Columbia University

Cincinnati Children's Hospital Medical Center

Jonathan Matthew Barasch

Andong Qiu

Prasad Devarajan

Juan A Oliver

Jun Yang

Kiyoshi Mori

Paul Rosenstiel

Thomas L Nickolas

Katherine Xu

Paolo Guarnieri

Nicholas Barasch

In one aspect the present invention is directed to mutant Neutrophil gelatinase-associated lipocalin (NGAL) proteins that have the ability to bind to siderophores, such as enterochelin, and to chelate and transport iron, and that are excreted in the urine. Such NGAL mutants, and complexes thereof with siderophores, can be used to clear excess iron from the body, for example in the treatment of iron overload. The NGAL mutants of the invention also have antibacterial activity and can be used in the treatment of bacterial infections, such as those of the urinary tract.

Mutant NGAL proteins and uses thereof

The present invention provides methods for treatment of volume-dependent Acute Kidney Injury (vAKI) and ischemic Acute Kidney Injury (iAKI), as well as methods for diagnosing vAKI and iAKI. The methods are based on determining the levels of PAPPA2, NGAL, KRT20, or TACSTD2 protein in a sample from a patient, such as a urine sample. The present invention also provides a device and a diagnostics kit for determining whether a sample from a subject contains PAPPA2, NGAL, KRT20, or TACSTD2 protein.

Methods of treating volume depletion and kidney injury

In one aspect the present invention is directed to mutant NGAL proteins that have the ability to bind to siderophores, such as enterochelin, and to chelate and transport iron, and that are excreted in the urine. Such NGAL mutants, and complexes thereof with siderophores, can be used to clear excess iron from the body, for example in the treatment of iron overload. The NGAL mutants of the invention also have antibacterial activity and can be used in the treatment of bacterial infections, such as those of the urinary tract.

In one aspect the present invention is directed to mutant Neutrophil Gelatinase Associated Lipocalin (NGAL) proteins that have the ability to bind to siderophores, such as enterochelin, and to chelate and transport iron, and that are excreted in the urine. Such NGAL mutants, and complexes thereof with siderophores, can be used to clear excess iron from the body, for example in the treatment of iron overload. The NGAL mutants of the invention also have antibacterial activity and can be used in the treatment of bacterial infections, such as those of the urinary tract.

A high molecular weight form of Ngal is provided which can be used to diagnose chronic kidney disease. High molecular weight Ngal is about 75 kDa to about 350 kDa, and comprises non-Ngal proteins, such as polymeric immunoglobulin receptor, alpha-2-macroglobulin and immunoglobulin heavy chain. Methods are disclosed for assessing high molecular weight Ngal in a diagnostic sample from a subject.

High molecular weight Ngal as a biomarker for chronic kidney disease

Use of neutrophil gelatinase-associated lipocalin (NGAL) as a therapeutic and in a method of treating, reducing, or ameliorating an injury selected from an ischemic injury, an ischemic-reperfusion injury, and a toxin-induced injury, to an organ in a patient. The invention includes administering to the patient NGAL in an amount effective to treat, reduce or ameliorate ischemic, ischemic-reperfusion, or toxin-induced injury to the organ, such as the kidney. A siderophore can be co-administered with the NGAL. The invention also relates to administering a sideophore to enhance a response to secretion of NGAL following an ischemic or toxin-induced injury to an organ in a patient.

NGAL for reduction and amelioration of ischemic and nephrotoxic injuries

A method for distinguishing between kidney dysfunctions in a mammal, including pre-renal azotemia, an acute renal injury that may progress to acute renal failure, and chronic kidney disease, using a urinary or circulating NGAL assay result that is compared to a predetermined NGAL cutoff level, and a single serum or plasma creatinine measurement. Typically the single creatinine measurement cannot distinguish acute renal injury from chronic kidney disease or pre-renal azotemia, a single measurement of urinary NGAL, combined with the single serum or plasma creatinine measurement, has sufficient sensitivity and specificity to distinguish acute renal injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes. Patients admitted to the emergency department of the hospital with any of acute kidney injury, prerenal azotemia, chronic kidney disease, or even normal kidney function, can be evaluated based on the single measurements of urinary or circulating NGAL, and serum or plasma creatinine. Urinary NGAL level is highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit.

Method for distinguishing between kidney dysfunctions

This invention provides methods of using a gp130 receptor ligand, e.g. leukemia inhibitory factor, to induce the formation of kidney epithelia, to treat subjects suffering from kidney failure, and to preserve kidneys for transplantation.

Method of inducing formation of kidney epithelia from mesenchymal precursors

This invention provides methods of using a gpl3O receptor ligand, e.g. leukemia inhibitory factor, to induce the formation of kidney epithelia, to treat subjects suffering from kidney failure, and to preserve kidneys for transplantation.

Growing community of inventors

New York, NY, United States of America

Jonathan Matthew Barasch