| Eligibility |
Inclusion Criteria:
- Provision of written informed consent by the subject or parent(s)/legal guardian(s),
prior to any study related procedures taking place. Where consent is provided by the
parent(s)/legal guardian(s), assent by the subject should also be sought, if
appropriate
- Age =30 days and <18 years
- Diagnosis of ADA-SCID based on either:
- 1) Evidence of ADA deficiency, defined as 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 Identified
mutations in ADA alleles consistent with a severe reduction in ADA activity
- 2) Evidence of ADA-SCID, defined as Family history of a first order relative with
ADA deficiency and clinical and laboratory evidence of severe immunologic
deficiency OR Evidence of severe immunologic deficiency in subjects prior to the
institution of immune restorative therapy, based on at least one of the
following:
- Lymphopenia (absolute lymphocyte count <400 cells/µL) OR absence or low
number of T cells (absolute CD3+ count < 300 cells/µL)
- 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)
- Identification of SCID by neonatal screening revealing low T cell receptor
excision circles (TREC) levels
- Ineligible for allogeneic bone marrow transplantation from an Human leukocyte antigen
(HLA)-identical sibling donor, with normal immune function
- For females of child-bearing potential, negative pregnancy test up to 30 days prior to
the Screening visit. For all subjects in the reproductive age range, agreement to use
highly effective and adequate method of contraception while receiving treatment and
for at least 12 months following drug administration
- Willingness and ability of the subjects and parent(s)/legal guardian(s) to comply with
study procedures and requirements, including remaining at the clinic for the required
duration of conditioning and treatment and compliance with follow-up evaluations
Exclusion Criteria:
- Ineligible for autologous HSCT as per clinical site criteria.
- Hematologic abnormality, defined as:
- Anemia (Hb <8.0 g/dL)
- Neutropenia (absolute neutrophil count (ANC) <500 cells/mm3). Note: ANC <500
cells/mm3 with absence of myelodysplastic syndrome on bone marrow aspirate and
biopsy and normal marrow cytogenetics are acceptable for eligibility
- Thrombocytopenia (platelet count <50,000 platelets/mm3)
- Prothrombin Time (PT) or International Normalized Ratio (INR) and Partial
thromboplastin time (PTT) >2 times the 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
- Pulmonary abnormality, defined as:
- Resting oxygen (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
- Cardiac abnormality, defined as:
- Abnormal electrocardiogram 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
- Neurologic abnormality, defined as:
- Significant neurologic abnormality revealed by examination
- Uncontrolled seizure disorder
- 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
times the ULN
- Hepatic/gastrointestinal abnormality, defined as:
- Serum transaminases >5 times the ULN
- Serum bilirubin >2 times the ULN
- Serum glucose >1.5 times the ULN
- 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
- Known sensitivity to busulfan
- Confirmation of infectious disease at time of Screening assessment for:
- Human Immunodeficiency Virus (HIV)-1 and HIV-2
- Hepatitis B and Hepatitis C
- Parvovirus B19
- Human T-cell lymphotropic virus (HTLV)-1 and HTLV-2
- Pregnant at the time of Screening
- Affected by a major congenital anomaly
- Likely to require treatment during the study with drugs that are not permitted by the
study protocol
- Previously treated with another form of gene therapy
- Affected by any other condition(s) which, in the opinion of the Principal
Investigator, contraindicate bone marrow harvest, the administration of busulfan and
the infusion of OTL-101, or which indicate an inability of the subject or subject's
parent(s)/legal guardian(s) to comply with the protocol
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