In vivo delivery of human acid ceramidase via cord blood transplantation and direct injection of lentivirus as novel treatment approaches for Farber disease

Autor: Thierry Levade, Jeffrey A. Medin, Stéphane Carpentier, Takahiro Nonaka, Carmen Bedia Girbés, Shobha Ramsubir
Přispěvatelé: Department of Medical Biophysics (MBP), University of Toronto, Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institute of Medical Science, Simon, Marie Francoise
Jazyk: angličtina
Rok vydání: 2008
Předmět:
Palliative care
Acid Ceramidase
MESH: Mice
Inbred NOD
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Genetic enhancement
MESH: Interleukin-2 Receptor alpha Subunit
Mice
SCID
Hematopoietic stem cell transplantation
Biochemistry
MESH: Hematopoietic Stem Cells
Mice
Endocrinology
Mice
Inbred NOD
MESH: Genetic Vectors
Lysosomal storage disease
MESH: Animals
MESH: Mice
SCID
Cells
Cultured
MESH: Lentivirus
Farber disease
MESH: Farber Lipogranulomatosis
Hematopoietic Stem Cell Transplantation
Cord Blood Stem Cell Transplantation
MESH: Cord Blood Stem Cell Transplantation
MESH: Cells
Cultured
Genetic Vectors
MESH: Acid Ceramidase
Biology
Ceramides
Article
Cell Line
In vivo
MESH: Mice
Inbred C57BL
Genetics
medicine
Animals
Humans
Progenitor cell
Molecular Biology
MESH: Mice
MESH: Hematopoietic Stem Cell Transplantation
MESH: Humans
Lentivirus
Interleukin-2 Receptor alpha Subunit
Genetic Therapy
Fibroblasts
Hematopoietic Stem Cells
medicine.disease
Molecular biology
MESH: Ceramides
MESH: Cell Line
Mice
Inbred C57BL
Farber Lipogranulomatosis
MESH: Fibroblasts
Cancer research
MESH: Gene Therapy
Zdroj: Molecular Genetics and Metabolism
Molecular Genetics and Metabolism, 2008, 95 (3), pp.133-41. ⟨10.1016/j.ymgme.2008.08.003⟩
ISSN: 1096-7192
1096-7206
DOI: 10.1016/j.ymgme.2008.08.003⟩
Popis: International audience; Farber disease is a rare lysosomal storage disorder (LSD) caused by a deficiency of acid ceramidase (AC) activity and subsequent accumulation of ceramide. Currently, there is no treatment for Farber disease beyond palliative care and most patients succumb to the disorder at a very young age. Previously, our group showed that gene therapy using oncoretroviral vectors (RV) could restore enzyme activity in Farber patient cells. The studies described here employ novel RV and lentiviral (LV) vectors that engineer co-expression of AC and a cell surface marking transgene product, human CD25 (huCD25). Transduction of Farber patient fibroblasts and B cells with these vectors resulted in overexpression of AC and led to a 90% and 50% reduction in the accumulation of ceramide, respectively. Vectors were also evaluated in human hematopoietic stem/progenitor cells (HSPCs) and by direct in vivo delivery in mouse models. In a xenotransplantation model using NOD/SCID mice, we found that transduced CD34(+) cells could repopulate irradiated recipient animals, as measured by CD25 expression. When virus was injected intravenously into mice, soluble CD25 was detected in the plasma and increased AC activity was present in the liver up to 14 weeks post-injection. These findings suggest that vector and transgene expression can persist long-term and offer the potential of a lasting cure. To our knowledge, this is the first report of in vivo testing of direct gene therapy strategies for Farber disease.
Databáze: OpenAIRE
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