Hematopoietic Stem Cell BCL11A Enhancer Gene Editing for Severe β-Hemoglobinopathies

Exclusion Criteria20

• Subjects who have concomitant condition or illness including, but not limited to:
• Uncontrolled infection, such as current febrile illness, infection requiring parenteral antibiotics, or systemic fungal infection.
• Active malignancy.
• Active complication of underlying hemoglobinopathy that would place the patient at unacceptable risk for participation, in the judgment of the Investigators.
• Major surgery in the past 30 days.
• Medical/psychiatric illness/social situations that would limit compliance with study requirements as determined by the treating physician.
• Contraindication to administration of conditioning medication (busulfan).
• Subjects who have undergone allogeneic or autologous hematopoietic stem cell transplant previously.
• Either or both of the following findings on screening bone marrow aspirate/biopsy: a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) or b) pathogenic mutation in any gene on the Rapid Heme Panel (RHP), a next-generation targeted sequencing clinical assay for hematologic malignancy associated mutations.
• For SCD patients:
• Severe cerebral vasculopathy (defined by occlusion or stenosis in the circle of Willis; or presence of Moyamoya disease)
• Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal transcranial Doppler (TCD) who have transitioned from transfusions to hydroxyurea for stroke prophylaxis are also not eligible for the study. Most recent TCD must be within one year of screening for patients up to 16 years old.)
• History of overt stroke or any neurologic event lasting \> 24 hours. (Note: patients with imaging evidence of silent stroke but not on a chronic transfusion regimen are not excluded.)
• Severe iron overload that is deemed to be grounds for exclusion based on the opinion of the Principal Investigator.
• Known positive HIV serology or HIV nucleic acid testing, or positive serology for HCV, HBV, or HTLV.
• Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on prior biopsy.
• Receipt of an investigational study drug or procedure within 90 days of study enrollment.
• Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception for fertile subjects. Females of child-bearing potential must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from Screening through at least 6 months after drug product infusion. Male subjects must agree to use effective contraception (including condoms) from Screening through at least 6 months after drug product infusion.
• An assessment by the Investigators that the subject will not comply with the study procedures outlined in the study protocol, or that, as determined by the investigators and/or transplant physician, the subject has any other condition rendering the subject ineligible for HSCT or other study procedures.
• Patients carrying at least one cytosine (C) alternate allele at the SNP site rs114518452, chr2:210530659-210530659 (GRCh38/hg38), where guanine (G) is the reference allele.