Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Autor:	Labrosse R; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.; Division of Allergy and Immunology, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada., Chu JI; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA., Armant MA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Everett JK; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Pellin D; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA., Kareddy N; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Frelinger AL; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Henderson LA; Division of Immunology, Boston Children's Hospital, Boston, MA., O'Connell AE; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA., Biswas A; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA., Coenen-van der Spek J; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Miggelbrink A; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Fiorini C; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Adhikari H; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Berry CC; Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, UC San Diego, La Jolla, CA., Cantu VA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Fong J; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Jaroslavsky J; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Karadeniz DF; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Li QZ; Department of Immunology, Microarray and Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX., Reddy S; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Roche AM; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Zhu C; Department of Immunology, Microarray and Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX., Whangbo JS; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Dansereau C; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA., Mackinnon B; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA., Morris E; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA., Koo SM; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA., London WB; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Baris S; Department of Pediatrics, Division of Allergy and Immunology, Marmara University, Istanbul, Turkey.; The Işıl Berat Barlan Center for Translational Medicine, Marmara University, Istanbul, Turkey., Ozen A; Department of Pediatrics, Division of Allergy and Immunology, Marmara University, Istanbul, Turkey.; The Işıl Berat Barlan Center for Translational Medicine, Marmara University, Istanbul, Turkey., Karakoc-Aydiner E; Department of Pediatrics, Division of Allergy and Immunology, Marmara University, Istanbul, Turkey.; The Işıl Berat Barlan Center for Translational Medicine, Marmara University, Istanbul, Turkey., Despotovic JM; Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX., Forbes Satter LR; Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX., Saitoh A; Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan., Aizawa Y; Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan., King A; Hospital Luis Calvo Mackenna, Clínica Alemana De Santiago Universidad del Desarrollo, Santiago, Chile., Nguyen MAT; Department of Pediatrics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam., Vu VDU; Department of Pediatrics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam., Snapper SB; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA., Galy A; Genethon, Évry, France.; University of Paris-Saclay, University of Évry, INSERM, Genethon, Integrare Research Unit UMR_S951, Évry, France., Notarangelo LD; Division of Immunology, Boston Children's Hospital, Boston, MA.; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Bushman FD; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Williams DA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Pai SY; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Oct 12; Vol. 142 (15), pp. 1281-1296.
DOI:	10.1182/blood.2022019117
Abstrakt:	Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.
Databáze:	MEDLINE
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