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. Building on this, the overall goal of the current proposal is to conduct preclinical studies that will provide a firm underpinning for effective treatment of LINCL patients. There are three Specific Aims:
Specific Aim 1 is to develop an inducible transgenic model that will allow time and concentration-regulated TPP1 expression in all cell types. For LINCL, this model will provide a gold standard to benchmark therapeutic approaches. It will also provide a facile system to investigate the window of therapeutic efficacy as well as dosing regimens. In addition, this transgenic and our existing mouse models will be used to investigate whether TPP1 is important for degradation of A2 peptide and/or aggregation products under physiological conditions, potentially opening new avenues for therapy in Alzheimer's Disease (AD).
Specific Aim 2 is to evaluate enzyme replacement therapy (ERT) for LINCL to correct the loss of TPP1 in neurons. To date, ERT is the most successful treatment for lysosomal storage diseases and this approach could be readily applicable to patients should preclinical studies demonstrate promise. We will evaluate the efficacy of both peripheral and intrathecal administration using our LINCL mouse.
Specific Aim 3 is to enhance the TPP1 protein by structure-based protein engineering for use as a therapeutic agent. Initial efforts will be to enhance the stability and biological half-life of TPP1, which may be crucial for successful implementation of enzyme replacement and/or gene therapy. Extensions of this aim will include engineering TPP1 variants with additional properties such as the ability to penetrate the blood-brain barrier.
The proposed research is focused on developing a cure for a fatal hereditary neurodegenerative disease of children, late infantile neuronal ceroid lipofuscinosis. This research may also be applicable to more widespread human disorders such as Alzheimer disease.
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