Ten years of gene therapy for primary immune deficiencies

Hematology Am Soc Hematol Educ Program. 2009:682-9. doi: 10.1182/asheducation-2009.1.682.

Abstract

Gene therapy with hematopoietic stem cells (HSC) is an attractive therapeutic strategy for several forms of primary immunodeficiencies. Current approaches are based on ex vivo gene transfer of the therapeutic gene into autologous HSC by vector-mediated gene transfer. In the past decade, substantial progress has been achieved in the treatment of severe combined immundeficiencies (SCID)-X1, adenosine deaminase (ADA)-deficient SCID, and chronic granulomatous disease (CGD). Results of the SCID gene therapy trials have shown long-term restoration of immune competence and clinical benefit in over 30 patients. The inclusion of reduced-dose conditioning in the ADA-SCID has allowed the engraftment of multipotent gene-corrected HSC at substantial level. In the CGD trial significant engraftment and transgene expression were observed, but the therapeutic effect was transient. The occurrence of adverse events related to insertional mutagenesis in the SCID-X1 and CGD trial has highlighted the limitations of current retroviral vector technology. For future applications the risk-benefit evaluation should include the type of vector employed, the disease background and the nature of the transgene. The use of self-inactivating lentiviral vectors will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events. Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Deaminase / deficiency
  • Animals
  • Cell Transformation, Neoplastic
  • Cells, Cultured / transplantation
  • Child
  • Clinical Trials as Topic
  • Clone Cells / pathology
  • Defective Viruses / genetics
  • Disease Models, Animal
  • Genetic Therapy* / adverse effects
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics
  • Genetic Vectors / therapeutic use
  • Granulomatous Disease, Chronic / surgery
  • Granulomatous Disease, Chronic / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Immunologic Deficiency Syndromes / epidemiology
  • Immunologic Deficiency Syndromes / surgery
  • Immunologic Deficiency Syndromes / therapy*
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Lentivirus / genetics
  • Membrane Glycoproteins / deficiency
  • Mice
  • Multipotent Stem Cells / transplantation
  • Mutagenesis, Insertional
  • NADPH Oxidase 2
  • NADPH Oxidases / deficiency
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / surgery
  • Severe Combined Immunodeficiency / therapy
  • Wiskott-Aldrich Syndrome / genetics
  • Wiskott-Aldrich Syndrome / surgery
  • Wiskott-Aldrich Syndrome / therapy
  • Wiskott-Aldrich Syndrome Protein / deficiency

Substances

  • IL2RG protein, human
  • Interleukin Receptor Common gamma Subunit
  • Membrane Glycoproteins
  • WAS protein, human
  • Wiskott-Aldrich Syndrome Protein
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Adenosine Deaminase