Compositions and Methods for Treatment of Hereditary Cystatin C Amyloid Angiopathy (HCCAA) and Other Neurodegenerative Disorders Associated with Aberrant Amyloid Deposits

Abstract

Compositions and Methods for the Treatment of Amyloid Deposit diseases, e.g., Hereditary cystatin C amyloid angiopathy and other neurodegenerative disorders, are disclosed.

What is claimed is: 
     
         1 . A method for treating amyloid deposit disease comprising delivering an effective amount of at least one antioxidant to a patient at risk for amyloid disease. 
     
     
         2 . The method of  claim 1  wherein said amyloid disease is hereditary cystatin C amyloid angiopathy (HCCAA) caused by mutated cystatin C. 
     
     
         3 . The method of  claim 2  wherein said mutated cystatin C comprises a L68Q cystatin C. 
     
     
         4 . The method of  claim 1 , wherein said antioxidant is selected from the group consisting of glutathione, N-acetyl cysteine or a derivative thereof and is effective to reduce amyloid disease symptoms. 
     
     
         5 . The method of  claim 4 , wherein said derivative is selected from NAC-amide, NAC-ethyl ester and zinc mercaptide N-acetyl cysteine carboxylate salt. 
     
     
         6 . A method for treatment of hereditary cystatin C amyloid angiopathy (HCCAA) in a human subject in need thereof, comprising administration of an effective amount of N-acetyl cysteine or functional derivative thereof in a pharmaceutically acceptable carrier, said administration being effective to reduce amyloid-cystatin protein aggregates, thereby alleviating symptoms of HCCAA, wherein said NAC derivative is selected from NAC-amide, NAC-ethyl ester and zinc mercaptide N-acetyl cysteine carboxylate salt. 
     
     
         7 . The method of  claim 6  further comprising performing a skin biopsy on said subject following treatment to assess reduction in amyloid-cystatin protein aggregates in skin. 
     
     
         8 . The method of  claim 6  comprising administration of an ionophore. 
     
     
         9 . The method of  claim 1  comprising administration of an anti-inflammatory agent. 
     
     
         10 . The method of  claim 9 , wherein said disease is HCCAA, said antioxidant is a NAC derivative is selected from NAC-amide, NAC-ethyl ester and zinc mercaptide N-acetyl cysteine carboxylate salt and said anti-inflammatory agent is selected from the group consisting of one or more of corticosteroids, aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, cytokine receptors for IL-1, tumor necrosis factor-alpha, IL-18 and derivatives and biosimilars thereof. 
     
     
         11 . The method of  claim 1 , comprising administration of one or more of glutathione, siRNA, monensin, papain, cathepsin B, and falcipain 
     
     
         12 . A method for treatment of a neurodegenerative disorder associated with pathogenic fibrillation protein aggregates in a human subject in need thereof, comprising administration of an effective amount of N-acetyl cysteine or functional derivative thereof in a pharmaceutically acceptable carrier, said administration being effective to reduce said protein aggregates, thereby alleviating symptoms of said neurodegenerative disorder. 
     
     
         13 . The method of  claim 1 , wherein said disorder is selected from Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob's disease, Huntington disease and other CAAs. 
     
     
         14 . The method of  claim 1  further comprising monitoring said patient for amyloid deposit levels. 
     
     
         15 . A method for identifying therapeutic agents which alter amyloid-cystatin protein aggregate formation for use in the method of  claim 1 , comprising,
 a) providing cells expressing a nucleic acid encoding a mutant hCC protein, said mutant causing formation of amyloid-cystatin protein aggregates;   b) providing cells which express a hCC protein which lacks the hCC mutation;   c) contacting the cells of steps a) and b) with a test agent and   d) analyzing whether said agent alters amyloid-cystatin protein aggregate formation of cells of step a) relative to those of step b), thereby identifying agents which alter amyloid-cystatin protein aggregation.   
     
     
         16 . The method of  claim 15  wherein said therapeutic has efficacy for the treatment of HCCAA or other disorders associated aberrant fibril formation. 
     
     
         17 . A method for the treatment of HCCAA in a patient in need thereof comprising administration of an effective amount of the agent identified by  claim 15 . 
     
     
         18 . The method of  claim 15 , wherein said agent is NAC or a functional derivative thereof. 
     
     
         19 . A pharmaceutical composition comprising an effective amount of an agent which acts as an antioxidant and, or a reducing agent for the treatment of amyloid deposit disease in a pharmaceutically acceptable carrier. 
     
     
         20 . The pharmaceutical composition of  claim 19  wherein said agent is glutathione, N-acetyl cysteine or a derivative thereof. 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein said derivative is selected from NAC-amide, NAC-ethyl ester and zinc mercaptide N-acetyl cysteine carboxylate salt. 
     
     
         22 . The pharmaceutical composition of  claim 19 , further comprising one or more of an ionophore, an anti-inflammatory agent or a protease.