Cyclophilin 40 for reduction of neurotoxic fibrils and treatment of neurodegenerative diseases

Abstract

The present invention concerns the use of peptidyl-prolyl isomerase cyclophilin 40 (CyP40) for reduction of neurotoxic fibrils and treatment and prevention of neurodegenerative diseases associated with amyloid fibril aggregation. Aspects of the invention include compositions, methods, dosage forms, and kits for treating or preventing a neurodegenerative disease or condition associated with amyloid fibril aggregation in a human or animal subject, and for disaggregating neurofibrillary aggregates in vitro or in vivo, using CyP40, or a biologically active fragment thereof.

1 . A method for treating or preventing a neurodegenerative disease or condition associated with amyloid fibril aggregation, said method comprising administering an effective amount of peptidyl-prolyl isomerase cyclophilin 40 (CyP40), or a biologically-active fragment thereof, to a human or animal subject in need thereof. 
     
     
         2 . The method according to  claim 1 , wherein said method further comprises identifying a subject as one in need of treatment. 
     
     
         3 . The method according to  claim 1 , wherein the disease or condition is characterized by the presence of neurofibrillary aggregates of the microtubule associated protein tau and/or α-synuclein. 
     
     
         4 . The method according to  claim 1 , wherein the disease or condition is Alzheimer' s disease, gangliogliomas, gangliocytomas, argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, frontotemporal dementia with parkinsonism linked to chromosome17, Pick's disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease (type C), Parkinsonism-dementia complex of Guam, postencephalitic parkinsonism, prion diseases, progressive subcortical gliosis, or progressive supranuclear palsy. 
     
     
         5 . The method according to  claim 1 , wherein the CyP40, or a biologically active fragment thereof, is administered to the subject orally, nasally, rectally, parenterally, subcutaneously, intramuscularly, intraspinal, intracranially, or intravenously. 
     
     
         6 . The method according to  claim 1 , wherein the CyP40, or a biologically fragment thereof, is administered to the subject as a polynucleotide encoding the CyP40, or the biologically active fragment thereof. 
     
     
         7 . The method according to  claim 6 , wherein the polynucleotide is provided in an expression construct. 
     
     
         8 - 10 . canceled 
     
     
         11 . The method according to  claim 7 , wherein the expression construct is an adeno-associated viral construct. 
     
     
         12 . The method according to  claim 1 , wherein said method further comprises administering a biologically active agent used in treating neurodegenerative diseases and/or conditions to the subject. 
     
     
         13 - 14 . canceled 
     
     
         15 . The method according to  claim 1 , wherein the subject has the neurodegenerative disease or condition at the time of said administering, and the CyP40, or a biologically-active fragment thereof, is administered as therapy. 
     
     
         16 . The method according to  claim 1 , wherein the subject does not have the neurodegenerative disease or condition at the time of said administering, and the CyP40, or a biologically-active fragment thereof, is administered as prophylaxis. 
     
     
         17 . A method for disaggregating neurofibrillary aggregates, comprising contacting the aggregates with an effective amount of peptidyl-prolyl isomerase cyclophilin 40 (CyP40), or a biologically-active fragment thereof, in vitro or in vivo. 
     
     
         18 . The method of  claim 17 , wherein the neurofibrillary aggregates comprise microtubule associated protein tau and/or α-synuclein. 
     
     
         19 . The method according to  claim 17 , wherein said contacting is in vivo and comprises administering the CyP40, or a biologically active fragment thereof, to a human or animal subject, and wherein the CyP40, or a biologically active fragment thereof, is administered to the subject orally, nasally, rectally, parenterally, subcutaneously, intramuscularly, intraspinal, intracranially, or intravenously. 
     
     
         20 . The method according to  claim 17 , wherein said contacting is in vivo and comprises administering the CyP40, or a biologically active fragment thereof, to a human or animal subject, and wherein the CyP40, or a biologically fragment thereof, is administered as a polynucleotide encoding the CyP40, or the biologically active fragment thereof. 
     
     
         21 - 28 . canceled 
     
     
         29 . A composition of matter, copmprising:
 (a) a composition comprising a peptidyl-prolyl isomerase cyclophilin 40 (CyP40) polypeptide, or a biologically active fragment thereof; or a polynucleotide encoding a CyP40 polypeptide, or a biologically active fragment thereof; or   (b) a packaged dosage formulation comprising at least one of i) a CyP40 polypeptide, or a biologically active fragment thereof; and/or ii) a polynucleotide encoding a CyP40 polypeptide, or a biologically active fragment thereof; in a pharmaceutically acceptable dosage in one or more packages, packets, or containers; or   (c) a kit comprising in one or more containers a CyP 40  polypeptide, or a biologically active fragment thereof, and/or a polynucleotide encoding said CyP40 polypeptide, or said biologically active fragment thereof.   
     
     
         30 - 43  canceled 
     
     
         44 . The composition of matter of  claim 29 , comprising (a). 
     
     
         45 . The composition of matter of  claim 29 , comprising (b). 
     
     
         46 . The composition of matter of  claim 29 , comprising (c).