Pathophysiology and Novel Therapies for Batten's Disease

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DESCRIPTION (provided by applicant): Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are inherited neurodegenerative diseases primarily affecting children. One hallmark of the NCLs is that accumulation of autofluorescent material in the lysosomes of many cell types including neurons of the brain. Children with NCL suffer from blindness, seizures, motor and mental deterioration and premature death. The earliest form of NCL, Infantile Neuronal Ceroid Lipofuscinosis (INCL), is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and is, therefore, classified as a lysosomal storage disease. Currently, there is no effective treatment for INCL. We recently obtained a newly developed mouse model of PPT1 deficiency. Although very little is known yet about the disease progression in this model, it is completely deficient in PPT1 activity and autofluorescent material accumulates in neurons of the brain. These two characteristics alone make this a valuable small animal model to study the disease progression and develop novel therapeutic approaches. It was recently shown in a murine model of another lysosomal storage disease that direct intracranial injection of agene transfer vector could reduce the accumulation of lysosomal storage in the brain and improve cognitive function. Due to the biochemical similarities between many lysosomal enzymes, we believe that a gene therapy approach using recombinant viral vectors may also prove efficacious for INCL. The long-term goals of this research are to determine the effects of PPT1 deficiency on visual and cognitive functions in the mouse and then evaluate the efficacy of viral-mediated gene transfer in correcting the enzyme deficiency and preserving these functions. We will accomplish these goals with the following specific aims: 1. We wil create and characterize in vitro recombinant AAV and lentiviral gone transfer vectors encoding human palmitoyl protein thioesterase-1 (PPT1). 2. We will determine the progression and extent of clinical disease, especially the retinal and cognitive dysfunction in the PPTl-deficient mouse. 3. We will determine the efficacy of viral-mediated gene therapy approaches for INCL in the PPT1 deficient mouse.