Treatment of SCID Due to ADA Deficiency With Autologous Transplantation of Cord Blood or Hematopoietic CD 34+ Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector

NCT02022696 | Completed Phase 1

• 2 other identifiers: 14003814-HG-0038
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This is a clinical gene transfer study that aims to verify the safety and efficacy of the use of the EFS-ADA lentiviral vector to introduce the human adenosine deaminase (ADA) gene into the hematopoietic progenitors of patients affected with severe combined immunodeficiency due to ADA deficiency. The EFS-ADA vector expresses the human ADA cDNA under the control of the elongation factor alpha short promoter (EFS). 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 in the study. To increase engraftment and selected advantage or gene-corrected cells, busulfan will be used as a cytoreductive agent. Enzyme replacement (PEG-ADA) will be discontinued 30 days after infusion of gene-corrected cells. CD34+ hematopoietic progenitors will be isolated from the patient bone marrow, peripheral blood or cord blood, exposed to lentiviral vector-mediated gene transfer and re-infused into the patient through a peripheral vein. Clinical, immunological and molecular follow-up studies will assess safety, toxicity, and efficacy of the procedure.

Conditions

Adenosine Deaminase Deficiency; ADA-SCID

Keywords

Adenosine Deaminase Deficiency; Gene Therapy; Lentiviral Vectors

Outcome Measures

Primary Outcomes (1)

• To examine the safety of autologous transplantation of hematopoietic CD34+ cells transduced with the EFS-ADA lentiviral vector after non-myeloablative conditioning with busulfan and while withholding of PEG-ADA enzyme replacement therapy@@...

  3 years

Interventions

Lentiviral Gene Transfer GENETIC

Eligibility Criteria

• Age: 1 Year - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• I. Children greater than or equal to 1.0 month of age with a diagnosis of ADA-deficient SCID based on:
• A. Confirmed absence (\<3% of normal levels) of ADA enzymatic activity in peripheral blood or (for neonates) umbilical cord erythrocytes and/or leukocytes, skin fibroblasts or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of enzyme replacement therapy.
• AND
• B. 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 prior to institution of immune restorative therapy, based on lymphopenia (absolute lymphocyte count \<200/microliters) or severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (DeltaCPM\<5,000),
• II. Ineligible for matched sibling allogeneic bone marrow transplantation due to absence of a medically eligible HLA-identical sibling with normal immune function who may serve as an allogeneic bone marrow donor.
• III. Signed written informed consent according to guidelines of the UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) Institutional Review Boards.
• It is a policy of the NIH Clinical Center not to admit patients younger than 1 year of age and weighing less than 10 kg because of the inadequacy of the existing emergency and intensive care services for very young children. We will comply with such policy.

You may not qualify if:

• Age less than or equal to 1.0 months
• Hematologic
• Anemia (hemoglobin \< 10.5 g/dl at \< 2 years of age, or \< 11.5 g/dl at \> 2 years of age).
• Neutropenia (absolute granulocyte count \<500/mm(3). If ANC\< 1,000, absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics.
• Thrombocytopenia (platelet count \< 150,000/mm(3), at any age).
• PT or PTT \> 2 times the upper limits of normal (patients with a correctable deficiency controlled on medication will not be excluded).
• Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
• Infectious
• a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, CMV or parvovirus B 19 by DNA PCR within 30-90 days prior to bone marrow harvest.
• Pulmonary
• Resting O2 saturation by pulse oximetry \< 95% on room air.
• Chest x-ray indicating active or progressive pulmonary disease.
• Cardiac
• Abnormal electrocardiogram (EKG) indicating cardiac pathology.
• Uncorrected congenital cardiac malformation with clinical symptomatology.

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead
• UCLA@@@Duke University Medical Center: collaborator
• Duke Univ. Medical Center: collaborator
• National Cancer Institute (NCI): collaborator
• National Institutes of Health Clinical Center (CC): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. N Engl J Med. 1995 Aug 17;333(7):431-40. doi: 10.1056/NEJM199508173330707. No abstract available.

  PMID: 7616993 BACKGROUND

• Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067-9. doi: 10.1016/s0140-6736(72)92345-8. No abstract available.

  PMID: 4117384 BACKGROUND

• Parkman R, Gelfand EW, Rosen FS, Sanderson A, Hirschhorn R. Severe combined immunodeficiency and adenosine deaminase deficiency. N Engl J Med. 1975 Apr 3;292(14):714-9. doi: 10.1056/NEJM197504032921402.

  PMID: 1089883 BACKGROUND

MeSH Terms

Conditions

Severe combined immunodeficiency due to adenosine deaminase deficiency

Study Officials

• Elizabeth K Garabedian, R.N.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2013
• First Posted: December 30, 2013
• Study Start: December 16, 2013
• Primary Completion: December 16, 2013
• Study Completion: September 21, 2017
• Last Updated: September 27, 2017

Record last verified: 2017-09-21

Locations

US (1)