Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
New England Journal of Medicine (Impact Factor: 55.87). 02/2009; 360(5):447-58. DOI: 10.1056/NEJMoa0805817
Source: PubMed


We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.
We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.
All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).
Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. ( numbers, NCT00598481 and NCT00599781.)

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Available from: Abdulaziz Rashed Al-Ghonaium,
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    • "Since the deleterious effects of genetic defects in PIDs are within HSC lineages, ex vivo HSC gene replacement is a rational therapeutic approach (Nienhuis, 2013; Zhang et al., 2013). Genome-integrating viral vectors such as gamma-retroviral vectors and lentiviral vectors have been used to deliver genes into isolated HSCs, and to replace the adenosine deaminase (ADA) gene and the interleukin-2 receptor subunit gamma (IL-2RG) gene for ADA-SCID (Aiuti et al., 2009; Gaspar et al., 2011) and X-linked SCID (Hacein- Bey-Abina et al., 2010), respectively. Although the early clinical trials revealed the risk of insertional mutagenesis due to gamma-retroviral vector integration, lentiviral vector proves to be safer. "
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    • "Hematopoietic stem cell (HSC) targeted gene therapy is potentially curative for various hereditary and acquired diseases, and recent clinical trials have demonstrated efficacy in disorders in which a selective advantage is conferred upon corrected cells [1], [2], [3], [4], [5], [6]. However, further improvement of transduction strategies for human HSCs remains necessary before widespread application. "
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