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Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.


ABSTRACT: We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

SUBMITTER: Candotti F 

PROVIDER: S-EPMC3488882 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

Candotti Fabio F   Shaw Kit L KL   Muul Linda L   Carbonaro Denise D   Sokolic Robert R   Choi Christopher C   Schurman Shepherd H SH   Garabedian Elizabeth E   Kesserwan Chimene C   Jagadeesh G Jayashree GJ   Fu Pei-Yu PY   Gschweng Eric E   Cooper Aaron A   Tisdale John F JF   Weinberg Kenneth I KI   Crooks Gay M GM   Kapoor Neena N   Shah Ami A   Abdel-Azim Hisham H   Yu Xiao-Jin XJ   Smogorzewska Monika M   Wayne Alan S AS   Rosenblatt Howard M HM   Davis Carla M CM   Hanson Celine C   Rishi Radha G RG   Wang Xiaoyan X   Gjertson David D   Yang Otto O OO   Balamurugan Arumugam A   Bauer Gerhard G   Ireland Joanna A JA   Engel Barbara C BC   Podsakoff Gregory M GM   Hershfield Michael S MS   Blaese R Michael RM   Parkman Robertson R   Kohn Donald B DB  

Blood 20120911 18


We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age  ...[more]

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