NCT00794508

MND-ADA Transduction of CD34+ Cells From the Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID): Effect of Discontinuation of PEG-ADA and Marrow Cytoreduction With Busulfan

Completed Phase 2 Results posted Last updated 21 April 2021

What this trial tests

Phase 2 trial testing ADA gene transfer in Severe Combined Immunodeficiency in 10 participants. Completed in 1 January 2015.

Timeline

1 November 2008

Primary endpoint
1 December 2014

1 January 2015

Quick facts

Lead sponsor	Donald B. Kohn, M.D.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	10
Start date	1 November 2008
Primary completion	1 December 2014
Estimated completion	1 January 2015
Sites	1 location across United States

Drugs / interventions tested

• ADA gene transfer — full drug profile →

Conditions studied

• Severe Combined Immunodeficiency — all drugs for Severe Combined Immunodeficiency →

Sponsor

Donald B. Kohn, M.D. — full company profile →

Who can join

Adults 1 Month to 18, any sex, with Severe Combined Immunodeficiency. Patients with the condition only — healthy volunteers not accepted.

What's being measured

Primary outcomes are the specific endpoints the trial is designed to prove or disprove.

• Number of Participants With Adverse Events
  Time frame: 2 years
  Examine the safety of the procedure: harvesting bone marrow, isolating CD34+ hematopoietic stem/progenitor cells, performing ex vivo gene transduction with the MND-ADA gamma-retroviral vector, giving 90 mg/m2 busulfan to "make space" in the bone marrow to aid engraftment, and re-infusing the autologous gene-modified cells.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.
   Candotti F, Shaw KL, Muul L, Carbonaro D, et al · · 2012 · cited 162× · PMID 22968453 · DOI 10.1182/blood-2012-02-400937
2. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders.
   Tucci F, Galimberti S, Naldini L, Valsecchi MG, et al · · 2022 · cited 109× · PMID 35288539 · DOI 10.1038/s41467-022-28762-2
3. Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency.
   Shaw KL, Garabedian E, Mishra S, Barman P, et al · · 2017 · cited 70× · PMID 28346229 · DOI 10.1172/jci90367
4. Clinical applications of gene therapy for primary immunodeficiencies.
   Cicalese MP, Aiuti A. · · 2015 · cited 53× · PMID 25860576 · DOI 10.1089/hum.2015.047
5. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.
   Reinhardt B, Habib O, Shaw KL, Garabedian E, et al · · 2021 · cited 43× · PMID 33974038 · DOI 10.1182/blood.2020010260
6. Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients.
   Cooper AR, Lill GR, Shaw K, Carbonaro-Sarracino DA, et al · · 2017 · cited 26× · PMID 28351939 · DOI 10.1182/blood-2016-12-756734
7. Gene therapy for primary immunodeficiencies: looking ahead, toward gene correction.
   Pessach IM, Notarangelo LD. · · 2011 · cited 22× · PMID 21440291 · DOI 10.1016/j.jaci.2011.02.027
8. Treatment of primary immunodeficiency with allogeneic transplant and gene therapy.
   Pai SY. · · 2019 · cited 20× · PMID 31808905 · DOI 10.1182/hematology.2019000052