Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina

TY - JOUR

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 -