This study will evaluate a new method for delivering gene transfer therapy to patients with
severe combined immunodeficiency disease (SCID) due to a defective adenosine deaminase (ADA)
gene. This gene codes for the adenosine deaminase enzyme, which is essential for the proper
growth and function of infection-fighting white blood cells called T and B lymphocytes.
Patients who lack this enzyme are vulnerable to frequent and severe infections.
Some patients with this disease receive enzyme replacement therapy with weekly injections of
the drug PEG-ADA (ADAGEN). This drug may increase the number of immune cells and reduce
infections, but it is not a cure. Gene transfer therapy, in which a normal ADA gene is
inserted into the patient s cells, attempts to correct the underlying cause of disease. This
therapy has been tried in a small number of patients with varying degrees of success. In this
study, the gene will be inserted into the patient s stem cells (cells produced by the bone
marrow that mature into the different blood components white cells, red cells and platelets).
Patients with ADA deficiency and SCID who are taking PEG-ADA and are not candidates for
HLA-identical sibling donor bone marrow transplantation may be eligible for this study.
Participants will be admitted to the NIH Clinical Center for 2 to 3 days. Stem cells will be
collected either from cord blood (in newborn patients) or from the bone marrow. The bone
marrow procedure is done under light sedation or general anesthesia. It involves drawing a
small amount of marrow through a needle inserted into the hip bone. The stem cells in the
marrow will be grown in the laboratory and a normal human ADA gene will be transferred into
them through a special type of disabled mouse virus. A few days later, the patient will
receive the ADA-corrected cells through an infusion in the vein that will last from 10
minutes to 2 hours.
Patients will be evaluated periodically for immune function with blood tests, skin tests, and
reactions to tetanus, diphtheria, H. influenza B and S. pneumoniae vaccinations. The survival
of ADA-corrected cells will be monitored through blood tests. The number and amount of blood
tests will depend on the patient s age, weight and health, but is expected that blood will
not be drawn more than twice a month. Patients will also undergo bone marrow biopsy aspirate
(as described above) twice a year. Patients will be followed once a year indefinitely to
evaluate the long-term effects of therapy.
This is a clinical gene transfer study that aims to verify the safety and efficacy of the use
of retroviral vectors to introduce the human adenosine deaminase (ADA) gene into the
hematopoietic progenitors of patients affected with severe combined immunodeficiency due to
ADA deficiency. In addition, this protocol will examine the effects of the ADA gene transfer
on the immune system of treated patients. Patients with ADA deficiency and ineligible for
matched sibling allogeneic bone marrow transplantation are eligible to participate to the
study. To increase engraftment and selective advantage of gene-corrected cells, busulfan will
be used as cytoreduction agent and enzyme replacement (PEG-ADA) therapy will be discontinued.
CD34+ hematopoietic progenitors will be isolated from the patient bone marrow or cord blood,
exposed to retroviral vector-mediated gene transfer and reinfused into the patient through a
peripheral vein. Clinical, immunological and molecular follow-up studies will assess safety,
toxicity, and efficacy of the procedure.
- 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
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.
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
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
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)
1. Absence of a medically eligible HLA-identical sibling with normal immune function who
may serve as an allogenic bone marrow donor
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
a. Age less than 1 month
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).
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
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.
a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B,
CMV or parvovirus B19 by DNA PCR at time of assessment.
1. Resting O2 saturation by pulse oximetry less than 95%.
2. Chest X-ray indicating active or progressive pulmonary disease.
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.
1. Significant neurologic abnormality by examination.
2. Uncontrolled seizure disorder.
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.
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.
a. Evidence of active malignant disease other than dermatofibrosarcoma protuberans
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.