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Stem Cell, Precursor Cell, or Target Cell-Based Treatment of Multi-Organ Failure and Renal Dysfunction

a multi-organ failure and renal dysfunction technology, applied in animal repellents, drug compositions, peptide/protein ingredients, etc., can solve the problems of recurrent infections, morbidity and death, and major unresolved medical problems of multi-organ failure (mof)

Inactive Publication Date: 2014-03-27
UNIV OF UTAH RES FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent provides methods of treating various kidney and organ failure conditions using stem cells. These methods include delivering a therapeutic amount of stem cells or a stimulant of stem cell mobilization to a patient in need. The stem cells can be pre-differentiated or non-transformed, and can be administered alone or in combination with other stem cells or other therapeutic agents. The technical effects of this patent include improved treatment options for acute and chronic kidney failure, as well as early dysfunction of kidney transplant, wound healing, and multi-organ failure.

Problems solved by technology

Multi-organ failure (MOF) remains a major unresolved medical problem.
Many of these patients have serious impairment of the healing of surgical or trauma wound, and, when infected, these wounds further contribute to recurrent infections, morbidity and death.
The most common cause of ARF is an ischemic insult of the kidney resulting in injury of renal tubular and postglomerular vascular endothelial cells.
Both ischemic and nephrotoxic forms of ARF result in dysfunction and death of renal tubular and microvascular endothelial cells.
However, the self-regeneration capacity of the surviving tubular and vascular endothelial cells may be exceeded in severe ARF.
This dismal prognosis has not improved despite intensive care support, hemodialysis, and the recent use of atrial natriuretic peptide, Insulin-like Growth Factor-I (IGF-I), more biocompatible dialysis membranes, continuous hemodialysis, and other interventions.
The risk of TA-ARE is increased with elderly donors and recipients, marginal graft quality, significant comorbidities and prior transplants in the recipient, and an extended period of time between harvest of the donor kidney from a cadaveric donor and its implantation into the recipient, known as “cold ischemia time.” Early graft dysfunction or TA-ARF has serious long-term consequences, including accelerated graft loss due to progressive, irreversible loss in kidney function that is initiated by TA-ARF, and an increased incidence of acute rejection episodes leading to premature loss of the kidney graft.
Currently available forms of therapy, such as the administration of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, other anti-hypertensive and anti-inflammatory drugs such as steroids, cyclosporine and others, lipid lowering agents, omega-3 fatty acids, a low protein diet, and optimal weight, blood pressure and blood sugar control, particularly in diabetics, can significantly slow and occasionally arrest the chronic loss of kidney function in the above conditions.
Despite these successes, the annual growth of patient numbers with ESRD, requiring chronic dialysis or transplantation, remains at 6%, representing a continuously growing medical and financial burden.
Taken together, therapies that are currently utilized in the treatment of ARF, the treatment of established ARF of native kidneys per se or as part of MOF, and ARF of the transplanted kidney, and organ failure in general have not succeeded to significantly improve morbidity and mortality in this large group of patients.
The intracoronary administration of stem cells in humans with myocardial infarction or coronary artery disease has most recently been reported to result in significant adverse events such as acute myocardial infarction, other complications and death.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Determine the Relative Renoprotective Potency of HSC, MSC, Precursor Vascular Endothelial or Tubular Cells Derived from MSC by Pre-Differentiation, Hemangioblasts, of Fully Differentiated Vascular Endothelial Cells, and of Fibroblasts Administered to Rats with ARF

[0070]In experiments, adult Sprague-Dawley or Fisher 344 rats (male or female) were studied. Ischemia / reperfusion-type of ARF (“ischemic ARF”) is induced in anesthetized rats by timed clamping of both renal pedicles, thereby interrupting the blood supply to the kidneys causing an “ischemic” insult that results in acute loss of kidney function, i.e., ARF. A model of severe ARF in rats used 45 minutes of bilateral renal ischemia, resulting in a rise in serum creatinine to 3.5-5.0 mg / dL, a glomerular filtration rate of <15% of normal, and a mortality of 50% at 72 hrs post reflow. Histological examination of the kidneys from this severe ARF model shows wide spread tubular necrosis, apoptosis and severe vascular congestion with ...

example 2

Determine the Ratio of MSC and HSC for Co-Administration Therapy

[0077]Using as a guideline the approximate ratio of HSC and MSC numbers in the normal bone marrow, protocols in which the ratios or doses of co-administered HSC / MSC given to rats with ARF, models and animal strains as in Example 1, were varied.

[0078]The relative renoprotective potency of various SC treatment protocols was tested by infusing intravenously (jugular, femoral or tail vein) or intra-arterially (into suprarenal aorta via carotid or femoral artery) HSC alone, MSC alone or HSC in combination with MSC at a HSC / MSC ratio of 1:1, 3:1, 5:1 or 8:1 to rats immediately after induction of severe or modest ARF as well as infusion of HSC alone, MSC alone or HSC / MSC in ratios of 1:1, 3:1, 5:1 or 8:1 24 hrs after induction of severe or modest ARF in rats (see above). The total number of cells administered in all studies was about 105 to 106 cells / animal.

[0079]Renal function, histological studies and outcomes in the experim...

example 3

Determine the Relative Potency for Wound Healing of HSC, MSC, Precursor Vascular Endothelial or Tubular Cells Derived from MSC by Pre-Differentiation, Hemangioblasts, of Fully Differentiated Vascular Endothelial Cells, and Define the Optimal Ratio of MSC and HSC for Co-Administration for Wound Healing

[0083]The administration of individual cell types, as above, or MSC and HSC mixes to rats with ARF resulted in improved outcome (see above). Also, the abdominal, well-healed incision initially created for the induction of ARF (clamping of both renal arteries), contained large numbers (˜40%) of tagged MSC and HSC-derived vascular and other cells, indicating that MSCs and HSCs can powerfully support the process of wound healing that includes angiogenesis. Further studies in animals with experimental abdominal wound infections alone or in the setting of LPS-induced shock with MOF, or in rats with combined ischemic ARF and cecal perforation-induced peritonitis / sepsis will examine whether ce...

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PUM

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Abstract

Methods for the treatment of acute renal failure, multi-organ failure, early dysfunction of kidney transplant, chronic renal failure, organ dysfunction, and wound healing are provided. The methods include delivering a therapeutic amount of hematopoietic stem cells, non-hematopoietic, mesenchymal stem cells, hemangioblasts, and pre-differentiated cells to a patient in need thereof.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 551,317, filed Sep. 29, 2005, which a National Stage of International Application No. PCT / US2004 / 009922, filed Mar. 31, 2004, which claims priority to U.S. Provisional Application No. 60 / 459,554, filed Apr. 1, 2003 and U.S. Provisional Application No. 60 / 475,178, filed Jun. 2, 2003, which are hereby incorporated by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The subject matter described herein was in-part made possible by support from the Department of Veterans Affairs. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention generally relates to methods for treating organ dysfunction, multi-organ failure and renal dysfunction, including, but not limited to acute renal failure, transplant associated acute renal failure, chronic renal failure, and wound healing. More specifically, the inventive ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/28A61K38/19A61K35/12A61K35/14A61K35/22A61K35/44A61K38/00A61K48/00
CPCA61K38/195A61K35/28A61K35/22A61K35/44A61P13/12
Inventor WESTENFELDER, CHRISTOF
Owner UNIV OF UTAH RES FOUND
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