Late-infantile neuronal ceroid lipofuscinosis (LINCL, or CLN2) is a progressive and fatal inherited neurodegenerative disease of children that is characterized brain atrophy as well as by progressive retinal degeneration resulting in vision loss that culminates in blindness. CLN2 results from a mutation in the gene that encodes synthesis of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Using a dog model of CLN2, we have demonstrated that periodic administration of recombinant TPP1 to the cerebrospinal fluid (CSF) or a single administration of AAV2-TPP1 gene therapy to the CSF results in uptake of active TPP1 by most brain regions, greatly inhibits brain degeneration, and substantially delays progression of neurological signs of the disease. Based on our studies with the canine model, TPP1 enzyme replacement therapy to the CSF is being employed in a human clinical trial that started in September of 2013. Unfortunately, delivery of TPP1 to the CSF does not prevent retinal degeneration and the resulting loss of vision because the TPP1 does not reach the retina from the CSF. To achieve continuous delivery of TPP1 to the retina, we propose to generate autologous bone marrow- derived mesenchymal stem cells (MSCs) from dogs that are homozygous for a null TPP1 mutation. The MSCs will be transduced to express and secrete high levels of TPP1 enzyme. The transgenic cells will then be implanted into the vitreous of the eyes of the same dogs from which the MSCs were obtained, and the dogs will be monitored for survival and location of the implanted cells, retinal TPP1 levels, and for preservation of retinal structure and function. We will also investigate the alternative approach o direct administration of AAV2-TPP1 gene therapy to the vitreous to transduce retinal cells to synthesize the TPP1 protein. If these studies are successful, they will serve as the basis for treating children with CLN2 who are receiving enzyme replacement therapy via infusion of TPP1 into the CSF or CSF TPP1 gene therapy. The addition of the eye treatment to the CSF treatments has the potential for preventing blindness in children with CLN2 who are benefiting from the brain treatments. In addition, these studies will establish intravitreal implantation of transgenic cells and direct gene therapy as means for treating many other retinal degenerative disorders, including inherited retinal degenerative diseases, age-related macular degeneration and diabetic retinopathy.

Public Health Relevance

Progressive degeneration of the retina occurs in a number of inherited lysosomal storage disorders. Studies will be performed to determine whether intravitreal implantation of genetically modified autologous mesenchymal stem cells or direct gene therapy can preserve retinal function in a dog model for one these disorders. If successful in our model system, these therapeutic approaches could be adapted for the treatment of retinal diseases in people.

National Institute of Health (NIH)
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Shen, Grace L
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University of Missouri-Columbia
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