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ADA-SCID Clinical Abstracts

The clinical papers listed below, in chronological order, provide an overview of important studies regarding SCID and ADA-SCID research and clinical trials. A brief summary is provided with each citation.

Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase
Hershfield MS, Buckley RH, Greenberg ML, et al. N Engl J Med. 1987;316(10):589-596.

This groundbreaking clinical paper was the first published report of the use of polyethylene glycol-modified adenosine deaminase (PEG-ADA) for the treatment of ADA-SCID. The authors describe the successful treatment of 2 patients.

Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99
Antoine C, Mülle S, Cant K, et al; for the European Group for Blood and Marrow Transplantation and the European Society for Immunodeficiency. Lancet. 2003;361:553–560.

This retrospective study reports on data gathered from 37 European medical centers in 18 countries in patients with SCID (n=475) and other immunodeficiency diseases (n=444). The objectives of the study were to measure 3-year survival rates for patients who had undergone stem cell transplantation. The results showed that patients with an HLA-matched donor had a higher 3-year survival rate (77%) versus the mismatched patients (54%) (P=0.002).

The multiple causes of human SCID
Buckley R. J Clin Invest. 2004;114:1409–1411.

This commentary provides an overview of the genetic causes of SCID, including ADA-SCID. Disease incidence of different types of SCID is provided.

Bone marrow transplantation for severe combined immune deficiency
Grunebaum E, Mazzolari E, Porta F, et al. JAMA. 2006;295:508-518.

This retrospective study compared success rates for different types of bone marrow transplant, related HLA-identical donors (RID), HLA-matched unrelated donors (MUD), and HLA-mismatched related donors (MMRD). The main outcome measure was 2-year survival. The results showed that survival was highest for RID (92.3%), followed by MUD (80.5%) and MMRD (52.5%). The authors conclude that if there is no HLA identical relative, MUD may offer a better results and a better chance of survival versus MMRD.

Update on clinical gene therapy in childhood
Qasim W, Gaspar HB, Thrasher AJ. Arch Dis Child. 2007;92:1028–1031.

This brief article reviews gene therapy for ADA-SCID and SCID-X1, complications that have arisen with gene therapy, and prospects for future development of the therapy.

Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients
Cassani B, Mirolo M, Cattaneo F. Blood. 2008;111:4209-4219.

The authors of this study investigate the molecular events underlying the immunologic defect of T cells in ADA-SCID patients. They present new information about the relative contribution of intracellular versus extracellular mechanisms of lymphotoxicity in ADA-SCID.

Towards a rAAV-based gene therapy for ADA-SCID: from ADA deficiency to current and future treatment strategies
Silver JN, Flotte TR. Pharmocogenomics. 2008;9:947-968.

This review article briefly summarizes enzyme replacement therapy and bone marrow transplant, and then engages in a more detailed overview of developments in gene therapy for ADA-SCID. The authors propose the vector rAAV for use in gene therapy for this disease, and discuss published and ongoing research to support their approach.

Gene therapy for immunodeficiency due to adenosine deaminase deficiency
Aiuti A, Cattaneo F, Galimberti S, et al. N Engl J Med. 2009;360:447-458.

This study is an extension of the first successful gene therapy trial for ADA-SCID (first reported in 2002). The study investigated the long-term outcome of gene therapy in 10 ADA-SCID patients who did not receive enzyme replacement therapy after receiving gene therapy. The patients were followed for 4 years. Eight patients had successful grafting of transplanted stem cells and did not require additional enzyme replacement therapy.

How I treat ADA deficiency
Gaspar HB, Aiuti A, Porta F, et al. Blood. 2009;114:3524-3532.

In this article, Gaspar reviews the data for currently available treatment options for ADA-SCID, including the results of his own experience in treating the disease. He discusses the factors that influence the decision on how to treat an individual patient, and offers recommendations for a general approach to treating the disease.

Update on gene therapy for immunodeficiencies
Kohn DB. Clin Immunol. 2010;135(2):247-254.

A review of new approaches using safer integrating vectors or direct correction of the defective gene underlying the PID are being developed and may lead to safer and effective gene therapy for PID.

Genotoxicity of retroviral hematopoietic stem cell gene therapy
Trobridge GD. Expert Opin Biol Ther. 2011;11(5):581-593.

This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced. Expert opinion: Continued research on virus-host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols.

Bone marrow transplantation and alternatives for adenosine deaminase deficiency
Gaspar HB. Immunol Allergy Clin North Am. 2010;30(2):221-236.

In this article Gaspar reviews the available data on the different treatment options, and offers an overview on when each of the different treatment options should be used.