Autologous Cryopreserved CD34+ Hematopoietic Cells Transduced With EFS-ADA Lentivirus for ADA SCID

This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical
study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101
(autologous CD34+ hematopoietic stem cells transduced ex vivo with EFS LV encoding for the
human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years,
who are not eligible for an HLA-matched sibling/family donor and meeting the
inclusion/exclusion criteria.

The aim of this clinical study is also to assess the success of treatment at the subject
level ("responder analysis") 6 months post OTL-101 infusion, using predictive criteria for
overall survival and event free survival and to compare data obtained from clinical studies
using the fresh formulation of OTL-101.

Eligible subjects will be hospitalized to undergo the harvesting of autologous CD34+ cells.
To enable the release of the cell product for infusion, the product must meet various quality
control criteria for safety, identity, viability, purity and potency. If OTL-101 meets the
acceptance criteria and is released, the subjects will be readmitted for conditioning prior
to infusion of OTL-101.

For subjects who have successfully received the OTL-101 product, PEG-ADA ERT will be
discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital,
the subjects will be seen at regular intervals to review their history, perform examinations
and draw blood samples at Months 1, 3, 6, 9, 12, 18, and 24. Any medically-indicated
interventions will be determined at these visits. After Month 24 visit, the subjects will
have completed the study and may enter a long term registry.

Inclusion Criteria:

1. Provision of written informed consent prior to any study related procedures. In this
study consent must be provided by the parents/legal guardians and, where applicable
according to local laws, a signed assent from the child,

2. Subjects ≥30 days and <18 years of age,

3. With a diagnosis of ADA-SCID based on:

Evidence of ADA deficiency, defined as:

i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or
in cultured fetal cells to levels consistent with ADA-SCID as determined by the
reference laboratory, or ii. Identified mutations in ADA alleles consistent with a
severe reduction in ADA activity,

Evidence of ADA-SCID based on either:

i. Family history of a first order relative with ADA deficiency and clinical and
laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe
immunologic deficiency in subjects prior to the institution of immune restorative
therapy, based on

- Lymphopenia (absolute lymphocyte count (ALC) <400 cells/µL) OR absence or low
number of T cells (absolute CD3+ count < 300 cells/µL), or

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

- Identification of SCID by neonatal screening revealing low T cell Receptor
Excision Circle (TREC) levels.

4. Ineligible for matched family allogeneic Bone Marrow (BM) transplantation, defined as
the absence of a medically eligible HLA-identical sibling or family donor, with normal
immune function, who could serve as an allogeneic bone marrow donor.

5. Females of child-bearing age will be required to provide a negative pregnancy test 30
days prior to Visit 2.

6. Subjects and their parents/legal guardians must be willing and able to comply with
study restrictions and to remain at the clinic for the required duration during the
study period and willing to return to the clinic for the follow up evaluation as
specified in the protocol.

Exclusion Criteria:

1. Ineligible for autologous HSCT as per clinical site criteria.

2. Other conditions which in the opinion of the Principal Investigator and/or Co
Investigators, contraindicate the harvest of bone marrow, the administration of
Busulfan and the infusion of transduced cells, or which indicate an inability of the
subject or subject's parent/legal guardian to comply with the protocol.

3. Hematologic abnormality, defined as:

- Anemia (Hb <8.0 g/dl).

- Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of myelodysplastic
syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are
acceptable for eligibility.

- Thrombocytopenia (platelet count <50,000/mm3, at any age).

- Prothrombin time or international normalized ratio (INR) and partial
thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a
correctable deficiency controlled on medication will not be excluded).

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

- Prior allogeneic HSCT with cytoreductive conditioning.

4. Pulmonary abnormality, defined as:

- Resting O2 saturation by pulse oximetry <90% on room air.

- Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X ray
indicating residual signs of treated pneumonitis is acceptable for eligibility.

5. Cardiac abnormality, defined as:

- Abnormal ECG indicating cardiac pathology.

- Uncorrected congenital cardiac malformation with clinical symptoms.

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

- Poor cardiac function as evidenced by left ventricular ejection fraction <40% on
echocardiogram.

6. Neurologic abnormality, defined as:

- Significant neurologic abnormality revealed by examination.

- Uncontrolled seizure disorder.

7. Renal abnormality, defined as:

- Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or ≥3+
proteinuria.

- Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at >2 x
ULN.

8. Hepatic/gastrointestinal abnormality, defined as:

- Serum transaminases >5 x ULN.

- Serum bilirubin >2 x ULN.

- Serum glucose >1.5 x ULN.

9. Oncologic disease, defined as:

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

- Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years
following the infusion of genetically corrected cells (if anti-neoplastic therapy
has been completed, a subject with a history of DFSP can be included).

- 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. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) PCR positive at
time of screening assessment for the following:

- HIV-1,

- Hepatitis B,

- Parvovirus B19.

12. The subject is pregnant or has a major congenital anomaly.

13. Is likely to require treatment during the study with drugs that are not permitted by
the study protocol.

14. The subject has previously received another form of gene therapy.