Journal
BLOOD
Volume 120, Issue 18, Pages 3635-3646Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-02-400937
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Funding
- Clinical Research Award from the Saban Research Institute of Children's Hospital Los Angeles, a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation
- NHLBI SCOR grant [1P50 HL54850]
- FDA [1 RO1 FD003005]
- UCLA GCRC [MO1 RR000865]
- Sigma-Tau Pharmaceuticals
- NHGRI
- NIDDK
- NCI
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We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency. (Blood. 2012;120(18):3635-3646)
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