ADA Gene Therapy

About this trial

Last updated 4 years ago

Study ID

ADA Gene Therapy

Status

Completed

Type

Interventional

Phase

Phase 2

Placebo

Accepting

1 to 18 Years

All

Not accepting

Healthy Volunteers

Trial Timing

Ended 11 years ago

Severe combined immune deficiency (SCID) may result from inherited deficiency of the enzyme adenosine deaminase (ADA). Children with ADA-deficient SCID often die from infections in infancy, unless treated with either a bone marrow transplant or with ongoing injections of PEG-ADA (Adagen) enzyme replacement therapy. Successful BMT requires the availability of a matched sibling donor for greatest success, and treatment using bone marrow from a less-well matched donor may have a higher rate of complications. PEG-ADA may restore and sustain immunity for many years, but is very expensive and requires injections 1-2 times per week on an ongoing basis. This clinical trial is evaluating the efficacy and safety of an alternative approach, by adding a normal copy of the human ADA gene into stem cells from the bone marrow of patients with ADA-deficient SCID. Eligible patients with ADA-deficient SCID, lacking a matched sibling donor, will be eligible if they meet entry criteria for adequate organ function and absence of active infections and following the informed consent process. Bone marrow will be collected from the back of the pelvis from the patients and processed in the laboratory to isolate the stem cells and add the human ADA gene using a retroviral vector. The patients will receive a moderate dosage of busulfan, a chemotherapy agent that eliminates some of the bone marrow stem cells in the patient, to "make space" for the gene-corrected stem cells to grow once they are given back by IV. Patients will be followed for two years to assess the potentially beneficial effects of the procedure on the function of their immune system and to assess possible side-effects. This gene transfer approach may provide a better and safer alternative for treatment of patients with ADA-deficient SCID.

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.

MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID