Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency

Plain-language summary

This study evaluates a gene transfer therapy (CD34+ cells with the ADA gene inserted) in Severe Combined Immunodeficiency (SCID) caused by Adenosine Deaminase (ADA) enzyme deficiency. It included patients with confirmed ADA deficiency and immunodeficiency. It was a Phase 1 study and has been completed.

The summary above is a plain-language rendering of the official record. The original English title is shown for reference.

Trial details

Phase

Phase 1

Status

Completed

Sponsor

National Human Genome Research Institute (NHGRI)

Intervention

CD34+ cells transduced with ADA retrovir

Start date

6/20/2001

Estimated completion

9/17/2014

Countries

United States

Related genes

Locations

• Bethesda, United States

Eligibility criteria

Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.

* INCLUSION CRITERIA:

Patients will be enrolled into this study if they fulfill the following three criteria:

A. Patients of age greater than or equal to 1 month with a diagnosis of ADA-deficiency based on:

1. Confirmed absence (less than 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
2. 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 less than 200) or severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (cpm less than 5,000) prior to institution of immune restorative therapy

   OR
3. Evidence of genetic mutations affecting the ADA gene as determined by the CLIA certified laboratory and clinical evidence of combined immunodeficiency based on lymphopenia (absolute lymphocyte counts less than 2SD of age-matched control values) and hypogammaglobulinemia (less than 2SD of age-matched control values) or lack of specific antibody response to vaccination. Evidence of life-threatening illness (increased frequency and/or severity of infections resulting in hospitalization and/or the administration of intravenous antibiotics) is necessary for patients to be eligible under this criterion.

B. Patients ineligible for allogeneic (matched sibling) bone marrow transplantation (BMT) based on:

1. Absence of a medically eligible HLA-identical sibling with normal immune function who may serve as an allogenic bone marrow donor

   OR
2. Election by the parents or the adult patients to forgo allogeneic BMT in favor of PEG-ADA enzyme therapy after being invited to discuss alternative treatment options with a physician not connected with the protocol.

   C. Written informed consent according to guidelines of the NHGRI IRB, NIH or the Committee on Clinical Investigations (CCI) at Children's Hospital Los Angeles (CHLA).

   This study is also open to delayed/late onset ADA-deficient patients who fulfill the criteria A, B.1, and C 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:

   Age:

   a. Age less than 1 month

   Hematologic:
   1. Anemia (hemoglobin less than 10.5 mg/dl, for subjects 2 years of age or less or hemoglobin less than 11.5 mg/dl for subjects older than 2 years of age in the presence of normal iron studies).
   2. Neutropenia

   i. absolute granulocyte count \<500/mm (3) or

   ii. absolute granulocyte count 500-999/mm (3) (ages 1-12 months) or 500-1,499/mm (3) for ages \>1 year) and bone marrow studies showing myelodysplasia or other gross abnormalities.

   c. Thrombocytopenia (platelet count less than 150,000 mm(3) at any age)

   d. PT or PTT greater than 2 times normal.

   e. Cytogenic abnormalities on peripheral blood.

   Infectious:

   a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, CMV or parvovirus B19 by DNA PCR at time of assessment.

   Pulmonary:
   1. Resting O2 saturation by pulse oximetry less than 95%.
   2. Chest X-ray indicating active or progressive pulmonary disease.

   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, or hypotension.

   Neurologic:
   1. Significant neurologic abnormality by examination.
   2. Uncontrolled seizure disorder.

   Renal:
   1. Renal insufficiency: for pediatric patients serum creatinine greater than or equal to 1.2 mg/dl, or greater than or equal to 3+ proteinuria, for adults values at grades greater than or equal to of the NCI Common Toxicity Criteria (CTC).
   2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by DAIDS Toxicity Scale or NCI CTC.

   Hepatic/Gl:
   1. Serum transaminases greater than 5 times normal.
   2. Serum bilirubin greater than 3.0 mg/dl.
   3. Serum glucose greater than 250 mg/dl.
   4. Intractable severe diarrhea.

   Oncologic:

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

   General:
   1. Expected survival less than 6 months.
   2. Major congenital anomaly.
   3. Subject pregnant.
   4. Medically eligible HLA-identical sibling available.
   5. Known hypersensitivity to busulfan.
   6. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate infusion of transduced cells or ability to follow protocol.