Compositions and Methods for Treating and Preventing Pancreatitis, Renal Injury and Cancer

Abstract

The present invention includes compositions and methods for detecting, treating and preventing renal and pancreatic diseases and disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to U.S. Provisional Application No. 61 / 994,279, filed May 16, 2014, which is hereby incorporated by reference in its entirety herein.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under grants RC1DK086465, RC1DK086402 and R01DK081037, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Renalase (also designated RNLS and gene C10orf59) is a novel secretory flavoprotein oxidase (Farzaneh-Far et al., 2010, PLoS One 5:e13496; Desir et al., 2012, J. Am. Heart Assoc. 1:e002634; Desir et al., 2012, 6:417-426; J. Am. Soc. Hypertension; Xu et al., 2005, J. Clin. Invest. 115:1275-1280; Li et al., 2008, Circulation 117:1277-1282). Single nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease and diabetes (Farzaneh-Far et al.,...

AI Technical Summary

Benefits of technology

[0012]In one embodiment, the invention is a method of treating or preventing a renal disease or disorder in a subject in need thereof, by administering to the subject a therapeutically effective amount of a composition comprising at least one PMCA4b activator. In various embodiments, the PMCA4b activator is a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a small molecule chemical compound, or a combination thereof. In one embodiment, the PMCA4b activator is a renalase polypeptide, or a fragment or conjugate or analogue or homolog thereof. In one embodiment, the renalase polypeptide comprises the amino acid sequence of SEQ ID NO: 8, or a fragment or conjugate or analogue or homolog thereof. In another embodiment, the renalase polypeptide comprises the amino acid sequence of SEQ ID

[0013]NO: 9, or a fragment or conjugate or analogue or homolog thereof. In another embodiment, the PMCA4b activator is a renalase polypeptide fragment. In one embodiment, the renalase polypeptide fragment comprises the amino acid sequence of SEQ ID NO: 3, or a fragment or conjugate or analogue or homolog thereof. In another embodiment, the renalase polypeptide fragment comprises the amino acid sequence of SEQ ID NO: 4, or a fragment or conjugate or analogue or homolog thereof. In one embodiment, the renalase polypeptide fragment comprises the amino acid sequence of SEQ ID NO: 5, or a fragment or conjugate or analogue or homolog thereof. In some embodiments, the at least one PMCA4b activator is administered one time. In some embodiments, the at least one PMCA4b activator is administered repeatedly. In some embodiments, the at least one PMCA4b activator is administered locally, regionally or systemically. In various embodiments, the PMCA4b activator is an activator of PMCA4b expression, an activator of PMCA4b activity, or a combination thereof. In various embodiments, the renal disease or disorder that is treated or prevented is selected from the group consisting of acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemic injury, renal reperfusion injury, renal ischemic-reperfusion injury, toxic renal injury, renal tubular necrosis, renal tubular inflammation, renal tubular apoptosis, hypertension, and any combination thereof. In one embodiment, the subject is human.

[0014]In another embodiment, the invention is a method of treating or preventing cancer in a subject in need thereof, by administering to the subject a therapeutically effective amount of a composition comprising at least one PMCA4b inhibitor. In various embodiments, the PMCA4b inhibitor is a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, an antisense nucleic acid molecule, or any combination thereof. In one embodiment, the PMCA4b inhibitor is caloxin 1b, or analogue or homolog thereof. In another embodiment, the PMCA4b inhibitor is cisplatin, or analogue or homolog thereof. In various embodiments, the cancer that is treated or prevented is selected from the group consisting of brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, liver cancer, kidney cancer, lymphoma, leukemia, lung cancer, melanoma, metastatic melanoma, mesothelioma, neuroblastoma, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, skin cancer, thymoma, sarcoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, uterine cancer, or any combination thereof. In one embodiment, the subject is human.

[0015]In one embodiment, the invention is a method of treating or preventing a pancreatic disease or disorder in a subject in need thereof, by administering to the subject a therapeutically effective amount of a composition comprising at least one agent, wherein the at least one agent is at least one selected from the group consisting of a renalase polypeptide, a renalase polypeptide fragment, and an activator of renalase, or a fragment or conjugate or analogue or homolog thereof. In one embodiment, the renalase polypeptide is a recombinant renalase polypeptide, or a fragment or conjugate or analogue or homolog thereof. In another embodiment, the renalase polypeptide comprises the amino acid sequence of SEQ ID NO: 8, or a fragment or conjugate or analogue or homolog thereof. In one embodiment, the renalase polypeptide comprises the amino acid sequence of SEQ ID NO: 9, or a fragment or conjugate or analogue or homolog thereof. In another embodiment, the ren

Problems solved by technology

Renal injury can lead to chronic kidney disease (CKD), which is associated with increased morbidity and mortality, is largely due to cardiovascula

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