Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
2000-03-27
2003-05-13
Priebe, Scott D. (Department: 1636)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S008000, C800S009000, C800S003000, C800S014000, C800S018000, C800S021000, C800S022000, C800S025000, C435S320100, C435S325000, C435S455000
Reexamination Certificate
active
06563016
ABSTRACT:
The invention relates to the overproduction of perlecan in transgenic animals and transfected animal cells as screening tools to identify lead therapeutics for the amyloid diseases.
BACKGROUND OF THE INVENTION
The Amyloid Diseases
The “amyloid diseases” consist of a group of clinically and generally unrelated human diseases which all demonstrate a marked accumulation in tissues of an insoluble extracellular substance known as “amyloid”, and usually in an amount sufficient to impair normal organ function. Rokitansky in 1842 (Rokitansky, “Handbuch der pathologischen Anatomie”, Vol. 3, Braumuller and Seidel, Vienna) was the first to observe waxy and amorphous looking tissue deposits in a number of tissues from different patients. However, it wasn't until 1854 when Virchow (Virchow,
Arch. Path. Anat
. 8:416 (1854)) 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 1850's for demonstrating cellulose. Although cellulose is not a constituent of amyloid, nonetheless, the staining that Virchow observed was probably due to the present of proteoglycans (PGs) which appear to be associated with all types of amyloid deposits. The name amyloid has remained despite the fact that Friederich and Kekule in 1859 discovered the protein nature of amyloid (Friedrich and Kekule,
Arch. Path. Anat. Physiol
. 16:50 (1859)). 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 proteins which are totally unrelated (Glenner,
N. England J. Med
. 302:1283-1292 (1980)).
Although the nature of the amyloid itself has been found to consist of completely different and unrelated proteins, all amyloids appear similar when viewed under the microscope due to amyloid's underlying protein structure to adapt into a fibrillar structure. All amyloids regardless of the nature of the underlying protein 1) stain characteristically with the Congo red dye and display a classic red/green birefringence when viewed under polarized light (Puchtler et al,
J. Histochem, Cytochem
. 10:355-364 (1962)), 2) ultrastructurally consists of fibrils with a diameter of 7-10 nanometers and of indefinite length, 3) adopt a predominant beta-pleated sheet secondary structure. Thus, amyloid fibrils viewed under an electron microscope (30,000 times magnification) from the post-mortem brain of an Alzheimer's disease patient would look nearly identical to the appearance of amyloid present in a biopsied kidney from a rheumatoid arthritic patient. Both these amyloids would demonstrate a similar fibril diameter of 7-10 nanometers.
In the mid to late 1970's 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. Secondary amyloid, appeared as a complication of a previously existing disorder. 10-15% of patients with multiple myeloma eventually develop amyloid (Hanada et al.,
J. Histochem. Cytochem
. 19:1-15 (1971)). Patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis can develop secondary amyloidosis as with patients with tuberculosis, lung abscesses and osteomyelitis (Benson and Cohen,
Arth. Rheum
. 22:36-42 (1979); Kamei et al.,
Acta Path. Jpn
. 32:123-133 (1982); McAdam et al.,
Lancet
2:572-575 (1975)). Intravenous drug users who self-administer and who then develop chronic skin abscesses can also develop secondary amyloid (Novick,
Mt. Sin. J. Med
. 46:163-167 (1979)). Secondary amyloid is also seen in patients with specific malignancies such as Hodgkin's disease and renal cell carcinoma (Husby et al.,
Cancer Res
. 42:1600-1603 (1982)). 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 showed 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 and this disorder is called Familial Mediterranean Fever and is characterized by amyloid deposition, along with recurrent inflammation and high fever (Mataxas,
Kidney
20:676-685 (1981)). Another form of inherited amyloid is Familial Amyloidotic Polyneuropathy, and has been found in Swedish (Skinner and Cohen, Biochem. Biophys. Res. Comm. 99:1326-1332 (1981)), Portuguese (Saraiva et al.,
J. Lab. Clin. Med
. 102:590-603 (1983);
J. Clin. Invest
. 74:104-119 (1984)) and Japanese (Tawara et al.,
J. Lab. Clin. Med
. 98:811-822 (1981)) nationalities. Amyloid deposition in this disease occurs predominantly in the peripheral and autonomic nerves. Hereditary amyloid angiopathy of Icelandic origin is an autosomal dominant form of amyloid deposition primarily affecting the vessels in the brain, and has been identified in a group of families found in Western Iceland (Jennson et al.,
Clin. Genet
. 36:368-377 (1989)). 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 described above tend to involve many organs of the body including heart, kidney, liver, spleen, gastrointestinal tract, skin, pancreas, and adrenal glands. These amyloid diseases are also referred to as “systemic amyloids” since so many organs within the body demonstrate amyloid accumulation. For most of these amyloidoses, there is no apparent cure or effective treatment and the consequences of amyloid deposition can be detrimental to the patient. For example, amyloid deposition in kidney may lead to renal failure, whereas amyloid deposition in heart may lead to heart failure. For these patients, amyloid accumulation in systemic organs leads to eventual death generally within 3 to 5 years.
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 (Wright et al.,
Lab. Invest
. 30:767-773 (1974); Pitkanen et al., Am. J. Path. 117:391-399 (1984)). Up to 90% of type II diabetic patients (non-insulin dependent form of diabetes) have isolated amyloid deposits in the pancreas restricted to the beta cells in the islets of Langerhans (Johnson et al.,
New Engl. J. Med
. 321:513-518 (1989);
Lab Invest
66:522-535 (1992)). Isolated forms of amyloid have also been found in endocrine tumors which secrete polypeptide hormones such as in medullary carcinoma of the thyroid (Butler and Khan,
Arch. Path. Lab. Med
. 110:647-649 (1986); Berger et al.,
Virch. Arch. A Path. Anat. Hist
. 412:543-551 (1988)). A serious complication of long term hemodialysis is amyloid deposited in the medial nerve and clinically associated with carpal tunnel syndrome (Gejyo et al.,
Biochem. Biophys. Res. Comm
. 129:701-706 (1985);
Kidney Int
. 30:385-390 (1986)). By far, the most common type and clinically relevant type of organ-specific amyloid, and amyloid in general, is that found in the brains of patients with Alzheimer's disease (see U.S. Pat. No. 4,666,829 and Glenner and Wong,
Biochem. Biophys. Res. Comm
. 120:885-890 (1984); Masters et al.,
Proc. Natl. Acad. Sci. USA
82:4245-4249 (1985)). In this disorder, amyloid is predominantly restricted to the central nervous system. Similar deposition of amyloid in the brain occurs in Down's syndrome patients
Fukuchi Ken-Ichiro
Hassell John
Snow Alan D.
Dwyer Patrick M.
Kaushal Sumesh
Priebe Scott D.
University of Washington
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