| Eligibility |
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:
1. . Evidence of ADA deficiency, defined as: i. Decreased ADA enzymatic activity in
erythrocytes, leukocytes, skin fibroblasts, or in cultured foetal 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,
2. . 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 <400 cells/mL) OR absence or low number of
T-cells (absolute CD3+ count < 300 cells/mL), 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 or with no available matched family donor for 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 hematopoietic stem cell (HSC) procedure.
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. Haematologic abnormality, defined as:
Anaemia (Hb <8.0 g/dl). Evidence of bi/trilineage cytopaenia (haemoglobin <8 g/dl,
neutrophils <0.5 x 109/L, platelets 50 x 109/L). Thrombocytopaenia (platelet count
<50,000/mm3). Prothrombin time or 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 of Peripheral Blood (PB), BM or amniotic fluid (if
available). If cytogenetic testing has not been performed on cells from
amniocentesis, assessment should be by karyotype, Comparative genomic
hybridization (CGH), and or whole exome sequencing (WES).
- Prior allogeneic HSC transplant (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. Known history of significant renal abnormality.
8. Known history of significant hepatic or gastrointestinal abnormality.
9. Oncologic disease, defined as:
- 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 (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) polymerase chain
reactions (PCR) positive at time of screening assessment according to local
protocols/procedures (including HIV-1 and hepatitis B).
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.
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