Treatment of protein aggregation diseases
Inventors
Wilson, Stuart Mark • Stanley, Christopher John
Assignees
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Publication Number
US-8383617-B2
Publication Date
2013-02-26
Expiration Date
Abstract
A method of treatment for the prevention or therapy of a protein aggregation disease includes the administration in combination of a first active medicament and a second active medicament, wherein the first active medicament is active to impede aggregation of amyloid protein and the second active medicament is active to disaggregate previously formed aggregates of amyloid protein.
Core Innovation
The invention relates to treating protein aggregation diseases by administering a synergistic effective amount of a combination comprising a first active medicament and a second active medicament. The first active medicament impedes aggregation of amyloid protein, while the second active medicament disaggregates previously formed aggregates of amyloid protein. The described protein aggregation diseases include Alzheimer’s disease, prion diseases, Parkinson’s disease, and Huntington’s disease.
A screening approach is described using the Seprion assay, including a Seprion ligand, to detect aggregation and to determine whether compounds prevent aggregation versus reverse aggregation. The document connects Seprion assay readouts with aggregation state concepts such as protofibrils and fibrils, and with additional detection approaches referenced for aggregate assessment.
Representative supportive results are described for phenothiazines such as fluphenazine and tricyclic antidepressants such as trimipramine. In the described examples, fluphenazine decreases a Seprion signal and disaggregates preformed aggregates as assessed by PAGE, whereas trimipramine increases a Seprion signal and does not disaggregate preformed aggregates as assessed by PAGE.
Claims Coverage
The independent claim covers a two-medicament synergistic treatment method for a protein aggregation disease with two distinct functional roles. The dependent claims add patient-selection and monitoring features tied to positive diagnostic testing and related eligibility criteria, while staying within the same two-medicament combination framework.
Synergistic two-medicament combination treatment method
A method for treatment for the therapy of a protein aggregation disease comprising the administration of a synergistic effective amount of a combination comprising a first active medicament and a second active medicament.
First medicament impedes amyloid protein aggregation
The first active medicament is fluphenazine and is administered to impede aggregation of amyloid protein.
Second medicament disaggregates previously formed amyloid aggregates
The second active medicament is trimipramine and is administered to disaggregate previously formed aggregates of amyloid protein.
Treatment based on positive aggregated amyloid testing
The method further includes administering the method of claim 1 to a mammal tested for aggregated amyloid in a derived sample and found positive.
Treatment based on known infectious exposure risk
The method further includes administering the method of claim 1 to a mammal known to have been exposed to an infectious source of protein aggregation disease under potentially infectious circumstances.
Treatment based on positive genetic predisposition
The method further includes administering the method of claim 1 to a mammal that has tested positive for genetic predisposition to contracting a protein aggregation disease.
Testing for presence of protein aggregation disease before, during, and/or after treatment
The method further includes conducting a test for the presence of a protein aggregation disease prior to, during, and/or after conducting the treatment.
Overall, the claim set is directed to administering a synergistic effective amount of fluphenazine and trimipramine with the functional division of roles: impeding amyloid protein aggregation and disaggregating previously formed amyloid aggregates, optionally refined by diagnostic and eligibility testing features and by conducting tests for disease presence before, during, and/or after treatment.
Stated Advantages
Greatest reduction in amyloid plaques and aggregate measures when using the combination therapy in the described hAPP(751) mice context.
Reduction in prion content with the combination therapy in the described prion cell line studies.
Clinical improvement is reported in a case report of GSS treated with trimipramine plus fluphenazine.
Documented Applications
Treatment of protein aggregation diseases including Alzheimer’s disease, prion diseases, Parkinson’s disease, and Huntington’s disease via a synergistic combination therapy using fluphenazine and trimipramine.
Screening/selection of compounds to prevent versus reverse aggregation using the Seprion assay and Seprion ligand.
Assessment of amyloid plaque and aggregate reduction in hAPP(751) mice using the fluphenazine plus trimipramine combination.
Assessment of prion content reduction in a scrapie-infected cell line using fluphenazine alone and especially fluphenazine plus trimipramine.
Case report use in GSS, where trimipramine plus fluphenazine is administered and clinical improvement is observed.
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