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Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease.
Urbinati, Fabrizia; Wherley, Jennifer; Geiger, Sabine; Fernandez, Beatriz Campo; Kaufman, Michael L; Cooper, Aaron; Romero, Zulema; Marchioni, Filippo; Reeves, Lilith; Read, Elizabeth; Nowicki, Barbara; Grassman, Elke; Viswanathan, Shivkumar; Wang, Xiaoyan; Hollis, Roger P; Kohn, Donald B.
Afiliación
  • Urbinati F; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Wherley J; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Geiger S; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Fernandez BC; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Kaufman ML; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Cooper A; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Romero Z; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Marchioni F; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Reeves L; Translational Core Laboratory, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Read E; Consultant, San Francisco, California, USA.
  • Nowicki B; UCLA BM/Stem Cell Transplant Laboratory, University of California, Los Angeles, USA.
  • Grassman E; Translational Trials Development and Support Labs, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Viswanathan S; Translational Trials Development and Support Labs, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Wang X; Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, USA.
  • Hollis RP; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
  • Kohn DB; Department of Microbiology, Immunology and Molecular Genetics and the Eli & Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA. Electronic address: e-dkohn@mednet.ucla.edu.
Cytotherapy ; 19(9): 1096-1112, 2017 09.
Article en En | MEDLINE | ID: mdl-28733131
ABSTRACT
BACKGROUND

AIMS:

Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials.

METHODS:

Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/ßAS3-FB vector and cryopreserving CD34+ cells from human bone marrow (BM) at clinical scale. In vitro and in vivo characterization of the FCP was performed, showing that all the release criteria were successfully met. In vivo toxicology studies were conducted to evaluate potential toxicity of the Lenti/ßAS3-FB LV in the context of a murine BM transplant.

RESULTS:

Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/ßAS3-FB vector in cells from primary and secondary transplanted mice.

CONCLUSIONS:

We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Terapia Genética / Trasplante de Células Madre Hematopoyéticas / Anemia de Células Falciformes Tipo de estudio: Clinical_trials / Guideline / Observational_studies Límite: Adult / Animals / Humans Idioma: En Revista: Cytotherapy Asunto de la revista: TERAPEUTICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Terapia Genética / Trasplante de Células Madre Hematopoyéticas / Anemia de Células Falciformes Tipo de estudio: Clinical_trials / Guideline / Observational_studies Límite: Adult / Animals / Humans Idioma: En Revista: Cytotherapy Asunto de la revista: TERAPEUTICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos