Means and methods for counteracting polyq expansion disorders
AssigneeAcademisch Medisch Centrum
InventorEric Albert Julius Reits
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Abstract
The present invention provides means and methods for counteracting and/or preventing aggregation of a polyQ protein. Further provided are improved poly constructs which are, amongst other things, useful for testing assays. According to the invention, several peptidases like, e.g. tripeptidyl peptidase II (TPPII), appear to be capable of cleaving long polyQ peptides comprising at least 45 glutamine residues. Hence, according to the invention, administration of such peptidases to an individual suffering from a polyQ expansion disorder results in degradation of long polyQ peptides.
Claims23
A method for treating and/or decreasing susceptibility to a protein aggregation disorder, in a subject in need thereof, comprising administering to said subject a protocol comprising pharmaceutically effective amount of
- a peptidase capable of cleaving a polyQ peptide comprising at least 45 glutamine residues or a functional catalytic domain thereof, or
- a nucleic acid sequence encoding said peptidase or functional catalytic domain, or
- a compound capable of enhancing the expression, amount and/or peptidase activity of said peptidase.
A method for counteracting and/or preventing aggregation of a polyQ protein in a cell, comprising providing said cell with a protocol comprising
- a peptidase capable of cleaving a polyQ peptide comprising at least 45 glutamine residues or a functional catalytic domain thereof, or
- a nucleic acid sequence encoding said peptidase or functional catalytic domain, or
- a compound capable of enhancing the expression, amount and/or peptidase activity of said peptidase.
A method to identify a candidate compound that counteracts protein aggregation,
- the method comprising determining whether said candidate compound is capable of increasing the expression, amount and/or peptidase activity of a peptidase that cleaves a polyQ peptide comprising at least 45 glutamine residues,
- wherein a compound that is capable of increasing the expression, amount and/or peptidase activity of said peptidase is identified as a compound that counteracts protein aggregation.
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A pharmaceutical composition comprising:
- (a) a peptidase capable of cleaving a polyQ peptide comprising at least 45 glutamine residues or a functional catalytic domain thereof, and/or
- a nucleic acid sequence encoding said peptidase or functional catalytic domain, and/or
- a compound capable of enhancing the expression, amount and/or peptidase activity of said peptidase;
- and
- (b) a DnaJ heat shock protein or a functional protein aggregation inhibiting part thereof, or
- a nucleic acid sequence encoding a DnaJ heat shock protein or a functional protein aggregation inhibiting part thereof, or
- a compound capable of enhancing the expression, amount and/or protein aggregation inhibiting activity of a DnaJ heat shock protein;
- and, optionally, a pharmaceutical acceptable carrier, diluent or excipient.
A ubiquitin-polyQ fusion construct consisting of ubiquitin and a polyQ peptide, wherein said polyQ peptide consists of glutamine residues.
Dependencies are inferred from the claim text.