients may not have a history of receiving the following therapies: prior HCT or prior gene therapy
• Currently receiving concomitant immunosuppressants including 6-mercaptopurine, azathioprine, cyclosporine, methotrexate or concomitant inhibitors of TNF-α.
• Patient may not have a history of significant alloantibodies which, in the opinion of the treating physician and study investigator, significantly increase the risk of participation in this clinical trial.
• Currently receiving any other investigational agents.
• A history of progressive multifocal leukoencephalopathy
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to motixafortide or natalizumab.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (including but not limited to HIV, active/untreated Hepatitis C and/or active/untreated Hepatitis B), ongoing/active vaso-occlusive pain crisis or uncontrolled SCD-related symptoms, symptomatic congestive heart failure, cerebrovascular accident, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 7 days of study entry and prior to each study agent administration/HSC mobilization.
• Determined by the investigator to be unable or unlikely to comply with the study procedures included in this protocol.