Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-02-08
2002-04-30
Clark, Deborah J. R. (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S320100, C435S325000, C435S455000, C800S013000
Reexamination Certificate
active
06380374
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of the invention is ion transporters, particularly sodium phosphate co-transporters.
2. Background of the Invention
Phosphorous plays an important role in membrane structure, transport and energy storage. At normal physiological pH (e.g. pH of 7.4), inorganic phosphate (Pi) in plasma is made up of a 4:1 mixture of HPO
4
2−
and H
2
PO
4
−
. Of the 700 g of phosphorous present in the body, 0.1% is present in the extracellular fluid in a freely diffusible form. The plasma level of Pi is maintained through control of Pi absorption in the small intestine, under the influence of vitamin D, and Pi excretion in the kidney, under the influence of parathyroid hormone.
Absorption of Pi requires transepithelial transport. A critical step of transepithelial transport of Pi is the uptake of Pi into epithelial cells. Pi uptake is accomplished by sodium phosphate co-transporters present on the apical surface of appropriate epithelial cells, e.g. intestinal and renal epithelial cells. A variety of sodium phosphate co-transporters have been identified to date, including: NaPi-1(rabbit); NPT1 (human); Npt1 (mouse); NaPi-2 (rat); NaPi-3 (human); NaPi-4 (opossum); NaPi-5 (flounder); NaPi-6 (rabbit); NaPi-7 (mouse); and NaPi of NBL-1 cells (bovine).
A variety of disease conditions are associated with disorders in Pi metabolism, where such disease conditions include those characterized by the presence of hypophosphatemia, e.g. osteomalacia, hypocalciuria and rickets, and those characterized by the presence of hyperphosphatemia, e.g. hyperparathyroidism, hypocalcemia, vitamin D deficiency, soft tissue or metastatic calcification, and the like. In particular, hyperphosphatemia is a characteristic of renal disease and failure, and is an underlying cause of many of the deleterious symptoms observed with such renal complications.
Methods of treating abnormalities in Pi metabolism are varied. For example, for disease conditions associated with the presence of hypophosphatemia, treatment methodologies include: changes in diet to include phosphorous rich foods, supplementation with phosphorous salts, use of therapeutic agents, e.g. dipyridamole, and the like. For those disease conditions associated with hyperphosphatemia, treatment in the absence of renal insufficiency may include hydration and/or the use of aluminum based antacids that bind phosphorous in the intestinal lumen. Where renal insufficiency is present, phosphate binders and/or dietary modification to restrict phosphorous intake are potentially useful, but dialysis is typically employed.
Because of the wide variety of disease conditions characterized by the presence of abnormal Pi metabolism, there is continued interest in the identification of the molecular components responsible for Pi metabolism. Of particular interest would be the identification of the intestinal transporter responsible for absorption and uptake of Pi in the intestine.
Relevant Literature
Hilfiker et al., Proc. Nat'l Acad. Sci. USA (1998) 95:14564-14569 discloses the mouse Npt2B nucleic acid sequence. Also of interest is: Feild et al., “Cloning and Characterization of a Sodium Dependent Phosphate Transporter Isoforn Expressed in Human Small Intestine and Lung,” Published on Dec. 24, 1998 under GenBank Accession No. 4071357 and submitted by Smithkline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pa. 19406 on Dec. 7, 1998). References disclosing sodium phosphate co-transporters include: Werner et al., Proc. Nat'l Acad. Sci. USA (1991) 88:9608-9612; Chong et al., Genomics (1993) 18:355-359; Chong et al., Am. J. Physiol. (1995) 268:F1038-F1045; Magagnin et al., Proc. Nat'l Acad. Sci. USA (1993) 90:5979-5983; Sorribas et al., J. Biol. Chem. (1994) 269:6615-6621; Werner et al., Am. J. Physiol. (1995) 267:F311-F317; Verri et al., Am J. Physiol. (1995) 268:F626-F633; Collins et al., FASEB J. (1994) 8:862-868; and Helps et al., Eur. J. Biochem. (1995) 228:927-930.
Also of interest is WO 98/37198.
References providing background information on the role of sodium phosphate co-transporters in phosphorous metabolism include: Tenenhouse, J. Bone Min. Res. (1997) 12:159; and Harrison's Principles of Internal Medicine, 14
th
Ed. (1998) pp2259-2263.
SUMMARY OF THE INVENTION
A novel human intestinal sodium phosphate co-transporter (i.e. Npt2B) and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptide and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications, as well as in treatment therapies. Also provided are methods of treating disease conditions associated with intestinal Npt2B function, e.g. conditions characterized by abnormal serum phosphate levels, such as hypo- and hyperphosphatemia.
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Hilfiker, Helene, et al., “Characterization of a Murine Type II Sodium-Phosphate Cotransporter Expressed in Mammalian Small Intestine,”Proc. Natl. Acad. Sci. USA(Nov. 1998) vol. 95:14564-14569.
Kohl, Beate, et al., “Na-PiCotransport in Flounder: Same Transport System in Kidney and Intestine,”Am. J. Physiol. 270(Renal Fluid Electrolyte Physiol, 39):F937-F944 (1996).
Cannon Paul David
Sankuratri Suryanarayana
Borden Paula A.
Bozicevic Field & Francis LLP
Clark Deborah J. R.
Field Bret E.
Paras, Jr. Peter
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