title: Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina.
abstract: 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.
authors.affiliation: Department of Ophthalmology and.
authors.forename: Gila
authors.initials: G
authors.lastname: Jung
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Bettina
authors.initials: B
authors.lastname: Petrowitz
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Riecken
authors.forename: Katharina
authors.initials: K
authors.lastname: Kruszewski
authors.forename: Wanda
authors.initials: W
authors.lastname: Jankowiak
authors.forename: Frank
authors.initials: F
authors.lastname: Kunst
authors.forename: Christos
authors.initials: C
authors.lastname: Skevas
authors.forename: Gisbert
authors.initials: G
authors.lastname: Richard
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.forename: Udo
authors.initials: U
authors.lastname: Bartsch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D055495:Neurogenesis; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018874:Spheroids, Cellular; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D020934:Ciliary Neurotrophic Factor; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse
keywords: Ciliary neurotrophic factor; Lentiviral vector; Neural stem cell; Retinal photoreceptors; Stem cell transplantation