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Vesiculins

Vesiculins description/claims

The inventions relate generally to peptides and proteins and related compositions and formulations and their preparation and use, nucleic acids encoding such peptides and proteins and related vectors and host cells, and methods for the prevention and treatment of conditions, diseases and disorders that would be improved, eased, or lessened by the administration of a composition of the invention, including but not limited to glucose metabolism diseases and disorders and diseases and disorders and conditions treated or treatable with insulin and other hypoglycemic agents.

The following includes information that may be useful in understanding the present inventions. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.

Insulin-like growth factor II (IGF-II) is a polypeptide growth factor which stimulates the proliferation of a wide range of cell types. Originally reported from human serum, human IGF-II is a 7.5 kDa single-chain polypeptide containing 67 amino acid residues. Rinderknecht, E. and Humbel, R. Proc. Natl. Acad. Sci. USA 73:4379-4381 (1976). For a general review of IGF-II, see, e.g., Binoux M., Diabete et Metabolisme, “The IGF system in metabolism regulation” 21(5):330-7 (1995).

IGF-II may exist in various forms as a result of amino acid insertions (Jansen, M., et al., FEBS Lett. 179:243 (1985); Hampton, B., et al., Journal of Biological Chemistry 264:19155-19160 (1989)), post-translational glycosylation (Hudgins, W., et al., J. Biol. Chem. 267:8153 (1992); Daughaday, et al., Proc. Natl. Acad. Sci. USA 90:5823-5827 (1993), differential processing of the COOH-terminal E-domain peptide (Hudgins, et al., J. Biol. Chem. 267:8153 (1992); Zumstein, P, et al., Proc. Natl. Acad. Sci. USA 82:3169-3172 (1985); Gowan, et al., Endocrinol. 121:449 (1987); Haselbacher and Humbel, Endocrinol. 110:1822 (1982); Haselbacher et al., Proc. Natl. Acad. Sci. USA 82:2153-2157 (1985); Daughaday, W., et al., N. Engl. J. Med. 319:1434 (1988); Shapiro et al., J. Clin. Invest. 85:1672 (1990); Hoekman, et al., Annals in Oncology 5:277 (1994)), and endoproteolysis (see Jansen, J., et al., Biochem. J. 266:513-520 (1990), reporting a double-chain molecule of IGF-II proposed to result from a naturally occurring single-point cleavage occurring between Ser29 and Arg30).

Altered IGF-II proteins have been reported, for example, [Leu27]-, [Glu27]-, and [Glu48]IGF-II (Burgisser, D., et al., J. Biol. Chem. 266:1029-1033 (1991)), and [Ser26]-, [Leu27]-, [Leu43]-, [Thr48, Ser49, Ile50]-, and [Arg54, Arg55]IGF-II (Sakano, K., et al., J. Biol. Chem. 266:20626-20635 (1991)). IGF-II deletion mutants have also been reported, for example, (7-67)- and (9-67)IGF-II (Luthi, C., et al., Eur. J. Biochem. 205:483-490 (1992)) and des(37-40)[Arg33]IGF-II (Zarn et al., Eur. J. Biochem. 210:665-669 (1992)). See also Roth, B., et al., “Mutants of human insulin-like growth factor II: expression and characterization of analogs with a substitution of TYR27 and/or a deletion of residues 62-67,” Biochem Biophys Res Commun. 181:907-14 (1991).

Diabetes mellitus, characterized by hyperglycemia and altered β-cell function, is a common disorder affecting millions of Americans. According to statistics provided by the American Diabetes Association (ADA), there are 18.2 million people in the United States, or 6.3% of the population, who have diabetes. Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at $132 billion.

Type 1 and type 2 diabetes are both diseases of the pancreas characterized by hyperglycemia. In type 1 diabetes the pancreatic islet β-cells, which secrete both insulin and amylin, peptide hormones that exert profound effects on glucose metabolism, are destroyed. In type 2 diabetes these cells progressively lose function, and often fail in the late stages of the disease. As one would expect given the severity of diabetes, and difficulties associated with it, the islet β-cells play a major role in physiology.

While therapeutic regimens exist to replace insulin and amylin function, diabetic individuals remain prone to complications which are a major threat to both the quality and the quantity of life. Many patients with diabetes die early, often as a result of cardiovascular or renal complications, preceded by many years of crippling and debilitating disease beforehand. It is estimated that diabetic individuals have a 25-fold increase in the risk of blindness, a 20-fold increase in the risk of renal failure, a 15- to 40-fold increase in the risk of amputation as a result of gangrene, and a 2- to 6-fold increased risk of coronary heart disease and ischemic brain damage. See, Klein R., et al., Diabetes Care 8:311-5 (1985). The ADA reports that two out of three people with diabetes die from heart disease and stroke, that diabetes is the leading cause of new cases of blindness in people ages 20-74 (with 12,000 to 24,000 people losing their sight because of diabetes), that diabetes is the leading cause of end-stage renal disease (kidney failure), accounting for about 43 percent of new cases (with approximately 41,046 people with diabetes initiating treatment for end stage renal disease and 129,183 undergoing dialysis or kidney transplantation in the year 2000), that more than 60 percent of nontraumatic lower-limb amputations in the U.S. occur among people with diabetes (with more than 82,000 amputations are performed among people with diabetes), that people with diabetes are two to four times more likely to suffer strokes (and once having had a stroke, are two to four times as likely to have a recurrence), that deaths from heart disease in women with diabetes have increased 23 percent over the past 30 years (compared to a 27 percent decrease in women without diabetes), and that deaths from heart disease in men with diabetes have decreased by only 13 percent (compared to a 36 percent decrease in men without diabetes).

Type 1 diabetes is characterized by an early loss of endocrine function in the pancreas due to autoimmune destruction of the pancreatic islet β-cells, resulting in hypoinsulinemia, hypoamylinemia, and hyperglycemia. Type 2 diabetes is a polygenic and heterogeneous disease resulting from an interaction between genetic factors and environmental influences. See, e.g., Kecha-Kamoun et al., Diabetes Metab Res Rev 17:146-152 (2001).

Although type 2 diabetes is initially characterized by hyperinsulinemia, peripheral insulin resistance and resulting hyperglycemia characterize type 2 diabetes. β-cells often compensate for this insulin resistance with both an increase in insulin secretory capacity and β-cell mass. Levels of insulin eventually decrease as a result of the loss of β-cell function and eventual β-cell failure. Thus, there is a progression from normal glucose tolerance, to impaired glucose tolerance, to type 2 diabetes, and to late stage type 2 diabetes, which is associated with altered β-cell function, β-cell loss and, eventually, a decline in insulin secretion. See, e.g., Dickson et al., J. Biol. Chem. 276:21110-21120 (2001). In other words, hyperglycemia worsens as β-cells fail to sustain levels of insulin output sufficient to overcome increasing resistance to insulin. Kaytor, et al., J Biol Chem. 16:16 (2001). Eventual β-cell failure is primarily a failure in function but later proceeds to β-cell loss such as that seen in type 1 diabetes. One of the most striking functional β-cell defects is a loss of acute glucose-induced insulin secretion (GIIS). β-cells initially adapt to increased demand for insulin but then decompensate as type 2 diabetes worsens. One hypothesis is that β-cells can become de-differentiated, leading to a loss of specialized functions, such as GIIS. Weir et al., Diabetes, 50 Supplement 1, S154-S159 (2001).

It is understood that integrated networks of signaling events act in concert to control β-cell mass adaptation to insulin demand, and there is some evidence to suggest that increased β-cell growth might in some part be due to a circulating growth factor. See, e.g., Flier et al. (2001) Proc. Nat. Acad. Sci. USA, 98:7475-7480, which reported that transplantation of normal islets into the pancreas or kidney capsule of insulin resistant mice led to a marked increase in β-cell mass.

Despite decades of research into diabetes and its causes, despite enormous research on β-cells themselves and the proteins they produce, and despite the existence and use of therapies for the treatment of people with type 1 and type 2 diabetes, serious problems remain.

The identification of other relevant proteins relating to diabetes and the pancreas, for example, β-cell proteins, would be of great benefit in the continuing effort to further improve the lives of people with diabetes including, for example, proteins that increase β-cell mass and address issues relating to hyperglycemia and the long-term complications of diabetes and the loss of circulating proteins as a result of β-cell destruction.

A new β-cell peptide hormone has been discovered and is described and claimed herein. The peptide has bioactivity including increasing glucose uptake.

The inventions described and claimed herein have many attributes, aspects, and embodiments including, but not limited to, those set forth or described or referenced in this Brief Summary. It is not intended to be all-inclusive and the inventions described and claimed herein are not limited to or by the features or embodiments identified in this Brief Summary, which is included for purposes of illustration only and not restriction.

The inventions described and claimed herein relate to the discovery of a previously unknown peptide, termed vesiculin. The peptide is present in pancreatic β-cell secretory granules, including human β-cell secretory granules.

In a first aspect isolated vesiculins are provided. Also provided are vesiculin nucleic acid sequences. Vesiculins and vesiculin polynucleotides may be recombinant, isolated, pure or purified, or substantially pure.

In another aspect vesiculin A chain polypeptides and polynucleotides are provided, for example, human vesiculin A chain polypeptides and polynucleotides. Also provided are A chain fragments.

In yet another aspect vesiculin B chain polypeptides and polynucleotides are provided, for example, human vesiculin B chain polypeptides and polynucleotides. Also provided are B chain fragments.

Vesiculin A and B chain polypeptides and fragments, and polynucleotides coding therefor, may be recombinant, isolated, pure or purified, or substantially pure.

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