Pathophysiology and Novel Therapies for Batten's Disease

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DESCRIPTION (provided by applicant): Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1) activity. This leads to the accumulation of autofluorescent material in enurons and glia of the brain. The first clinical sign of INCL is visual dysfunction followed by cognitive deficits, seizures and premature death. The PPT1-deficient mouse is a powerful tool to uncover the mechanisms of disease and test novel therapeutic approaches for INCL. During the initial funding period of this grant we made significant progress in understanding the underlying pathophysiology of INCL. However, there is still much to be understood regarding the underlying mechanisms of disease. Currently, there is no effective therapy for INCL and traditional approaches such as enzyme replacement therapy (ERT) and bone marrow transplantation (BMT) are only minimally effective for rapidly progressing LSDs with profound CNS components. Successful treatment of INCL will require the development of new and innovative approaches. We showed that significant reductions in the accumulation of autofluorescent storage material, and improvments in behavior and seizure phenotype can be achieved following AAV- mediated, CNS-directed gene therapy. Although statistically significant, these improvments were modest. This is in contrast to other models of LSD that respond more completely to CNS-directed gene therapy. These data highlight the differences between LSDs and the need to develop more effective therapies for eac of these disorders, The goals of this research are to more completely understand the mechanisms of disease and devise more effective therapies approaches for INCL. We will accoumplish these goals with the following Specific Aims: 1) We will complete the biochemical, histological and physiological characterization of the PPT1-deficient mouse on the congenic C57BI/6 background. 2) We will determine the individual contributions of astrocytes and neurons to the progression of INCL i the congenic murine model of INCL. 3) We will determine the efficacy of CNS-directed AAV2/5-mediated gene therapy alone, and in combination with bone marrow transplantation or small molecule substrate depletion in the congenic PPT1-deficient mouse.