Delivery of enzyme across the blood-brain barrier to correct neuronal storage represents a major unmet need since nearly 90% of lysosomal storage diseases involve the central nervous system and conventional enzyme replacement therapy does not correct storage in the brain. The broad goal of this research is to continue studies of newly discovered routes of transport of lysosomal enzymes to brain and their relevance to correcting neuronal storage by enzyme replacement therapy. We will use 2- glucuronidase and 1-iduronidase as model enzymes and murine mucopolysaccharidosis type VII (MPS VII;Sly disease) and MPS I (Hurler disease) as model lysosomal storage diseases. We seek to capitalize on recent breakthroughs addressing correction of neuronal storage, including: 1) The discovery that mannose 6-phosphate (M6P) mediated transcytosis (endocytosis at the luminal membrane followed rapidly by exocytosis at the abluminal membrane without going through the lysosome) can be upregulated pharmacologically in adult mouse brain to allow transport of enzyme across the blood-brain barrier comparable to that seen in the neonate;2) The discovery of a novel route for chemically modified enzyme to correct neuronal storage when maintained at a high circulating level in plasma over a sustained period;and, 3) The findings that resistant sites not accessible to native enzyme can be targeted successfully using chimeric enzymes that target other cell surface receptors. We have four Specific Aims: 1) Determine the mechanism and significance of pharmacological upregulation of M6P receptor mediated transcytosis of lysosomal enzymes across the blood-brain barrier. 2) Determine the mechanism, efficacy, and generality of neuronal correction by periodate (PerT) modified enzyme. 3) Determine the efficacy of transferrin-iduronidase and transferrin-2-glucuronidase chimeric enzymes in crossing the BBB and correcting neuronal storage in murine MPS I and MPS VII mouse models. We will use a variety of biochemical, cell biological, immunological, and molecular genetic approaches and take advantage of novel mouse models of MPS VII produced in our laboratory by transgenic and mouse knockout technologies. We combine histochemistry, histopathology, and immunoelectron microscopy to measure enzyme delivery to brain and other resistant sites of storage. The answers sought have fundamental significance and should provide information leading to novel therapeutic approaches to enzyme replacement for lysosomal and other storage diseases involving the central nervous system.

Public Health Relevance

We seek to address a major unmet need in lysosomal disease research: delivering enzyme to brain to correct neuronal storage, which occurs in 90% of these diseases. We will use a variety of biochemical, cell biological, immunological, and molecular genetic approaches and take advantage of novel mouse models of MPS VII produced in our laboratory by transgenic and mouse knockout technologies. The answers sought have fundamental significance and should provide information leading to novel therapeutic approaches to enzyme replacement for lysosomal and other storage diseases involving the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034182-24
Application #
8055281
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Marino, Pamela
Project Start
1995-06-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
24
Fiscal Year
2011
Total Cost
$365,063
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Fox, Joyce E; Volpe, Linda; Bullaro, Josephine et al. (2015) First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient. Mol Genet Metab 114:203-8
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Sly, William S; Vogler, Carole (2013) The final frontier -- crossing the blood-brain barrier. EMBO Mol Med 5:655-7
Arechederra, Robert L; Waheed, Abdul; Sly, William S et al. (2013) Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion. Bioorg Med Chem 21:1544-8
Kivela, Antti J; Knuuttila, Aija; Rasanen, Jari et al. (2013) Carbonic anhydrase IX in malignant pleural mesotheliomas: a potential target for anti-cancer therapy. Bioorg Med Chem 21:1483-8
Rowan, Daniel J; Tomatsu, Shunji; Grubb, Jeffrey H et al. (2013) Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII. J Inherit Metab Dis 36:235-46
Schneider, Hans-Peter; Alt, Marco D; Klier, Michael et al. (2013) GPI-anchored carbonic anhydrase IV displays both intra- and extracellular activity in cRNA-injected oocytes and in mouse neurons. Proc Natl Acad Sci U S A 110:1494-9
Tomatsu, Shunji; Mackenzie, William G; Theroux, Mary C et al. (2012) Current and emerging treatments and surgical interventions for Morquio A syndrome: a review. Res Rep Endocr Disord 2012:65-77

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