A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe Sickle Cell Disease

Subject participation for this study will be 2 years post-transplant. Subjects who enroll in
this study will be asked to participate in a subsequent long-term follow up study that will
monitor the safety and efficacy of the treatment they receive for up to 13 years
post-transplant.

Inclusion Criteria:

1. Be ≥12 and ≤50 of age at time of consent.

2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype.

3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD
(e.g.,pain management plan, hydroxyurea) have experienced severe VOEs as defined
below: at least 4 episodes requiring hospital inpatient admission in the 24 months
prior to informed consent. Exception: priapism does not require hospital admission but
does require a medical facility visit; 4 priapism episodes that require a visit to a
medical facility (without inpatient admission) are sufficient to meet criterion.

For the purposes of this study, a severe VOE is defined as an event with no medically
determined cause other than a vaso-occlusion requiring hospital inpatient admission
over 24 hours and including:

1. An episode of acute pain with no medically determined cause other than a
vaso-occlusive event requiring admission over 24 hours

2. Acute chest syndrome (ACS), defined by an acute event with pneumonia-like
symptoms (e.g., chest pain, fever [>38.5°C], tachypnea, wheezing or cough,
findings upon lung auscultation,) and the presence of a new pulmonary infiltrate
consistent with acute chest syndrome.

3. Acute hepatic sequestration, defined by a sudden increase in liver size
associated with pain in the right upper quadrant, abnormal results of
liver-function test not due to biliary tract disease, and reduction in hemoglobin
concentration by at least 2 g/dL below the baseline value

4. Acute splenic sequestration, defined as sudden enlargement of the spleen and
reduction in hemoglobin concentration by at least 2 g/dL below the baseline value

5. Acute priapism: defined as a sustained, unwanted painful erection lasting more
than 2 hours and requiring care at a medical facility (with or without
hospitalization)

4. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status
of ≥60 (<16 years of age).

5. Have either experienced HU failure at any point in the past or must have intolerance
to HU (defined as inability to be maintained on an adequate dose of HU due to marrow
suppression or severe drug-induced toxicity [e.g. gastrointestinal distress,
fatigue]).

6. Have been treated and followed for at least the past 24 months in medical center(s)
that maintained detailed records on SCD history.

Exclusion Criteria:

1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2),
hepatitis B virus (HBV), or hepatitis C (HCV).

2. Clinically significant and active bacterial, viral, fungal, or parasitic infection.

3. Inadequate bone marrow function, as defined by an absolute neutrophil count of <
1000/µL (< 500/µL for subjects on hydroxyurea treatment) or a platelet count <
120,000/µL (without hypersplenism).

4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke;
abnormal transcranial Doppler [≥200 cm/sec] needing chronic transfusion; or occlusion
or stenosis in the polygon of Willis; or presence of Moyamoya disease

5. Advanced liver disease, defined as:

1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin
value >3× the upper limit of normal (ULN), or

2. Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of
arising from liver disease, or

3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of
cirrhosis, or

4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive
evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up
liver biopsy in subjects ≥18 years of age. In subjects <18 years of age, these
MRI findings are exclusionary, unless in the opinion of the Investigator, a liver
biopsy could provide additional data to confirm eligibility and would be safe to
perform. If a liver biopsy is performed based on MRI findings, any evidence of
cirrhosis, bridging fibrosis, or significant active hepatitis will be
exclusionary.

6. Any contraindications to the use of plerixafor during the mobilization of
hematopoietic stem cells 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.

7. Any prior or current malignancy or immunodeficiency disorder, except previously
treated, non-life threatening, cured tumors such as squamous cell carcinoma of the
skin.

8. Prior receipt of an allogeneic transplant.

9. Immediate family member with a known or suspected Familial Cancer Syndrome.

10. Diagnosis of significant psychiatric disorder of the subject that, in the
Investigator's judgment, could seriously impede the ability to participate in the
study.

11. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception
for fertile subjects.

12. Participation in another clinical study with an investigational drug within 30 days of
Screening.

13. Prior receipt of gene therapy.

14. Patients needing curative anticoagulation therapy during the period of conditioning
through platelet engraftment (patients on prophylactic doses of anticoagulants are
eligible).

15. Unable to receive RBC transfusion.