Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Separation or purification
Reexamination Certificate
2001-10-09
2004-06-01
Carlson, Karen Cochrane (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Separation or purification
C530S300000, C530S350000
Reexamination Certificate
active
06743899
ABSTRACT:
FIELD OF THE INVENTION
The invention is a process that reduces, eliminates or inactivates the agent that causes transmissible spongiform encephalopathy (TSE) from lipoproteins in a manner that does not adversely affect the biological activity of the lipoproteins.
BACKGROUND OF THE INVENTION
Water-insoluble lipids like cholesteryl esters, triglycerides and the more polar phospholipids and unesterified cholesterol must travel through the aqueous environment of plasma (Bradely, W. A. and Gotto, A. M.: American Physiological Society, Bethesda, Md., pp 117-137 (1978)). The solubility of these lipids is achieved through physical association with proteins termed apolipoproteins, and the lipid-protein complexes are called lipoproteins (Dolphin, P. J.,
Can. J. Biochem. Cell. Biol.
63, 850-869 (1985)). Five distinct classes of lipoproteins have been isolated from human plasma: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL) and lipoprotein (a) (Lp(a)) (Alaupovic, P. (1980) In Handbook of Electrophoresis. Vol. 1, pp. 27-46; Havel, R. J., Eder, H. A.; Bragdon, J. H.,
J. Clin. Invest.
34, 1343 (1955)). Dietary triglycerides and cholesterol are assembled by enterocytes (intestinal cells) into a chylomicron particle, which enters circulation through the lymphatic system (Brown, M. S. and Goldstein, J. L Sci. American (1984) 251, 58-66). Chylomicrons provide fatty acids to peripheral cells and cholesterol to liver. The liver in turn repackages cholesterol together with triglycerides into another lipoprotein called VLDL.
The function of VLDL is similar to chylomicrons, i.e. supply of free fatty acids to the muscle and adipose tissues and cholesterol to peripheral cells (Brown, M. S. and Goldstein, J. L Sci. American (1984) 251, 58-66). In the circulatory system, triglycerides in the VLDL particle are hydrolyzed by an enzyme called lipoprotein lipase (LPL) and additional processing by hepatic lipase finally converts it to LDL (Dolphin, P. J.: Can. J. Biochem. Cell. Biol. (1985) 63, 850-869). Thus, the liver produces VLDL, the precursor of LDL. Because VLDL is a precursor to LDL, decreases in VLDL production translate into lowered LDL levels. High levels of circulating LDL have been positively correlated with the development of coronary disease. While LDL cholesterol is clearly an independent positive risk factor, HDL cholesterol is considered to be a negative risk factor (Tribble, D. L.; Krauss, R. M. Advances in Internal Medicine (1993) 38:1-29).
HDL promotes reverse cholesterol transport, a process by which excess cholesterol is extracted from peripheral cells by HDL and delivered to the liver for its elimination. Reverse cholesterol transport, therefore, reduces cholesterol accumulation in the artery wall (Reichl, D and Miller, N. E.,
Arteriosclerosis
9, 785 (1989)). Because there is no cholesterol accumulation in extrahepatic organs, cholesterol must be transported to the liver by HDL for ultimate excretion into bile, either as free cholesterol, or as bile acids that are formed from cholesterol (Kwiterovich, P. O.,
Amer. J. Cardiol.
82, 13Q, (1998)). HDL can acquire part of its anti-atherogenic character by promoting the reverse transport of cholesterol.
In humans, low HDL cholesterol levels can relate to defects in synthesis or catabolism of Apo-Al, with catabolic defects being more common (Brinton, E. A., et al.,
Ateriosclerosis Thromb.
14, 707 (1994)); Fridge, N., et al.,
Metabolism
29, 643 (1980)). Low HDL is often associated with hypertriglyceridemia, obesity, and insulin resistance (Brinton, E. A., et al.,
Ateriosclerosis Thromb.
14, 707 (1994)). HDL from hypertriglyceridemic subjects characterized by low HDL levels have small HDL particles which are susceptible to renal filtration and degradation. The liver is the principal organ of HDL apolipoprotein degradation (Horowitz, B. S., et al.,
J Clin. Invest.
91, 1743 (1993)).
HDL has other important characteristics that can contribute to its anti-atherogenic properties. Recent evidence suggests that HDL can have antioxidant and antithrombotic properties (Tribble, D., et al.,
J. Lipid Res.
36, 2580 (1995); Mackness, M. I., et al.,
Biochem. J.
294, 829 (1993); Zeither, A. M., et al.,
Circulation
89, 2525 (1994)). HDL can also affect the production of some cell adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), (Cockerill, G. W., et al.,
Arterioscler. Thromb.,
15, 1987 (1995)). These properties of HDL also provide protection against coronary artery disease.
Cholesterol and cholesterol-containing lipoproteins obtained from mammalian serum are also useful to promote the growth of various organisms. J. Bacteriol., Vol. 135, pp. 818-827 (1978) describes the use of a cholesterol-containing bovine serum fraction in the growth of Mycoplasma pneumoniae and Mycoplasma arthritidis. J. Gen. Microbiology, Vol. 116, pp. 539-543 (1980) describes the use of USP cholesterol in the growth of Treponema hyodysenteriae.
U.S. Pat. No. 4,290,774 describes the production of a specific cholesterol-rich fraction from mammalian plasma or serum by a process that involves the step of treatment with an alkaline carbonate and an alkaline earth salt. Zeit. Klin. Chem. 6(3), pp. 186-190 (1968) describes the removal of certain lipoproteins from human serum by use of colloidal silicic acid.
U.S. Pat. No. 4,762,792 discloses a process for isolating a cholesterol-rich fraction from mammalian blood plasma or serum using a silica adsorbant followed by several alkaline steps.
Transmissible Spongiform Encephalopathy
The transmissible degenerative encephalopathies, also known as spongiform encephalopathies or transmissible spongiform encephalopathies (TSE), constitute a distinct group of fatal neurological diseases of mammals. In 1994, Prusiner described the “remarkable discoveries in the past three decades (which have) led to the molecular and genetic characterization of the transmissible pathogen causing scrapie in animals and several illnesses in humans: Kura, Creutzfeldt Jacob Disease (CJD), Gerstmann-Straussler-Scheinker disease, and Fatal Familial Insomnia. To distinguish this infectious pathogen from viruses and viroids, the term PRION was introduced to emphasize its proteinaceous and infectious nature.” Prusiner, “Biology and Genetics of Prion Diseases,”
Annu. Rev. Microbiol.
48:655-686 (1994). A prion is composed solely of one host-encoded protein (referred to as the “PrP”) that resists most inactivation procedures such as heat, radiation and/or proteases. The latter characteristic has led to the term “protease-resistant isoform” of the prion protein. Amino acid sequences of PrP obtained from normal and infected brains are identical, and these two proteins differ only in their biochemical and biophysical behavior. In particular, PrP from TSE individuals resists proteinase K digestion, while PrP-c found in normal individuals is degraded by proteinase K. PrP-res is not associated with an increase in mRNA, instead the accumulation is post-translational. Infected animals accumulate their own PrP-res, not that used for, or which created, the infection (Dormont,
Agents that cause transmissible subacute spongiform encephalopathies
, Biomed & Pharmacother 1999:53:3-8).
Prions resist almost all of the general procedures used to inactivate conventional viruses. Dormont, id.
Mad cow disease, or bovine spongiform encephalopathy (BSE), is the most well known TSE. All of the transmissible spongiform encephalopathies are progressive degenerative disorders that affect the central nervous system of animals and humans. These neurologic diseases take part of their name from the spongiform or “sponge-like” degeneration of brain tissue that they cause. These diseases share many clinical and pathological features, and some scientific evidence now suggests that they develop through common or closely related mechanisms. This degeneration is most common in the cerebral cortex, the basal ganglia and the thalamus. Among other unique featu
McCall Thomas M.
Montalto Joseph G.
Vollmer-Gash Judith A.
Adams Stephanie D.
Carlson Karen Cochrane
King & Spalding LLP
Knowles Sherry M.
Serologicals Royalty Company
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