Reducing polyglutamine-based aggregation
AssigneeNorthwestern University
InventorsRichard Morimoto, James Morley
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Abstract
The disclosure features, inter alia, methods for treating or preventing neurodegenerative disorders and disorders that caused at least in part by polyglutamine aggregation. The method can include reducing activity of the IGF-1/GH axis in a subject. One exemplary neurodegenerative disorder that is also caused at least in part by polyglutamine aggregation is Huntington's disease.
Claims33
A method of treating or preventing Huntington's Disease in a subject, the method comprising:
- reducing activity of the IGF-1/GH axis in a subject who has or is at risk of having Huntington's disease.
A method of evaluating a compound for ability to modulate Huntington's disease-related polyglutamine aggregation in a cell, the method comprising
- a) providing a test compound;
- b) contacting the test compound to a GH/IGF-1 axis component in vitro;
- c) evaluating interaction between the test compound and the growth hormone/IGF-1 axis component;
- d) contacting the test compound to a cell;
- and
- e) evaluating polyglutamine aggregation in or around the cell or evaluating the cell for a cellular symptom of polyglutamine aggregation.
A method for evaluating compounds for ability to modulate Huntington's disease-related polyglutamine aggregation in an organism, the method comprising
- a) providing a library of compounds;
- b) contacting each compound of the library to a GH/IGF-1 axis component in vitro;
- c) evaluating interaction between each compound and the GH/IGF-1 axis component;
- d) selecting a subset of compounds from the library based on the evaluated interactions;
- and
- e) for each compound of the subset, contacting the compound to a cell, and evaluating polyglutamine aggregation in or around the cell or evaluating the cell for a cellular symptom of polyglutamine aggregation.
A method of evaluating a compound for ability to modulate Huntington's disease-related polyglutamine aggregation in an organism, the method comprising
- a) providing a test compound;
- b) contacting the test compound to a GH/IGF-1 axis component in vitro;
- c) evaluating interaction between the test compound and the growth hormone/IGF-1 axis component;
- d) administering the test compound to a subject organism;
- and
- e) evaluating the subject organism for polyglutamine aggregation, a symptom of polyglutamine aggregation, or a neurological symptom.
A method for evaluating compounds for ability to modulate Huntington's disease-related polyglutamine aggregation in an organism, the method comprising
- a) providing a library of compounds;
- b) contacting each compound of the library to a GH/IGF-1 axis component in vitro;
- c) evaluating interaction between each compound and the GH/IGF-1 axis component;
- d) selecting a subset of compounds from the library based on the evaluated interactions;
- and
- e) for each compound of the subset, administering the compound to a subject organism, and evaluating the subject organism for polyglutamine aggregation, a symptom of polyglutamine aggregation, or a neurological symptom.
A non-human organism that comprises a deficiency in a GH/IGF-1 axis component and a heterologous nucleic acid encoding a protein with a polyglutamine repeat region that includes at least 35 glutamines and at least 50 amino acids from exon 1 of the Huntingtin protein.
A cultured cell preparation comprising:
- an engineered mammalian cell that expresses a protein that comprises at least 50 amino acid of exon 1 of the Huntingtin protein and a polyglutamine repeat region of at least 35 glutamines;
- and
- medium containing an agonist of the GH/IGF-1 axis.
A method for gathering genetic information, the method comprising:
- a) determining the identity of at least one nucleotide in gene encoding an IGF-1/GH axis component of a human subject;
- and
- b) creating a record which includes information about the identity of the nucleotide and information relating to a Huntington's disease-related parameter from an evaluation of the subject.
A method for evaluating a gene encoding an IGF-1/GH axis component, the method comprising:
- a) determining the identity of at least one nucleotide in gene encoding an IGF-1/GH axis component for a plurality of subjects who have Huntington's disease or are associated with Huntington's disease;
- and
- b) evaluating the distribution of one or more nucleotide identities for a given position in the gene among or between subjects of the plurality.
Dependencies are inferred from the claim text.