Rodent models of human amyloidoses

Details Rodent models of human amyloidoses Rodent models of human amyloidoses

1996-10-03

2002-01-22

Crouch, Deborah (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

The nonhuman animal is a model for human disease

C514S008100, C514S012200, C435S040500, C435S040520

Reexamination Certificate

active

06340783

ABSTRACT:

TECHNICAL FIELD
The invention provides animal models for the evaluation of candidate drugs and therapies for the prevention and treatment of amyloidoses, including Alzheimer's disease. For example, a rapid animal model of congophilic and fibrillar &bgr;/A4 amyloid deposition in brain is provided for in vivo screening of candidate therapeutic agents and protocols. Heparin, heparan sulphate glycosaminoglycans, and related macromolecules, as well as heparin-binding peptides, are provided as therapeutic agents for amyloid deposition in Alzheimer's disease brain and other amyloidoses.
BACKGROUND OF THE INVENTION
Amyloid and Amyloidosis
Amyloid is a generic term referring to a group of diverse, but specific extracellular protein deposits which all have common morphological properties, staining characteristics and x-ray diffraction spectra. Regardless of the nature of the amyloid protein deposited all amyloids have the following characteristics: 1) an amorphous appearance at the light microscopic level and appear eosinophilic using hematoxylin and eosin stains; 2) all stain with congo red and demonstrate a red/green birefringence as viewed under polarized light; 3) all contain a predominant beta-pleated sheet secondary structure; and 4) ultrastructurally amyloid usually consists of non-branching fibrils of indefinite length and with a diameter of 8-12 nm.
Amyloidosis: Early Historical Perspectives
Rokitansky in 1842 was the first to observe waxy, eosinophilic tissue deposits in a number of tissues from different patients. However, it wasn't until 1854 when Virchow termed these deposits as “amyloid” meaning “starch-like” since they gave a positive staining with the sulfuric acid-iodine reaction, which was used in the 1850s for demonstrating cellulose. Although cellulose is not a constituent of amyloid, nonetheless, the staining that Virchow observed is probably due to the presence of different carbohydrates, known as highly sulfated glycosaminoglycans and proteoglycans, which appear to be associated with all types of amyloid deposits (see below). The name amyloid has remained despite the fact that Freiderich & Kekule in 1859 discovered the protein nature of amyloid.
Amyloid is not a Single Disease
For many years, based on the fact that all amyloids have the same staining and structural properties, lead to the postulate that a single pathogenetic mechanism was involved in amyloid deposition, and that amyloid deposits were thought to be composed of a single set of constituents. Current research has clearly shown that amyloid is not a uniform deposit and that amyloids may consist of different protein which are totally unrelated.
Amyloidosis is not an “Immune Disorder”
It is interesting that the pathology textbook by Robbins has “amyloidosis” under the heading of “possible immune disorders”. Obviously these authors thought like many of the predecessors studying amyloidosis in the 1960s and 1970s. This is based on a number of early observations made about amyloidosis. 1) Clinically, many types of amyloid were due to a complication of long-standing inflammatory disorders such as rheumatoid arthritis or osteomyelitis. 2) Histologically, tissue reactions in many of these disorders were characterized by the presence of immunologically competent cells (e.g. monocytes, macrophages, plasma cells. 3) Amyloid was developed in animals used for raising antisera. Repeated injections of antigens were not uncommonly followed by systemic amyloid deposits. Therefore, clinical, histological, and experimental data focused attention, not illogically, upon the immune system. However, by the mid-late 1970s, the isolation, characterization and sequencing of amyloid proteins from different clinical settings showed that a basic immunological disturbance could not account for the diversity of proteins seen as amyloids in the different diseases.
Clinical Classification of Amyloidosis
Let's look at how amyloid was classified initially in the mid to late 1970s and then compare it to the classification according to protein type which is used today. Basically, amyloid was clinically classified into 4 groups, primary amyloid, secondary amyloid, familial amyloid, and isolated amyloid.
Primary amyloid, is amyloid appearing de novo, without any preceding disorder. In 25-40% of these cases, primary amyloid was the antecedent of plasma cell dysfunction such as the development of multiple myeloma or other B-cell type malignancies. Here the amyloid appears before rather than after the overt malignancy. Regardless of which clinical element appeared first, the type of amyloid protein in primary amyloid is most often the same as that seen in amyloid secondary to a variety of B-cell dysfunctions.
Secondary amyloid, appears as a complication of a previously existing disorder. 10-15% of patients with multiple myeloma eventually develop amyloid. Patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis can develop secondary amyloidosis as with patients with tuberculosis, lung abscesses and osteomyelitis. Intravenous drug users who self-administer and who then develop chronic skin abscesses can also develop secondary amyloid. Secondary amyloid is also seen in patients with specific malignancies such as Hodgkin's disease and renal cell carcinoma. Although these were all initially classified as secondary amyloid, once the amyloid proteins were isolated and sequenced, many of these turned out to contain different amyloid proteins.
The familial forms of amyloid also show no uniformity in terms of the peptide responsible for the amyloid fibril deposited. Several geographic populations have now been identified with genetically inherited forms of amyloid. One group is found in Israel, predominantly among Sephardic Jews, and this disorder is called Familial Mediterranean Fever and it is characterized by amyloid deposition, along with recurrent inflammation and high fever. Another form of inherited amyloid is known as Familial Amyloidotic Polyneuropathy, and it has been found in at least three nationalities, namely, Swedish, Portuguese and Japanese. Amyloid deposition in this disease occurs predominantly in the peripheral and autonomic nerves. Hereditary amyloid angiopathy of Icelandic origin is a autosomal dominant form of amyloid deposition primarily affecting the vessels in the brain, and has been identified in 128 members distributed in at least 8 families restricted to a small geographic area of western Iceland. These patients clinically have massive cerebral hemorrhages in early life which usually causes death before the age of 40.
The primary, secondary and familial forms of amyloid that I have so far described tend to involve many organs of the body including heart, kidney, liver, spleen, GI tract and skin.
Isolated forms of amyloid, on the other hand, tend to involve a single organ system. Isolated amyloid deposits have been found in the lung, and heart. Up to 90% of type II diabetic patients (non-insulin form of diabetes) have isolated amyloid deposits in the pancreas restricted to the beta cells in the islets of Langerhans. Isolated forms of amyloid have also been found in endocrine tumors which secrete polypeptide hormones such as in medullary carcinoma of the thyroid. A serious complication of long-term hemodialysis is amyloid deposited in the medial nerve and clinically associated with carpal tunnel syndrome. By far the most common type of organ-specific amyloid, and amyloid in general, is that found in the brains of patients with Alzheimer's disease. In this disorder, amyloid is predominantly restricted to the central nervous system (CNS). Similar deposition of amyloid in the brain occurs in Down's syndrome patients once they reach the age of 35 years. Other types of CNS amyloid deposition include rare but highly infectious disorders such as Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome and scrapie in animals.
Current Classification of Amyloid: By Protein Type
It was misleading to group the various amyloidotic disorders strictly on the basis of their clinical featur

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