RNA-based gene therapy for HIV with lentiviral vector-modified CD34 + cells in patients undergoing transplantation for AIDS-related lymphoma

Science Translational Medicine

Volumn 2, Issue 36, 2010, Pages

  DiGiusto, David L ^a   Krishnan, Amrita ^a   Li, Lijing ^a   Li, Haitang ^a   Li, Shirley ^a   Rao, Anitha ^a   Mi, Shu ^b   Yam, Priscilla ^a   Stinson, Sherri ^c   Kalos, Michael ^d   Alvarnas, Joseph ^a   Lacey, Simon F ^b   Yee, Jiing Kuan ^a   Li, Mingjie ^e   Couture, Larry ^a,f   Hsu, David ^f   Forman, Stephen J ^a   Rossi, John J ^a   Zaia, John A ^a  

^a Department of Hematology and Hematopoietic Cell Transplantation ^*  (United States)

^b Clinical Immunobiology Correlative Studies Laboratory   (United States)

^c General Clinical Research Center   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

^e WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f Center for Applied Technology Development   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD34 ANTIGEN; CHEMOKINE RECEPTOR CCR5; LENTIVIRUS VECTOR; SHORT HAIRPIN RNA; SMALL INTERFERING RNA; TAR DNA BINDING PROTEIN; RNA;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ADULT; APHERESIS; ARTICLE; AUTOTRANSPLANTATION; CD34 SELECTION; CELL LINEAGE; CLINICAL ARTICLE; CLINICAL EFFECTIVENESS; CLINICAL TRIAL; CONTROLLED STUDY; DISEASE ASSOCIATION; DNA MODIFICATION; EXON; GENE EXPRESSION PROFILING; GENE TARGETING; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; MALE; NONHODGKIN LYMPHOMA; PRIORITY JOURNAL; PROCESS DEVELOPMENT; RIBOZYME THERAPY; STEM CELL GENE THERAPY; VIRAL GENE DELIVERY SYSTEM; VIRUS LOAD; B CELL LYMPHOMA; FEMALE; GENE THERAPY; GENE VECTOR; GENETICS; METHODOLOGY; MIDDLE AGED; TREATMENT OUTCOME;

ADULT; FEMALE; GENE THERAPY; GENETIC VECTORS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HIV INFECTIONS; HUMANS; LYMPHOMA, AIDS-RELATED; MALE; MIDDLE AGED; RNA; TREATMENT OUTCOME;

EID: 77955608799     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3000931     Document Type: Article

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43. Acknowledgments: We thank N. Gonzalez and A. Ahmed (Division of Hematology) for Quality Systems support; L.-F. Cao (CPDM Laboratory) for quality control release testing; G. Duarte and M. Wardlow (Division of Hematology) for patient care; C. Arbayo for assistance in patient consenting; S. Broyer and R. Stan (Center for Applied Technology Development) for assistance with the IND application and other regulatory applications; C.-A. Tran and L. Brown for assistance with cell sorting; A. Levine for her advice and encouragement; and the staff at Benitec Ltd., especially K. Reed and S. MacLeman, for continuing support in the preclinical and clinical phases of this project. Funding: NIH grants AI42552 and HL07470 (J.J.R.), P50 CA107399 (Lymphoma SPORE), P30 CA33572-26 (Cancer Center Support Grant) (S.J.F.), and AI61839 (J.A.Z.); National Center for Research Resources grant S10RR025083-01 (D.L.D.); and General Clinical Research Center grant M01 RR00043 (J.A.Z.). A grant from Benitec Ltd. supported vector manufacture, process development, and a portion of the clinical trial. Author contributions: D.L.D. developed and supervised cell manufacturing operations and in vitro correlative studies, interpreted the data, and wrote the manuscript. A.K. was responsible for trial design, patient recruiting, enrollment, and treatment on trial and wrote the manuscript. L.L., A.R., and P.Y. performed manufacturing of cell products and in vitro correlative assays. S.L. performed sample processing and distribution. H.L. performed RNA analysis on in vitro and in vivo samples. S.S. performed manufacturing operations. J.-K.Y. conceived and developed the vector production system. L.C. and D.H. manufactured lentiviral vectors. J.J.R. conceived and designed the triple-gene vector, supervised the development of the siRNA and CCR5 ribozyme assays from clinical samples, and wrote the manuscript. M.L. constructed the clinical vector and assisted in optimizing vector production strategies. M.K. supervised the development and qualification of the in vivo gene-marking assays and product release testing. S.M. performed the in vivomarking assays. J.A. participated in the study design and patient follow-up. S.F.L. supervised in vivo gene-marking assays. S.J.F. conceptualized and designed clinical studies. J.A.Z. coordinated the clinical, laboratory, and regulatory processes; interpreted the data; and wrote the manuscript. Competing interests: J.J.R. is a Scientific Advisory Board member of Benitec Inc., which supported vector production and some clinical costs for this trial. The other authors have no competing interests.