title: Ten years of gene therapy for primary immune deficiencies.
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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured / Q000637:transplantation; D002648:Child; D002986:Clinical Trials as Topic; D002999:Clone Cells / Q000473:pathology; D003673:Defective Viruses / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use; D006105:Granulomatous Disease, Chronic / Q000601:surgery / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000453:epidemiology / Q000601:surgery / Q000628:therapy*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D016086:Lentivirus / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D039902:Multipotent Stem Cells / Q000637:transplantation; D016254:Mutagenesis, Insertional; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000601:surgery / Q000628:therapy; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000601:surgery / Q000628:therapy; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency
chemical_list: C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D008562:Membrane Glycoproteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000243:Adenosine Deaminase