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This study examined a gene therapy (ADA gene transfer) in children with ADA-deficient severe combined immunodeficiency (ADA-SCID). It was open to children older than 1 month with confirmed ADA-SCID who did not have a suitable matched bone marrow donor. Run by Donald B. Kohn, M.D., the study was conducted in Phase 2 and has been completed.
The summary above is a plain-language rendering of the official record. The original English title is shown for reference.
Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.
Inclusion Criteria:
1. Children \> 1.0 months of age with a diagnosis of ADA-deficient SCID based on:
* Confirmed absence (\<3% of normal levels) of ADA enzymatic activity in peripheral blood or (for neonates) umbilical cord erythrocytes and/or leukocytes, or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of enzyme replacement therapy.
AND
* Evidence of severe combined immunodeficiency based on either:
* Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency,
OR
* Evidence of severe immunologic deficiency in subject based on lymphopenia (absolute lymphocyte count \<200) or severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (deltaCPM\<5,000), prior to institution of immune restorative therapy.
OR
* Fulfillment of criterion:
* A in addition to evidence of genetic mutations affecting the ADA gene as determined by a CLIA certified laboratory and clinical evidence of combined immunodeficiency based on lymphopenia (absolute lymphocyte counts \<2SD of age-matched control values) and hypogammaglobulinemia (\<2SD of age-matched control values) or lack of specific antibody response to vaccination. In addition, for patients to be eligible under this criterion, they must present with a clinical history indicating life-threatening illness characterized by increased frequency and/or severity of infections resulting in hospitalization and/or the administration of intravenous antibiotics, for bacterial or opportunistic infection.
2. Ineligible for allogeneic (matched sibling) bone marrow transplantation (BMT):
* Absence of a medically eligible HLA-identical sibling with normal immune function who may serve as an allogeneic bone marrow donor.
3. Written informed consent according to guidelines of the Institutional Review Board (IRB) at the University of California Los Angeles (UCLA).
This study is also open to delayed/late onset ADA-deficient patients who fulfill the criteria 1, 2.A, and 3 and who are not receiving PEG-ADA treatment after being invited to discuss all alternative treatment options with a physician not connected with the protocol.
Exclusion Criteria:
1. Age less than 1 month
2. Hematologic
a. Anemia (hemoglobin \<10.5 mg/dl at \<2 years of age, or \< 11.5 at \>2 years of age,with normal serum iron studies). b. Neutropenia i. absolute granulocyte count \<500/mm3 or ii. absolute granulocyte count 500-999/mm3 (1 month - 1 year of age) or 500-1499/mm3 (\> 1 year of age)\] and bone marrow aspirate and biopsy showing myelodysplasia or other gross abnormality. c. Thrombocytopenia (platelet count 150,000/mm3, at any age). d. PT or PTT \>2X normal. e. Cytogenetic abnormalities on peripheral blood, or on cells collected by amniocentesis, if diagnosed in utero.
3. Infectious
a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, CMV or parvovirus B 19 by DNA PCR at time of assessment.
4. Pulmonary
1. Resting O2 saturation by pulse oximetry \<95%.
2. Chest x-ray indicating active or progressive pulmonary disease.
5. Cardiac
1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
2. Uncorrected congenital cardiac malformation.
3. Active cardiac disease, including clinical evidence of congestive heart failure,cyanosis, hypotension.
6. Neurologic
1. Significant neurologic abnormality by examination.
2. Uncontrolled seizure disorder.
7. Renal
1. Renal insufficiency: serum creatinine \> or = 1.2 mg/dl, or \> 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 normal.
2. Serum bilirubin \> 3.0 mg/dl.
3. Serum glucose \> 250mg/dl.
4. Intractable severe diarrhea.
9. Oncologic (see below\*)
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. Medically eligible HLA-matched sibling.
5. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate infusion of transduced cells or indicate patient's inability to follow protocol.