A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

Inclusion Criteria:

1. Informed consent is obtained from a competent custodial parent or guardian with legal
capacity to execute a local IRB/Independent Ethics Committee (IEC) approved consent
(informed assent will be sought from capable subjects, in accordance with the
directive of the IRB/IEC and with local requirements).

2. Males aged 17 years and younger, at the time of parental/guardian consent and, where
appropriate, subject assent.

3. Active cerebral ALD as defined by:

1. Elevated VLCFA values, and

2. Active CNS disease established by central radiographic review of brain magnetic
resonance imaging (MRI) demonstrating:

i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and ii. Gadolinium
enhancement on MRI of demyelinating lesions.

4. Neurologic Function Score (NFS) ≤ 1.

Exclusion Criteria:

1. Receipt of an allogeneic transplant or gene therapy.

2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female
heterozygotes).

3. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels. Note:
subjects must discontinue use of these medications at time of consent.

4. Receipt of an investigational study drug or procedure within 3 months before Screening
that might confound study outcomes. Use of investigational study drugs is prohibited
throughout the course of the study.

5. Any conditions that make it impossible to perform MRI studies (including allergies to
anesthetics or contrast agents).

6. Hematological compromise as evidenced by:

- Peripheral blood ANC count < 1500 cells/mm3,

- Platelet count < 100,000 cells/mm3, or

- Hemoglobin < 10 g/dL.

- Uncorrected bleeding disorder.

7. Hepatic compromise as evidenced by:

- Aspartate transaminase (AST) value > 2.5×ULN

- Alanine transaminase (ALT) value > 2.5×ULN

- Total bilirubin value > 3.0 mg/dL, except if there is a diagnosis of Gilbert's
Syndrome and the subject is otherwise stable

8. Renal compromise as evidenced by abnormal renal function (actual or calculated
creatinine clearance < 50 mL/min)

9. Cardiac compromise as evidenced by left ventricular ejection fraction <40%

10. Immediate family member with a known or suspected familial cancer syndrome (including
but not limited to hereditary breast and ovarian cancer syndrome, hereditary
non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).

11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated
infection

12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B;
hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that subjects who have been
vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are
negative for other markers of prior hepatitis B infection [eg, negative for hepatitis
B core antibody (Ab)] are eligible. Subjects with past exposure to HBV [HBcAb positive
and/or HBeAb positive] are also eligible for the study provided they have a negative
test for HBV DNA. Also note that subjects who are positive for anti-hepatitis C
antibody are eligible as long as they have a negative hepatitis C viral load).

13. Any clinically significant cardiovascular or pulmonary disease, or other disease or
condition that would be contraindicated for any of the other study procedures.

14. Absence of adequate contraception for fertile subjects. Male subjects and their female
partners are required to use two different effective methods of contraception from
Screening through at least 6 months after drug product infusion.

15. Any contraindications to the use of G-CSF during the mobilization of HSCs, and any
contraindications to the use of busulfan or cyclophosphamide, including known
hypersensitivity to the active substances or to any of the excipients in their
formulations.