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Lipofuscinosis: Lysosomal Storage and Enzyme Replacement Therapy
B.S., Tsinghua University - 2005
Thesis Advisor: Peter Lobel, Ph.D.
Graduate Program in Cellular
& Molecular Pharmacology
CABM Room 010
Tuesday, February 22, 2011
Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases caused by deficiencies in lysosomal function. They usually affect children and most have neurological manifestation. Most of the LSDs result from defects of a single lysosomal hydrolase involved in degradation of macromolecules (lipids, glycoproteins and mucopolysaccharides, etc.) and are characterized by a significant accumulation of the undigested substrates inside the lysosomes. Several therapies have been proposed and under development to treat LSDs, but for the neurological LSDs, there is no treatment to date.
Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease primarily affecting children and is caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1 (TPP1). LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1.
Through a proteomic analysis of storage material in brain from a LINCL mouse model, one protein, glial fibrillary acidic protein (GFAP), was found to be elevated in the LINCL mice compared with normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. However, when examined for its intracellular distribution using subcellular fractionation and morphological methods, GFAP is not localized to the lysosome and is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be re-examined. It remains unclear whether other proteins that were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice are true constituents of the storage material or they just associate with this material upon purification.
In order to explore and develop practical and effective treatment for LINCL, enzyme replacement therapy (ERT) was evaluated using recombinant human TPP1 protein in a mouse model. ERT has proved effective in treatment of visceral manifestations of other LSDs but to date, only marginal improvement in survival has been obtained in animal models for neurological LSDs due to insufficient enzyme delivery to the brain. The development and utilization of large-volume intrathecal administration in the present study, however, successfully facilitated delivery of therapeutic amounts of TPP1 to the brain. Acute administration studies indicate a reversal of pathology, improvement in neurological phenotype, and significant increase in survival. These results provide a strong basis for both clinical investigation of delivery of TPP1 to the brain via the cerebrospinal fluid and extension of this approach towards other neurological lysosomal storage diseases.