title: Concise review: lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases.
abstract: Thirty years ago, retroviral transfer of genetic material into hematopoietic stem and progenitor cells (HSC/Ps) led to predictions that this technology would transform modern medicine [Nature 1983;305:556-558; Nature 1984;310:476-480]. Studies in several immunodeficiency diseases in the past 15 years have demonstrated clear proof of principle that gene therapy can have long-lasting, potentially curative effects without the need to search for allogeneic donors and without risk of graft-versus-host disease. Improvement in gene transfer efficiency for target HSC/Ps brought to light issues of insertional mutagenesis caused by transfer vectors, resulting in oncogene transactivation and leukemias. Lessons from these adverse events have now led to a new generation of vectors, refinements in conditioning regimens, and manufacturing, which are paving the way for expanded applications of the current technology and recent emphasis on gene targeting/genome editing as the next advancements in the field.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, and Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts, USA; Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000628:therapy*; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D015513:Oncogene Proteins
keywords: Clinical trials; Gene therapy; Hematopoietic cells; Immunodeficiency; Progenitor cells