Compositions and methods for stimulating amyloid removal in amyloidogenic diseases using advanced glycosylation endproducts

• US 5,935,927 A
• Filed: 08/10/1996
• Issued: 08/10/1999
• Est. Priority Date: 02/03/1994
• Status: Expired due to Fees

• Current Assignee: Alteon Incorporated
• Original Assignee: The Picower Institute For Medical Research
• Inventors: Vitek, Michael P., Zhang, Xini, Vlassara, Helen, Cerami, Anthony, Bucala, Richard J., Ulrich, Peter C.
• Primary Examiner(s): DUFFY, PATRICIA ANN
• Application Number:
  US08/501,127
• Time in Patent Office: 1,095 Days
• Field of Search: 530/300, 530/322, 514/2, 514/647, 514/12, 514/23, 514/569, 514/663, 514/665, 514/79, 514/91, 514/95, 514/359, 514/438, 514/439, 514/443, 514/642, 548/100, 548/121, 548/122, 536/1.11
• US Class Current: 514/17.8
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The present invention relates generally to methods and compositions for treating amyloidogenic diseases such as Alzheimer'"'"'s disease and the development of type II diabetes, in which deposition of amyloid in organs such as the brain and pancreas interfere with neurological function and insulin release, respectively. The methods and compositions are directed toward increasing the activity of scavenger cells within the body at recognizing and removing amyloid deposits from affected tissues and organs. Scavenger cells may be targeted to amyloid deposits by means of spontaneously-occurring chemical modifications called advanced glycosylation endproducts (AGEs). Compositions are described which increase scavenger cell activity towards AGE-modified amyloid. Amyloid removal may also be enhanced by increasing AGE levels in amyloid deposits within the body by administering AGE-modified amyloid targeting agents, which after becoming situated at sites containing amyloid, subsequently attract scavenger cells to degrade attendant amyloid. These methods and associated compositions result in a decrease in the extent of amyloid deposits in tissues, reducing the attendant pathology.

Claims

1. A method for enhancing removal of amyloid from a peripheral tissue of a mammal afflicted with or developing a disease or disorder associated with amyloidosis, comprising administering to said mammal an amyloid targeting agent conjugated with advanced glycosylation endproducts (AGEs) or AGE precursors.

2. The method of claim 1 wherein said amyloid targeting agent is selected from the group consisting of Congo Red and thioflavin.

3. The method of claim 2 wherein the amiyloid targeting agent conjugated with AGEs or AGE precursors is administered via a route selected from the group consisting, of intraventricular, intracranial, intravenous, intraarterial, oral, nasal, and combinations thereof.

4. The method of claim 1 wherein said disease or disorder associated with amyloidosis involves the pancreas and the agent is AGE-amylin.

9. The agent of claim 2 which has a structure as depicted in formula 8:

5. A purified advanced glycosylation endproduct-modified (AGR)-amyloid polypeptide selected from the group consisting of AGE-amylin and AGE-serum amyloid A.

6. A pharmaceutical composition comprising the AGE-amyloid polypeptide of claim 5 and a pharmaceutically acceptable carrier.

7. An agent for enhancing removal of amyloid from tissue of a mammal comprising an amyloid targeting agent conjugated with advanced glycosylation endproducts (AGEs) or AGE precursors wherein said amyloid targeting agent is selected from the group consisting of Congo Red and thioflavin.

8. The agent of claim 7 which has a structure as depicted in formula 6a:

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