YEARS

2002-2006

AUTHORS

Christopher B Eckman

TITLE

Protein Tranduction for Treatment of Krabbe Disease

ABSTRACT

DESCRIPTION (provided by applicant): Krabbe disease is a degenerative neurological disorder primarily affecting infants and young children although rare cases of adult onset have been described. Affected individuals typically present with symptoms in the first few months of life. Disease progression is generally rapid, leading to death within 1-2 years. The disease is inherited as an autosomal recessive trait caused by mutations in the galactocerebrosidase (GALC) gene that severely affect the activity of the enzyme. Obvious therapeutic approaches include delivery of active GALC enzyme to the brain through either gene or protein therapy. While significant advances have been made in gene therapy over the years, stable expression of proteins in the brain has not yet been achieved. Enzyme replacement therapy offers another possible therapeutic approach and has been shown to be safe and effective for the treatment of peripheral clinical manifestations in another lysosomal storage disorder, Type I Gaucher's disease. For diseases such as Krabbe disease, however, the therapeutic enzyme must be delivered to the brain to have a significant clinical impact. Recently, Steven Dowdy and colleagues have made a significant advance in the delivery of macromolecules to the brain (Schwarze et al., 1999). They have shown that that even very large proteins can cross the blood-brain barrier to enter into the brain in biologically active form when coupled to an 11 amino acids protein transduction domain derived from the IRV TAT protein. In this application we propose experiments to generate TAT PTD/GALC fusion proteins and examine whether these will get to the brain and restore normal function and enhance survivability in an animal model of Krabbe disease. The lessons learned from these experiments may be useful for other diseases where delivery of a therapeutic protein may be desired, such as Alzheimer's disease and Parkinson's.

FUNDED PUBLICATIONS

  • Suppression of galactosylceramidase (GALC) expression in the twitcher mouse model of globoid cell leukodystrophy (GLD) is caused by nonsense-mediated mRNA decay (NMD).
  • Molecular characterization of mutations that cause globoid cell leukodystrophy and pharmacological rescue using small molecule chemical chaperones.
  • Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.
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    22 TRIPLES      17 PREDICATES      23 URIs      9 LITERALS

    Subject Predicate Object
    1 grants:380e12e97a18f81031972447e95edbc1 sg:abstract DESCRIPTION (provided by applicant): Krabbe disease is a degenerative neurological disorder primarily affecting infants and young children although rare cases of adult onset have been described. Affected individuals typically present with symptoms in the first few months of life. Disease progression is generally rapid, leading to death within 1-2 years. The disease is inherited as an autosomal recessive trait caused by mutations in the galactocerebrosidase (GALC) gene that severely affect the activity of the enzyme. Obvious therapeutic approaches include delivery of active GALC enzyme to the brain through either gene or protein therapy. While significant advances have been made in gene therapy over the years, stable expression of proteins in the brain has not yet been achieved. Enzyme replacement therapy offers another possible therapeutic approach and has been shown to be safe and effective for the treatment of peripheral clinical manifestations in another lysosomal storage disorder, Type I Gaucher's disease. For diseases such as Krabbe disease, however, the therapeutic enzyme must be delivered to the brain to have a significant clinical impact. Recently, Steven Dowdy and colleagues have made a significant advance in the delivery of macromolecules to the brain (Schwarze et al., 1999). They have shown that that even very large proteins can cross the blood-brain barrier to enter into the brain in biologically active form when coupled to an 11 amino acids protein transduction domain derived from the IRV TAT protein. In this application we propose experiments to generate TAT PTD/GALC fusion proteins and examine whether these will get to the brain and restore normal function and enhance survivability in an animal model of Krabbe disease. The lessons learned from these experiments may be useful for other diseases where delivery of a therapeutic protein may be desired, such as Alzheimer's disease and Parkinson's.
    2 sg:endYear 2006
    3 sg:fundingAmount 559314.0
    4 sg:fundingCurrency USD
    5 sg:hasContribution contributions:08ee4864d2b2064af99243c77ad1dcab
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    10 sg:hasFundedPublication articles:19103df8a887cab8e10bdf184bbdaf8f
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    12 articles:ea36905d7869ceede0cb72920649e542
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    14 sg:hasRecipientOrganization grid-institutes:grid.417467.7
    15 sg:language English
    16 sg:license http://scigraph.springernature.com/explorer/license/
    17 sg:scigraphId 380e12e97a18f81031972447e95edbc1
    18 sg:startYear 2002
    19 sg:title Protein Tranduction for Treatment of Krabbe Disease
    20 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=6798819
    21 rdf:type sg:Grant
    22 rdfs:label Grant: Protein Tranduction for Treatment of Krabbe Disease
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