Sustained delivery of therapeutics to the visual system using genetically modified autologous mesenchymal stem cells to treat blinding diseases

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PROJECT SUMMARY The objective of the proposed research is to evaluate the safety and efficacy of a novel method of delivering therapeutics to the central nervous system (CNS) and the retina to treat diseases associated with visual impairment. The hypothesis tested is that autologous genetically modified mesenchymal stem cells (MSCs) can serve as effective vehicles for sustained delivery of therapeutics to visual centers in the brain and to the retina for the treatment of blinding diseases that result from pathology in one or more parts of the visual system. Proof of concept studies will be performed using a well-characterized and validated canine model of CLN2 neuronal ceroid lipofuscinosis, a disease with pediatric onset characterized by widespread neurodegeneration resulting in progressive loss of vision due to degeneration of both the retina and visual processing centers in the brain, cognitive and motor decline, and seizures. CLN2 disease is caused by mutations in TPP1, which result in deficiencies of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). It is hypothesized that providing TPP1 to the CNS using implantation of autologous MSCs that have been genetically modified to produce and secrete the protein will ameliorate disease-related vision loss in the canine model.