Abstract
A sustained intraocular administration of neurotrophic factors is among the strategies aimed at establishing treatments for currently untreatable degenerative retinal disorders. In the present study we have analyzed the neuroprotective effects of a continuous neural stem (NS) cell-based intraocular delivery of ciliary neurotrophic factor (CNTF) on photoreceptor cells in the nclf mouse, an animal model of the neurodegenerative lysosomal storage disorder variant late infantile neuronal ceroid lipofuscinosis (vLINCL). To this aim, we genetically modified adherently cultivated NS cells with a polycistronic lentiviral vector encoding a secretable variant of CNTF together with a Venus reporter gene (CNTF-NS cells). NS cells for control experiments (control-NS cells) were modified with a vector encoding the reporter gene tdTomato. Clonal CNTF-NS and control-NS cell lines were established using fluorescent activated cell sorting and intravitreally grafted into 14 days old nclf mice at the onset of retinal degeneration. The grafted cells preferentially differentiated into astrocytes that were attached to the posterior side of the lenses and the vitreal side of the retinas and stably expressed the transgenes for at least six weeks, the latest post-transplantation time point analyzed. Integration of donor cells into host retinas, ongoing proliferation of grafted cells or adverse effects of the donor cells on the morphology of the host eyes were not observed. Quantitative analyses of host retinas two, four and six weeks after cell transplantation revealed the presence of significantly more photoreceptor cells in eyes with grafted CNTF-NS cells than in eyes with grafted control-NS cells. This is the first demonstration that a continuous intraocular administration of a neurotrophic factor attenuates retinal degeneration in an animal model of neuronal ceroid lipofuscinosis.
Highlights
Neuronal ceroid lipofuscinosis (NCL) comprises a heterogeneous group of neurodegenerative lysosomal storage diseases of mainly childhood and youth
The neuronal ceroid lipofuscinoses (NCLs) comprise a genetically heterogeneous group of neurodegenerative lysosomal storage disorders that are characterized by intracellular accumulation of autofluorescent material
For NCL forms caused by mutations in genes encoding soluble lysosomal enzymes, enzyme replacement therapy is among the strategies that are being explored as a potential treatment option
Summary
Neuronal ceroid lipofuscinosis (NCL) comprises a heterogeneous group of neurodegenerative lysosomal storage diseases of mainly childhood and youth. Mutations in more than a dozen different genes have been identified that cause NCL. Most of these genes encode soluble lysosomal enzymes or transmembrane proteins localized in lysosomes or the endoplasmic reticulum (ER). Other locations described for some NCL proteins include the ER-Golgi intermediate complex, the cytosol, synaptic vesicles or the plasma membrane Despite the heterogeneity of the disease-associated genes, several symptoms are common to most of these fatal storage disorders, including progressive mental deterioration, motor malfunctions, seizures, and premature death. Loss of vision due to retinal degeneration is another characteristic symptom of several NCL forms, and has been described in CLN1, CLN2, CLN3, CLN5, CLN6, CLN7 and CLN8 patients [4, 6, 7]
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