Lentivector Transduction Improves Outcomes Over Transplantation of Human HSCs Alone in NOD/SCID/Fabry Mice

Autor: Makoto Yoshimitsu, Jeffrey A. Medin, Nobuo Mizue, Toshihiro Takenaka, Natalia Pacienza, Xin Fan, James C.M. Wang, Bryan Au
Rok vydání: 2012
Předmět:
medicine.medical_treatment
GENE THERAPY
Antigens
CD34
Mice
SCID
Hematopoietic stem cell transplantation
Nod
Kidney
purl.org/becyt/ford/1 [https]
Mice
chemistry.chemical_compound
0302 clinical medicine
Mice
Inbred NOD
Transduction
Genetic
Drug Discovery
purl.org/becyt/ford/3.4 [https]
Lung
0303 health sciences
Trihexosylceramides
Hematopoietic Stem Cell Transplantation
MOUSE MODEL
Bioquímica y Biología Molecular
3. Good health
Liver
Molecular Medicine
purl.org/becyt/ford/3 [https]
Original Article
CIENCIAS NATURALES Y EXACTAS
CIENCIAS MÉDICAS Y DE LA SALUD
FABRY DISEASE
Genetic Vectors
Green Fluorescent Proteins
Congenic
Globotriaosylceramide
Tecnologías que involucran la identificación de ADN
proteínas y enzimas
y cómo influyen en el conjunto de enfermedades y mantenimiento del bienestar
Biology
Biotecnología de la Salud
Cell Line
Ciencias Biológicas
03 medical and health sciences
Genetics
medicine
Animals
Humans
purl.org/becyt/ford/1.6 [https]
Molecular Biology
030304 developmental biology
Pharmacology
Severe combined immunodeficiency
Myocardium
Lentivirus
Kidney metabolism
Genetic Therapy
Hematopoietic Stem Cells
medicine.disease
Fabry disease
Transplantation
chemistry
alpha-Galactosidase
Immunology
TRANSLACIONAL THERAPY
Fabry Disease
Spleen
030217 neurology & neurosurgery
Zdroj: CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
ISSN: 1525-0016
DOI: 10.1038/mt.2012.64
Popis: Fabry disease is a lysosomal storage disorder caused by a deficiency of a-galactosidase A (a-gal A) activity that results in progressive globotriaosylceramide (Gb(3)) deposition. We created a fully congenic nonobese diabetic (NOD)/severe combined immunodeficiency (SCID)/Fabry murine line to facilitate the in vivo assessment of human cell-directed therapies for Fabry disease. This pure line was generated after 11 generations of backcrosses and was found, as expected, to have a reduced immune compartment and background a-gal A activity. Next, we transplanted normal human CD34(+) cells transduced with a control (lentiviral vector-enhanced green fluorescent protein (LV-eGFP)) or a therapeutic bicistronic LV (LV-a-gal A/internal ribosome entry site (IRES)/hCD25). While both experimental groups showed similar engraftment levels, only the therapeutic group displayed a significant increase in plasma a-gal A activity. Gb(3) quantification at 12 weeks revealed metabolic correction in the spleen, lung, and liver for both groups. Importantly, only in the therapeutically-transduced cohort was a significant Gb(3) reduction found in the heart and kidney, key target organs for the amelioration of Fabry disease in humans. Fil: Pacienza, Natalia Alejandra. University Health Network; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Yoshimitsu, Makoto. Kagoshima University; Japón. University Health Network; Canadá Fil: Mizue, Nobuo. University Health Network; Canadá Fil: Au, Bryan C. Y.. University Health Network; Canadá Fil: Wang, James C. M.. University Health Network; Canadá Fil: Fan, Xin. University Health Network; Canadá Fil: Takenaka, Toshihiro. Kagoshima University; Japón Fil: Medin, Jeffrey A. University Health Network; Canadá. University of Toronto; Canadá
Databáze: OpenAIRE
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