Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-12-29
2003-03-11
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S012200, C514S912000, C530S351000, C435S335000
Reexamination Certificate
active
06531121
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the protection and enhancement of cells, tissues and organs of a mammalian body that may be isolated or separated from the vasculature by an endothelial cell barrier. Protection is provided to cells, tissues and organs in situ as well as those that may be temporarily removed, for instance, for transplant. Protection and enhancement is offered to cells, tissues and organs that are erythropoietin responsive or those that depend on erythropoietin-responsive cells for at least an aspect of function or viability.
BACKGROUND OF THE INVENTION
For many years, the only clear physiological role of erythropoietin (EPO) had been its control of the production of red blood cells. Recently, several lines of evidence suggest that EPO, as a member of the cytokine superfamily, performs other important physiologic functions which are mediated through interaction with the erythropoietin receptor (EPO-R). These actions include mitogenesis, modulation of calcium influx into smooth muscle cells and neural cells, and effects on intermediary metabolism. It is believed that EPO provides compensatory responses that serve to improve hypoxic cellular microenvironments. Although studies have established that EPO injected intracranially protects neurons against hypoxic neuronal injury, intracranial administration is an impractical and unacceptable route of administration for therapeutic use, particularly for normal individuals. Furthermore, previous studies of anemic patients given EPO have concluded that peripherally-administered EPO is not transported into the brain (Marti et al., 1997, Kidney Int. 51:416-8). Copending U.S. application Ser. No. 09/547,220, the entire contents of which is incorporated herein by reference in its entirety, describes the heretofore unrecognized and unappreciated property that a peripherally-administered erythropoietin is capable of crossing an endothelial cell barrier (e.g., the blood-brain barrier) and providing protection and enhancement of excitable tissue across that barrier, for example, for protection or enhancement of neuronal function. It also describes the use of an erythropoietin as a carrier molecule to facilitate the penetration across an endothelial cell barrier, such as the blood-brain barrier, to serve as a carrier for compounds which alone normally cannot cross such barriers.
It is towards the use of an erythropoietin for protecting or enhancing erythropoietin-responsive cells and associated cells, tissues and organs in situ and ex vivo, as well as delivery of an erythropoietin across an endothelial cell barrier for the purpose of protecting and enhancing erythropoietin-responsive cells and associated cells, tissues and organs distal to the vasculature, that the present invention is directed.
Citation or discussion of a reference herein shall not be construed as an admission that such is prior art to the present invention.
BRIEF SUMMARY OF THE INVENTION
In its broadest aspect, the present invention is directed to compositions and methods for protecting, maintaining or enhancing the function or viability of an erythropoietin-responsive mammalian cell and associated cells, tissues and organs, using compounds which may or may not have erythropoietic activity.
In one aspect, the invention is directed to protecting, maintaining or enhancing the viability of an erythropoietin-responsive mammalian cell, and associated cells, tissues and organs, wherein the mammalian cell, tissue or organ is distal to the vasculature by virtue of a tight endothelial cell barrier. The method involves administering to the vasculature an amount of an erythropoietin which is capable of translocation across the intact endothelial cell barrier and providing benefits to erythropoietin-responsive cells and to associated cells, tissues and organs dependent thereon distal to the vasculature.
The invention is based, in part, on the Applicant's discovery that particularly for chronic treatment for the various purposes herein, it is desirable to utilize an erythropoietin with positive effects on erythropoietin-responsive cells and tissues but lacking erythropoietic activity, to prevent an undesirable rise in hemoglobin concentrations and hematocrit over the course of therapy. Such non-erythropoietic forms of EPO may exhibit lack of stimulating erythropoiesis by any of several non-limiting reasons, such as altered pharmacokinetics or altered activity. For example, a suitable non-erythropoietic form of erythropoietin may have too short of a half-life in circulation to be present at a concentration adequate to recruit proerythroblasts via the erythropoietin receptor. Alternatively, a chemically-modified, mutant, or otherwise altered form of erythropoietin which is not recognized by the erythropoietin receptor on proerythroblasts but maintains or has improved activity at enhancing viability and other positive effects on erythropoietin-responsive cells is embraced herein. As described herein, in the case wherein the EPO is non-erythropoietic, the range of doses may be as described, or may be lower depending on the potency of the non-erythropoietic molecule. Units of activity may be determined based on equivalent activity against the target cells and tissues described herein, as the Units normally used for EPO relate to erythropoiesis and are irrelevant to non-erythropoietic EPOs.
The invention is also based, in part, on the Applicant's discovery that organs and other bodily parts isolated from a mammalian body, such as those intended for transplant, are benefitted by exposure to an erythropoietin.
Thus, one aspect of the invention is directed to a method for protecting, maintaining or enhancing the viability or function of a mammalian cell, tissue, organ or bodily part which includes an erythropoietin-responsive cell or tissue, in which the cell, tissue, organ or bodily part is isolated from the mammalian body. The method includes at least exposing the isolated mammalian cell, tissue, organ or bodily part to an amount of an erythropoietin for a duration which is effective to protect, maintain or enhance the aforementioned viability or function. In non-limiting examples, isolated refers to restricting or clamping the vasculature of or to the cell, tissue, organ or bodily part, such as may be performed during surgery; bypassing the vasculature of the cell, tissue, organ or bodily part; removing the cell, tissue, organ or bodily part from the mammalian body, such may be done in advance of xenotransplantation or prior to and during autotransplantation; or traumatic amputation of a cell, tissue, organ or bodily part. Thus, this aspect of the invention pertains both to the perfusion with an erythropoietin in situ and ex vivo. Ex vivo, the erythropoietin may be provided in a cell, tissue or organ preservation solution. For either aspect, the exposing may be by way of continuous perfusion, pulsatile perfusion, infusion, bathing, injection, or catheterization.
Such adverse conditions to function or viability mentioned above may result from clamping of the vascular supply to an organ during repair or other surgical procedure; isolating a viscus or limb during perfusion to provide high levels of, for example, a chemotherapeutic agent; bypass surgery; transcutaneous procedures in which blood flow to a particular tissue or organ may be temporally compromised, such as endarterectomy, angioplasty, stent placement, and cardiac catheterization. Need for protection of cells and tissues also occurs after traumatic amputation or severance of a bodily part such as a finger, toe or limb, such that may be applied to the severed part during the period before reattachment is performed. Administration of the pharmaceutical composition for the beneficial purposes described herein may be provided prior to the period of time during which the adverse conditions prevail, during the period of time, after the period of time, or any combination of times.
An erythropoietin useful for the practice of the invention includes human or another mammalian erythropoietin, an
Brines Michael
Cerami Anthony
Cerami Carla
Hamud Fozia
Kemmerer Elizabeth
Pennie & Edmonds LLP
The Kenneth S. Warren Institute, Inc.
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