Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-08-04
2004-04-13
Spector, Lorraine (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S085100, C424S093100, C424S093210, C514S012200, C514S04400A, C514S893000, C530S350000
Reexamination Certificate
active
06719969
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of liver injury and regeneration. More particularly, it concerns the surprisingly effective use of CXC chemokines to induce rapid hepatocyte proliferation and liver regeneration. The invention thus provides advantageous methods to treat liver injury caused by a variety of agents, including that associated with acetaminophen overdose and with gene therapy.
2. Description of Related Art
The liver is the only vital organ, aside from the brain, for which there is no pharmacological, mechanical, or extra corporeal means of support for a failing organ. In contrast, there is mechanical ventilation to support patients with pulmonary failure, dialysis to support patients with kidney failure, and a variety of mechanical and pharmacological interventions to maintain the failing heart. The liver is also unique in that it is the only mammalian organ that can regenerate its biologically functional parenchymal mass following resection or injury, instead of healing with biologically nonfunctional scar tissue.
A patient's ability to restore his or her pre-operative hepatic mass following major liver resection is well-known (Weinbren and Hadjis, 1990). A variety of mediators are known to be hepatic mitogens, both in vitro and in vivo, but the precise mechanisms involved in liver regeneration remain to be defined (Hoffman et al., 1994; Fausto et al., 1996). A significant problem with efforts to promote hepatic regeneration is that many agents have limited effectiveness in vivo, involving either the magnitude and/or time of response. The availability of biological or pharmacological maneuvers to accelerate the regeneration of an adequate functional hepatic mass would therefore be a significant advance that could prevent many deaths from liver failure.
The ability to induce or enhance hepatocyte proliferation in the clinical setting would have several important applications. It would allow previously unresectable hepatic malignancies to be resected by increasing the quantity of healthy hepatic tissue, preventing the patient's death from liver failure in the post-operative period due to inadequate remaining functional liver mass. Further, patients suffering from fulminant hepatic failure from toxic, metabolic, or viral causes may be spared death or a liver transplant if the native liver could be induced to regenerate at a rate that would restore adequate hepatic function prior to death from liver failure.
Treatments aimed at inducing liver regeneration would likely have particular benefits in connection with acetaminophen (APAP) overdoses. This is partly because the deleterious effects of accidental or intentional (Makin and Williams, 1997) acetaminophen overdose often manifest many hours after major hepatic injury has occurred. When administered within 8 hours, N-acetyl-cysteine (NAC), a precursor of glutathione that is the standard medical treatment for acetaminophen overdose cases, effectively inhibits liver injury and prevents fulminant hepatic failure (De Groote and Van Steenbergen, 1995). However, because the onset of symptoms of acetaminophen overdose may be delayed or misinterpreted, the therapeutic window for NAC treatment of acetaminophen toxicity is frequently missed (Delanty and Fitzgerald, 1996).
A more recent area for attention within clinical hepatology is connected with the side effects of gene therapy. Acute hepatocellular injury characterized by centrilobular hepatocyte necrosis is a major side effect of viral-based gene therapies targeted to the liver (Yang et al., 1996; Nielsen et al., 1998; Bao et al., 1996). The development of strategies to abrogate the hepatic injury associated with viral-mediated gene therapy is necessary as most viral vectors, including the replication-deficient adenoviruses, efficiently deliver transgenes into hepatocytes without altering the biochemical functions of these cells (Castell et al., 1997; Raper and Wilson, 1995). Although the inhibition of T cell function in the liver is partially effective in limiting the hepatotoxic effects of viral vectors, the prolonged use of immunosuppressants during hepatic gene therapy protocols may predispose patients to opportunistic infections (Yang et al., 1996; Kay et al., 1997; Sullivan et al., 1997). In addition, the potential for greatly enhanced liver injury exists when analgesics are concurrently administered during hepatic gene therapy.
At present, considerable attention is being directed to elucidating factors that promote rapid and maximal liver regeneration following exposure of the liver to toxic or mechanical insults (Fausto et al., 1995). Cytokines such as interleukin-1 (IL-1), and particularly TNF&agr; and interleukin-6 (IL-6), are among the factors believed to possess unique liver regenerative qualities (Khoruts et al., 1991; Diez-Ruiz et al., 1995; Yamada et al., 1997; Cressman et al., 1996).
IL-6-deficient mice have been shown to have impaired liver regeneration following partial hepatectomy (Cressman et al., 1996). Mice lacking type I TNF receptors exhibit impaired liver regeneration following partial hepatectomy, which was also reported to act through an IL-6-dependent pathway (Yamada et al., 1997). Similarly, Rai and colleagues have shown that TNF is important in hepatic regeneration and is further down-regulated by interleukin-10 (IL-10) in this setting (Rai et al., 1997).
Despite ongoing research efforts, there remains in the art a need for improved methods of promoting liver regeneration and repair. Few substances are known that exhibit the required properties and many of these, such as NAC, have limits to their effectiveness in a clinical setting. The development of therapeutic strategies capable of treating liver damage caused by a range of hepatotoxic agents and gene therapy vectors are thus urgently needed, particularly those that promote rapid hepatocyte proliferation. The development of new regimens for treating acetaminophen overdose outside the therapeutic window of NAC therapy would represent a particularly marked advance in this field.
SUMMARY OF THE INVENTION
The present invention overcomes the foregoing and other drawbacks inherent in the prior art by providing a range of new treatments by which to induce liver regeneration and repair. The invention is broadly based upon the surprising finding that CXC chemokines induce rapid hepatocyte proliferation in vitro and stimulate liver repair and regeneration in vivo. Particularly advantageous uses of the invention are in the treatment and/or prevention of liver injury caused by acetaminophen overdose and associated with gene therapy.
The invention is generally based on the use of components or agents, preferably CXC chemokines or CXC chemokine components, that activate or upregulate the CXC chemokine receptor 1 (CXCR1), or more preferably, that activate or upregulate the CXC chemokine receptor 2 (CXCR2). As used herein, the terms “CXC chemokines and CXC chemokine components” are used generically to indicate that the CXC chemokine may be a protein or nucleic acid that encodes a protein.
Therefore, unless otherwise specifically stated, all CXC chemokine biological agents are included within the term “CXC chemokine”. Although human CXC chemokines will be preferred for use in human therapy, CXC chemokines from any species may be used in the invention. For use in other animal species, such as in veterinary embodiments, a species of CXC chemokine matched to the animal being treated will be preferred.
A CXC chemokine “protein”, as used herein, refers to a proteinaceous CXC chemokine component that has sufficient biological activity to be biologically effective. Accordingly, “CXC chemokine proteins” include full-length CXC chemokine proteins and polypeptides, including those prior to natural biological processing and, preferably, those subsequent to the type of biological processing that occurs naturally.
CXC chemokine proteins and polypeptides also include CXC chemokine proteins and polypeptides that have been subject to non-n
Bone-Larson Cynthia L.
Colletti Lisa M.
Hogaboam Cory M.
Kunkel Steven L.
Lukacs Nicholas W.
Seharaseyon Jegatheesan
Spector Lorraine
The Regents of The University of Michigan
Williams, Morgan and Amerson
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