Autologous Transplant of EFS-ADA Modified Bone Marrow Cells for ADA-Deficient Severe Combined Immunodeficiency (SCID)

The study will be open to twenty (20) infants and children diagnosed with ADA-deficient SCID
who do not have a medically eligible, HLA-identical sibling donor for bone marrow
transplantation. The EFS-ADA lentiviral vector with the human ADA cDNA will be used to
transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects will
receive 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety is the
primary endpoint. During the follow-up phase, the investigators will determine whether the
cells can engraft and produce mature cells that contain and express the corrected ADA gene in
the absence of PEG-ADA enzyme replacement therapy (ERT), which will be withheld at Day +30
following transplant. Efficacy studies to evaluate level of immune reconstitution will begin
in the first year and will continue in the second year. This Phase I/II clinical trial will
be performed at Mattel Children's Hospital, UCLA and at the Mark O. Hatfield Clinical
Research Center, NIH.

Inclusion Criteria:

-Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased
ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal
cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or
confirmed ADA gene mutation(s) known to cause disease , AND

B. Evidence of severe combined immunodeficiency based on either:

1. Family history of first order relative with ADA deficiency and clinical and laboratory
evidence of severe immunologic deficiency, OR

2. Evidence of severe immunologic deficiency in subject prior to institution of immune
restorative therapy, based on

1. lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number
of T cells (absolute CD3+ count <300 cells/mcL) OR

2. severely decreased T lymphocyte blastogenic responses to phytohemagglutinin
(either <10% of lower limit of normal controls for the diagnostic laboratory,
<10% of the response of the normal control of the day, or stimulation index <10)

- Ineligible for matched sibling allogeneic bone marrow transplantation:
absence of a medically eligible HLA-identical sibling, with normal immune
function, who may serve as an allogeneic bone marrow donor

- Signed written informed consent according to guidelines of the IRB (UCLA
Office of Human Research Protection Program and National Human Genome
Research Institute (NHGRI) Institutional Review Board

Exclusion Criteria:

1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within
60 days of entering this trial.

2. Hematologic

1. Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years
of age).

2. Neutropenia (absolute granulocyte count <500/mm3.

3. Thrombocytopenia (platelet count < 150,000/mm3, at any age).

4. INR or PT > 2X the upper limits of normal or PTT > 2.33X the upper limit of
normal (patients with a correctable deficiency controlled on medication will not
be excluded).

5. Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid
(if available).

6. Prior allogeneic HSCT with cytoreductive conditioning

3. Infectious

a. Evidence of infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by
DNA PCR within 90 days prior to bone marrow harvest. If other infection is present, it
must be under control (e.g. stable or decreasing viral load) at the time of screening

4. Pulmonary

1. Resting O2 saturation by pulse oximetry < 95% on room air.

2. Chest x-ray indicating active or progressive pulmonary disease.

5. Cardiac

1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.

2. Uncorrected congenital cardiac malformation with clinical symptomatology.

3. Active cardiac disease, including clinical evidence of congestive heart failure,
cyanosis, hypotension.

4. Poor cardiac function as evidenced by LV ejection fraction < 40% on
echocardiogram.

6. Neurologic

1. Significant neurologic abnormality by examination.

2. Uncontrolled seizure disorder.

7. Renal

1. Renal insufficiency: serum creatinine >= 1.2 mg/dl, or >= 3+ proteinuria.

2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or
IV by Division of AIDS Toxicity Scale.

8. Hepatic/GI:

1. Serum transaminases > 5X the upper limit of normal (ULN).

2. Serum bilirubin > 2X ULN.

3. Serum glucose > 1.5x ULN.

4. Intractable severe diarrhea.

9. Oncologic

1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans
(DFSP)

2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years
following the infusion of genetically corrected cells

3. Evidence of DFSP expected to be life limiting within the 5 years following the
infusion of genetically corrected cells

10. Known sensitivity to Busulfan

11. General

1. Expected survival < 6 months.

2. Pregnant.

3. Major congenital anomaly.

4. Ineligible for autologous HSCT by the criteria at the clinical site.

5. Other conditions which in the opinion of the principal investigator and/or
co-investigators, contra-indicate the bone marrow harvest, the administration of
busulfan, infusion of transduced cells or indicate the patient or patient's
parents/primary caregivers inability to follow protocol.