Methods of treatment using stem cell mobilizers

a stem cell mobilizer and stem cell technology, applied in the field of stem cells, can solve the problems of inability to use pharmacologic or adjunct therapies in this clinical scenario, limited resources may be inaccessible, and the decision to proceed to transplantation is not always straightforward, so as to improve the appearance of cd34+ cells, reduce injury, and improve the effect of survival

Inactive Publication Date: 2014-08-07
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]The present invention is based, in part, on the discovery that the administration of at least one stem cell mobilizer can be used to treat subjects with acute liver injury. As described herein, the present inventors use pharmacologic mobilization of endogenous HSCs in the setting of liver injury to show that these cells can be of therapeutic benefit. The present invention shows survival advantage from the treatment provided, specifically, an elevation of serum leukocytes and CD34+ cells in animals treated with plerixafor and G-CSF. The present invention demonstrates the rapid appearance of CD34+ cells in the livers of only the animals who undergo injury and stem cell mobilization. These cells could differentiate into hepatocytes to directly support an animal with inadequate liver mass or perhaps supply some sort of paracrine support to mitigate injury or accelerate ongoing local repair mechanisms.

Problems solved by technology

Fewer than half of patients with ALF will spontaneously recover with supportive care alone, yet at present, no pharmacologic or adjunct therapies have been shown to be of benefit in this clinical scenario.
For these critically ill patients, liver transplantation frequently represents the only option for survival; however, this limited resource may be inaccessible at the time at which it is emergently needed.
Furthermore, the decision to proceed to transplantation is not always straightforward, because some patients will spontaneously recover, but the ability to predict recovery is markedly limited.
Under aggressive utilization of liver transplantation can result in devastating outcomes in potentially salvageable patients, while overly aggressive utilization of transplantation both commits patients who might have spontaneously recovered to a lifetime of immunosuppression, and also unnecessarily utilizes precious grafts that could be allocated to others in need.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Carbon Tetrachloride (CCL4) Administration Recapitulates Acute Liver Failure (ALF) in Rodents

[0097]Animals that were treated with increasing amounts of CCL4 showed a dose-dependent decrement in survival (FIG. 1A). Groups of ten animals that were treated with 2 ml / kg routinely showed one or two mortalities per ten within the first one to two days after treatment. The large majority of animals in this group were transiently ill but rapidly regained vigor. Animals that received 3 ml / kg showed higher mortality rates, typically 3 or 4 animals died but reliably more than half recovered spontaneously. A dose of 4 ml / kg would result in about 60% to 100% mortality among the animals over the course of three to seven days. Slight adjustments in the dose (i.e., 4.5 ml / kg) at this level would have obvious effects on mortality with all animals succumbing within 24-48 hours.

[0098]A dose of 4 ml / kg was eventually selected for the final model. Mortality with this dose was typically about 80% around ...

example 2

Plerixafor and G-CSF Mobilize a Population of CD34+HSCs in Rodents

[0100]Rats that received either plerixafor or G-CSF showed an increase in their peripheral white blood cell (WBC) counts at 1 and 6 hours (FIG. 2A). Animals receiving plerixafor alone had an average total WBC of 6,100 at one hour (n=3) and 7,300 at 6 hours (n=3). Animals receiving G-CSF alone had average total WBCs of 3,300 at 1 hour (n=3) and 7,800 at 6 hours (n=3). Animals receiving both drugs had an average total WBC count of 6,000 at 1 hour (n=3) and of 9,900 at 6 hours (n=3).

[0101]The lymphocyte compartment, which is thought to contain the majority of HSCs showed similar changes (FIG. 2A). Animals receiving plerixafor had total lymphocyte counts of 4,400 and 4,800 at one and six hours respectively. Animals receiving G-CSF had total lymphocyte counts of 2,000 and 4,100 at one and six hours respectively. Animals receiving both drugs had total lymphocyte counts of 3,600 and 5,200 at one and six hours respectively.

[0...

example 3

Stem Cell Mobilization Improves Survival in an Animal Model of ALF

[0104]Rodents (n=8) that were administered intraperitoneal CCl4 (4 ml / kg) displayed a high rate of mortality (75% at 6-7 days) consistent with the model. In contrast, animals (n=8) that received an identical injury (4 ml / kg) but twelve hours later initiated plerixafor (2 mg / kg / d×3 d) and G-CSF (300 μg / kg / d×3 d) survived at a much higher rate (13% mortality) (FIG. 3A). Examination of liver specimens from intentionally sacrificed animals from the treated and untreated groups after injury showed lesser histologic injury in the group that had received stem cell mobilization (FIG. 3B).

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Abstract

The present invention relates to the field of stem cells. In one aspect, the present invention provides methods of treating a subject with acute liver injury comprising administering to the subject a therapeutically effective amount of at least one stem cell mobilizer. In particular embodiments, the subject is treated with plerixafor and G-CSF

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 316,481, filed Mar. 23, 2010, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to the field of stem cells. More particularly, the methods and compositions of the present invention are useful for mobilizing stem cells to treat a variety of conditions including acute liver injury, and more particularly, acute liver failure (ALF).BACKGROUND OF THE INVENTION[0003]Acute liver failure (ALF) affects over two thousand Americans per year and results in approximately four hundred liver transplants annually. Defined as the abrupt loss of hepatocellular function in patients with previously normal liver function, the most common etiologies are acetaminophen overexposure and acute viral hepatitis. See Stravitz et al., 6 NAT REV. GASTROENTEROL. HEPATOL. 542-53 (2009). In the most severe cases, patients manifest a ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/19A61K31/395
CPCA61K31/395A61K38/193A61K31/4427A61P1/16A61K2300/00
Inventor CAMERON, ANDREW MACGREGOR
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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