Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning

This is an open labeled, multi-center, phase I/II, cohort study involving a single infusion
of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector
G2SCID in up to 10 patients with X-linked SCID (SCID-X1) at Boston Children's Hospital and
UCLA Mattel Children's Hospital. Patients will receive transduced cells after low dose
targeted busulfan pre-conditioning (n=10).

Enrolled subjects will be followed for 2 years after infusion on this protocol. Required
long-term monitoring for a total of 15 years after infusion will be performed on a separate
protocol.

Single infusion of autologous CD34+ cells transduced with the SIN lentiviral vector
rHIV_IL2RGcoG2SCID (hereafter G2SCID) The primary objective is to measure event free survival
and T cell immune reconstitution at 1 year post-infusion

Secondary objectives are to measure overall survival, event-free survival, safety related to
the procedure, and clinical and laboratory measures of efficacy including humoral immune
reconstitution and gene marking after gene transfer.

Exploratory objectives include: molecular characterization of gene transfer, detailed
assessment of biomarkers of T and B cell development and function, assessment of infections,
nutritional status, growth and development post gene therapy, assessment of T cell receptor
and B cell receptor repertoire by next generation sequencing, correlation of busulfan levels
with immune outcome and molecular measurements of gene transfer

Inclusion Criteria:

- 1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function
(proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed
by a mutation in IL2RG 2. Lack of an HLA identical (A, B, C, DR, DQ) related donor 3. Age 5
years old or younger 4. Signed informed consent 5. Documentation of willingness to follow
up for 15 years post-infusion as currently required by the FDA 6. If the patient has
previously undergone allogeneic transplant, lack of donor T cell engraftment must be
documented.

7. Age at least 8 weeks by the time of busulfan administration

Exclusion Criteria:

1. Patients with an active, therapy-resistant infection. Infections that are known to be
highly morbid in SCID patients will be considered active and therapy-resistant if the
infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate
therapy and is associated with significant organ dysfunction (including but not
limited to abnormalities listed below).

1. Mechanical ventilation including continuous positive airway pressure

2. Abnormal liver function defined by AST and ALT >10 times the upper range of
normal OR Bilirubin >2 mg/dL

3. Shortening fraction on echocardiogram <25% or ejection fraction <50%

4. Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or
dialysis dependence

2. Uncontrolled seizure disorder

3. Encephalopathy

4. Documented coexistence of any disorder known to affect DNA repair

5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative
disease

6. Patients with evidence of infection with HIV-1

7. Major (life-threatening) congenital anomalies. Examples of "major (life-threatening)
congenital anomalies" include, but are not limited to: unrepaired cyanotic heart
disease, hypoplastic lungs, anencephaly or other major central nervous system
malformations, other severe non-repairable malformations of the gastrointestinal or
genitourinary tracts that significantly impair organ function.

8. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate
collection and/or infusion of transduced cells or indicate patient's inability to
follow the protocol. These may include for example clinical ineligibility to receive
anesthesia, severe deterioriation of clinical condition of the patient after
collection of bone marrow but before infusion of transduced cells, or documented
refusal or inability of the family to return for scheduled visits. There may be other
unforeseen rare circumstances that would result in exclusion of the patient, such as
sudden loss of legal guardianship