Late infantile neuronal ceroid lipofuscinosis (LINCL) is a progressive hereditary neurodegenerative disease of childhood that is due to a deficiency in the lysosomal protease tripeptidyl peptidase I (TPP1). Disease progression is characterized by increasingly severe seizures, loss of vision and motor skills, and dementia. Early death is inevitable, typically at 8-15 years of age. There is currently no effective treatment for LINCL. Previous research has resulted in the identification of the molecular basis for LINCL, development of definitive diagnostic tests, large-scale production of the TPP1 enzyme, in-depth biochemical and structural characterization of the protein, development of mouse models, and exploration of potential therapies. Exciting new developments in the field suggest that it may be possible to increase survival of an LINCL mouse model by administration of recombinant human TPP1. Building on this collective research, the current proposal has four specific aims to address critical aspects of LINCL and the role of TPP1 in biology and medicine.
SPECIFIC AIM 1 is to develop an effective therapy by administering recombinant human TPP1 to a LINCL mouse model. To date, enzyme replacement therapy (ERT) is the most successful treatment for visceral manifestations of lysosomal storage disorders but delivery to the brain remains a significant challenge. Experiments will be conducted to extend promising studies on direct administration of TPP1 to the cerebrospinal fluid (CSF), determining dose and dosing intervals for chronic treatment regimens, and also determining when treatment needs to be initiated. Studies will also be conducted to pursue intriguing preliminary results that suggest that high dose peripheral administration may be effective in delivering enzyme to the brain.
SPECIFIC AIM 2 is to use mouse genetics to investigate critical aspects of LINCL disease, progression and therapy. Experiments will be conducted using mice with inducible TPP1 activity to determine the reversibility of disease and to provide a benchmark to judge efficacy of therapies that restore TPP1 activity. In addition, this will create a valuable model for the community that can be used to explore additional therapies for LINCL and other neurodegenerative diseases.
SPECIFIC AIM 3 is to use computational protein design to engineer TPP1 variants with improved therapeutic properties. Initial efforts will be to lengthen the lifetime of active TPP1 in the lysosome without affecting activity or proenzyme stability. Such properties could greatly facilitate use of TPP1 as a drug in ERT. In addition, this will provide further understanding of th structure and dynamics of this protein and this will facilitate future design efforts to engineer proteins with improved pharmaceutical properties.
SPECIFIC AIM 4 is a proteomic analysis of LINCL specimens including CSF and storage material with the primary objective of identifying potential biomarkers to monitor disease progression and therapeutic response. In addition, this should provide basic information on the biological function of TPP1 in lysosomal digestion and also identify potential targets for therapeutic intervention.
The proposed research is focused on developing a cure for a fatal hereditary neurodegenerative disease of children, late infantile neuronal ceroid lipofuscinosis (Batten Disease). This research may also be applicable to a number of closely-related diseases and to more widespread human disorders such as Alzheimer disease.
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