Canine Model of Late-Infantile Neuronal Ceroid Lipofuscinosis for Therapy Develop

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DESCRIPTION (provided by applicant): Neuronal ceroid lipofuscinoses (NCLs) are inherited, fatal neurodegenerative disorders. These disorders are characterized by progressive neurological symptoms, including seizures, blindness, and cognitive and motor deterioration. Onset of symptoms almost always occurs in childhood, usually between the ages of 6 months and 7 years, depending on the disease subtype. Pathologically, the hallmarks of the NCLs are the accumulation of autofluorescent lysosomal storage material throughout the central nervous system, accompanied by widespread neuronal death. Mutations in one of at least eight different genes can lead to NCL in humans. No effective treatment has yet been developed for any of the NCLs. The goal of the research outlined in this proposal is to develop and characterize a canine model for the late-infantile form of NCL (LINCL), also known as CLN2. Once developed, this model will be used to perform pre- clinical studies to test the safety and efficacy of gene therapy, enzyme replacement therapy and mesenchymal stem cell therapy for treating LINCL. CLN2 is a recessive disorder that results from mutations in the tripeptidyl peptidase 1 (TPP1) gene. TPP1 is a soluble lysosomal enzyme that is exchanged between cells via the cellular endocytic pathway. We discovered Dachshunds that have a frameshift mutation in the canine ortholog of TPP1 and develop a disease very similar to human CLN2. We propose to thoroughly characterize the phenotypic features of LINCL in a research colony of TPP1 mutant Dachshunds. These studies will be a prelude to the conduct of preclinical studies of the safety and efficacy of therapeutic interventions to supply the missing enzyme to the central nervous system. Both in vitro and in vivo experiments have demonstrated that supplying the enzyme exogenously can correct the biochemical defect in cells and tissues of animals and humans with TPP1 mutations. Once the canine model has been well characterized, we propose to seek funding under the NIH U01 funding mechanism to conduct pre-clinical studies in this model to determine whether the disease phenotype can be ameliorated by supplying functional TPP1 enzyme to the brain and retina via direct enzyme infusion, delivery by genetically modified autologous mesenchymal stem cells, or gene replacement therapy. PUBLIC HEALTH RELEVANCE: Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are inherited progressive neurodegenerative disorders that almost always have a childhood onset and are invariably fatal. Mutations in at least 8 different genes are known to cause NCL, and no effective therapies have yet been developed for any of these disorders. Using a unique dog model of one form of NCL, we plan to conduct pre-clinical research to evaluate promising therapies for these diseases.