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D. N. Sanders, M. L. Katz, M. D. Kirk; Mesenchymal Stem Cell Transplant as a Treatment for Batten's Disease. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2980. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The Neuronal Ceroid Lipofuscinoses (NCLs) are a group of diseases characterized by neurodegeneration and accumulation of autofluorescent storage material in neural cells. There is currently no effective clinical treatment for the NCLs. Several forms of NCL are associated with genes which produce soluble lysosomal proteins that can be transferred between neighboring cells. Because of this enzymatic exchange phenomenon, NCLs involving soluble enzymes may be amenable to treatment through stem cell transplantation. Here, we test the ability of mesenchymal stem cells (MSCs) to survive after intraocular transplant and correct NCL-specific symptoms in retinal tissue.
Using a murine gene-knockout (PPT1-/-) model of human infantile-onset NCL, we have analyzed the ability of MSCs isolated from enhanced green fluorescent protein (EGFP)-expressing mice to survive, incorporate benignly into host neural tissue and correct NCL-related symptoms such as autofluorescent storage body accumulation and neurodegeneration. MSCs were isolated by plastic adherence and injected into the vitreous of affected mice. Survival of fluorescent transplanted cells was measured by microscopic examination and image analysis. The effect of treatment on disease symptoms was measured by comparing the electroretinogram activity, pupillary light response, retinal cell loss and autofluorescent storage material accumulation of treated and sham treated eyes. Treated eyes were also examined for evidence of endoplasmic reticulum unfolded protein response and induction of apoptosis pathways by immunohistochemistry and Western blot.
MSCs initially injected into the vitreous of NCL-affected mice migrated toward and integrated with retinal tissues undergoing neurodegeneration. Cells survived without detectable proliferation, immune rejection or tissue disruption at 7 weeks post-transplant. At 7 weeks, the amount of autofluorescent storage material in treated retinas was ~20% of that found in untreated eyes. Ongoing experiments will quantify the effect of treatment on ERGs, pupillary light response, retinal cell loss and biochemical indicators of neurodegeneration.
Initial results for these experiments suggest that MSCs are capable of surviving long term after transplant into neural tissue and have a positive effect on NCL symptoms in affected animals. Further experiments in animal models will determine whether these results can be transferred to a systemic delivery system usable for treatment of human patients.
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