Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina
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Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina. / Jung, Gila; Sun, Jing; Petrowitz, Bettina; Riecken, Kristoffer; Kruszewski, Katharina; Jankowiak, Wanda; Kunst, Frank; Skevas, Christos; Richard, Gisbert; Fehse, Boris; Bartsch, Udo.
in: STEM CELL TRANSL MED, Jahrgang 2, Nr. 12, 01.12.2013, S. 1001-10.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina
AU - Jung, Gila
AU - Sun, Jing
AU - Petrowitz, Bettina
AU - Riecken, Kristoffer
AU - Kruszewski, Katharina
AU - Jankowiak, Wanda
AU - Kunst, Frank
AU - Skevas, Christos
AU - Richard, Gisbert
AU - Fehse, Boris
AU - Bartsch, Udo
PY - 2013/12/1
Y1 - 2013/12/1
N2 - A continuous intraocular delivery of neurotrophic factors (NFs) is being explored as a strategy to rescue photoreceptor cells and visual functions in degenerative retinal disorders that are currently untreatable. To establish a cell-based intraocular delivery system for a sustained administration of NFs to the dystrophic mouse retina, we used a polycistronic lentiviral vector to genetically modify adherently cultivated murine neural stem (NS) cells. The vector concurrently encoded a gene of interest, a reporter gene, and a resistance gene and thus facilitated the selection, cloning, and in vivo tracking of the modified cells. To evaluate whether modified NS cells permit delivery of functionally relevant quantities of NFs to the dystrophic mouse retina, we expressed a secretable variant of ciliary neurotrophic factor (CNTF) in NS cells and grafted the cells into the vitreous space of Pde6b(rd1) and Pde6b(rd10) mice, two animal models of retinitis pigmentosa. In both mouse lines, grafted cells attached to the retina and lens, where they differentiated into astrocytes and some neurons. Adverse effects of the transplanted cells on the morphology of host retinas were not observed. Importantly, the CNTF-secreting NS cells significantly attenuated photoreceptor degeneration in both mutant mouse lines. The neuroprotective effect was significantly more pronounced when clonally derived NS cell lines selected for high expression levels of CNTF were grafted into Pde6b(rd1) mice. Intravitreal transplantations of modified NS cells may thus represent a useful method for preclinical studies aimed at evaluating the therapeutic potential of a cell-based intraocular delivery of NFs in mouse models of photoreceptor degeneration.
AB - A continuous intraocular delivery of neurotrophic factors (NFs) is being explored as a strategy to rescue photoreceptor cells and visual functions in degenerative retinal disorders that are currently untreatable. To establish a cell-based intraocular delivery system for a sustained administration of NFs to the dystrophic mouse retina, we used a polycistronic lentiviral vector to genetically modify adherently cultivated murine neural stem (NS) cells. The vector concurrently encoded a gene of interest, a reporter gene, and a resistance gene and thus facilitated the selection, cloning, and in vivo tracking of the modified cells. To evaluate whether modified NS cells permit delivery of functionally relevant quantities of NFs to the dystrophic mouse retina, we expressed a secretable variant of ciliary neurotrophic factor (CNTF) in NS cells and grafted the cells into the vitreous space of Pde6b(rd1) and Pde6b(rd10) mice, two animal models of retinitis pigmentosa. In both mouse lines, grafted cells attached to the retina and lens, where they differentiated into astrocytes and some neurons. Adverse effects of the transplanted cells on the morphology of host retinas were not observed. Importantly, the CNTF-secreting NS cells significantly attenuated photoreceptor degeneration in both mutant mouse lines. The neuroprotective effect was significantly more pronounced when clonally derived NS cell lines selected for high expression levels of CNTF were grafted into Pde6b(rd1) mice. Intravitreal transplantations of modified NS cells may thus represent a useful method for preclinical studies aimed at evaluating the therapeutic potential of a cell-based intraocular delivery of NFs in mouse models of photoreceptor degeneration.
KW - Animals
KW - Cells, Cultured
KW - Ciliary Neurotrophic Factor
KW - Cyclic Nucleotide Phosphodiesterases, Type 6
KW - Disease Models, Animal
KW - Genetic Therapy
KW - Genetic Vectors
KW - Lentivirus
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Mutation
KW - Neural Stem Cells
KW - Neurogenesis
KW - Photoreceptor Cells, Vertebrate
KW - Retina
KW - Retinitis Pigmentosa
KW - Spheroids, Cellular
KW - Transduction, Genetic
KW - Transfection
U2 - 10.5966/sctm.2013-0013
DO - 10.5966/sctm.2013-0013
M3 - SCORING: Journal article
C2 - 24167317
VL - 2
SP - 1001
EP - 1010
JO - STEM CELL TRANSL MED
JF - STEM CELL TRANSL MED
SN - 2157-6564
IS - 12
ER -