Article

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
Blood (Impact Factor: 10.43). 09/2012; DOI: 10.1182/blood-2012-02-400937
Source: PubMed

ABSTRACT We conducted a gene therapy trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-deficient SCID) using two slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pre-transplant cytoreduction and remained on ADA enzyme replacement therapy (ERT) throughout the procedure. Only transient (months), low level (<0.01%) gene marking was seen in peripheral blood mononuclear cells (PBMC) of two older subjects (15 and 20 years old), whereas some gene marking of PBMC has persisted for the past nine years in two 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 post-procedure), 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 due to poor gene marking and immune recovery and one had a subsequent allogeneic hematopoietic stem cell transplant. These studies directly demonstrate the importance of providing non-myeloablative pre-transplant conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient SCID.

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