Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
1998-03-20
2004-02-24
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C514S298000, C514S564000
Reexamination Certificate
active
06696407
ABSTRACT:
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
This invention was made in part during work supported by a grant from the Office of Research and Development (Medical Research Service) of the Department of Veterans Affairs (APM, NAC, FML) and a grant from the National Institutes of Health NS32339 (APM) and a grant from NIA (National Institute of Aging) AG09873 (FML). The government has certain rights in the invention.
TECHNICAL FIELD
This invention relates to neurotrophic factor-associated activity. More specifically, it relates to methods of modulating neurotrophic factor-associated activity using aldose reductase inhibitors (ARIs).
BACKGROUND
Use of neurotrophic factors, a class of growth factors that act on neurons, has gained considerable attention as potentially effective treatment of neurological disorders. Yuen et al. (1995)
Mol. Med. Today
278-286. Neurotrophic factors have been shown to promote cell survival in vitro and to attenuate the behavioral and neurobiological consequences of central nervous system (CNS) damage in animal models of Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS) as well as peripheral nervous system (PNS) disorders including neuropathies. Neurotrophic factors also decrease damage due to trauma.
A serious problem with the concept of using neurotrophic factors in therapy has been delivery to neural tissue. These large, highly charged molecules are typically unable to penetrate the blood/brain barrier, thus hindering efforts to test efficacy in CNS disorders. At present, neurotrophic factors must be administered intrathecally (i.e., in cerebrospinal fluid), which involves technical obstacles and risk. Simpler modes of administration (such as subcutaneous) deliver only to motor neurons and the PNS. Even delivery within the PNS (across the blood
erve barrier) can be problematic.
Ciliary neurotrophic factor (CNTF), a member of the neuropoietic cytokine family (which also includes leukemia inhibitory factor, interleukin 6, and oncostatin-M), is a protein of 200 amino acids. Manthorpe et al. (1993) in
Neurotrophic Factors
, Louglin et al. eds., 443-473. The CNTF gene has been cloned. Stockli et al. (1989)
Nature
342:920-923: CNTF acts on ciliary ganglion and dorsal root ganglia (DRG) neurons, sympathetic neurons and motor neurons in the PNS. In the CNS, CNTF acts on several neuronal populations and has been shown to enhance survival of cultured hippocampal neurons and to prevent degeneration of injured medial septal neurons (cholinergic and non-cholinergic). In peripheral nerve, ciliary neurotrophic factor (CNTF) is present in abundance and has been localized to Schwann cells of myelinated fibers. Williams et al. (1984)
Int. J Dev. Sci
.12:177-180; Rende et al. (1992)
Glia
5:25-32; Friedman et al. (1992)
Neuron
9:295-305. CNTF activity increases following injury and has been suggested to provide neurotrophic support to axons that facilitates neuronal survival and regeneration. Longo et al. (1983)
Brain Res
. 261:109-117; Thoenen (1991)
TINS
14:165-170. Levels of CNTF-like activity in sciatic nerve are reduced after one to two months of hyperglycemia induced by galactose feeding or streptozotocin diabetes. Calcutt et al. (1992)
Brain Res
. 575:320-324.
CNTF has been indicated as having potential therapeutic potential for neurological disorders, such as neurodegenerative disease. Apfel et al. (1993)
Brain Res
. 604:1-6. However, as with neurotrophic factors in general, there have been serious problems associated with the administration of CNTF. Longo (1994)
Ann. Neurol
. 36:125-127; Yuen et al. (1995). Administration in animals has been accompanied by clear signs of toxicity, including fever, weight loss and induction of haptoglobin, an acute-phase protein, in the liver. Yuen et al. (1995). The short half-life of the molecule dictates high doses if administered exogenously, heightening the danger of toxicity and other possible undesirable cytokine-associated side effects. For example, in one clinical trial involving CNTF, a dose 30-fold lower than that demonstrated to produce a response in the Wobbler mouse was necessitated by intolerable side effects at higher doses. Miller et al. [(1996)
Ann. Neurol
39:256-260] showed that the lack of efficacy of CNTF in treating ALS may have been caused in part by poor penetration of subcutaneously administered CNTF into the CNS, by its very short plasma half-life of 2.9 min in the context of only once daily administration [Dittrich et al. (1994)
Ann. Neurol
. 35:151-163], and/or by differences in the pathological mechanisms between ALS and animal models.
Several studies with CNTF have focused on transplantation of genetically modified cells releasing neurotrophic factors into normal or damaged brain regions, such as implants of encapsulated human CNTF-producing fibroblasts. Emerich et al. (1996)
J. Neurosci
. 16:5168-5181. However, strategies based on implants of genetically modified cells are limited by several factors, including host immune response, surgical risks associated with implantation, control of CNTF secretion, and lack of diffusibility of CNTF (i.e., the factor is localized to the site of implantation).
Several studies have suggested that CNTF protects striatal neurons in animal models of Huntington's disease (HD). Loss of medium-sized GABAergic striatal neurons was mediated by intrastriatal infusion of CNTF via osmotic pump, or implantation of a hCNTF-secreting, encapsulated fibroblast cell line, prior to injection of quinolinic acid. Implants also led to behavioral and cognitive protection. Anderson et al. (1996)
Proc. Natl. Acad. Sci. USA
93:73-46-7351; Emerich et al. (1996)
J. Neuroscience
16:51-68-5181; Emerich et al. (1997)
Cell Transplantation
6:249-266; Emerich et al. (1997)
Nature
386:395-399. However, it remains unknown to what extent CNTF levels increased above endogenous levels in striatal tissue distant from the delivery source, and the use of implants of modified cells in treatments of HD is also subject to the limitations of implants described above.
A different area of research is the polyol pathway. The polyol pathway effects conversion of glucose to the polyhydric alcohol (polyol) sorbitol by the enzyme aldose reductase, followed by conversion of the sorbitol to fructose by sorbitol dehydrogenase. Kador et al. (1985)
Ann. Rev. Pharm. Toxicity
25:691-714; Bhatnagaretal. (1994)
Biochem. Med. and Metabolic Biol
. 48:91-121. Aldose reductase belongs to a family of NADPH-dependent oxidreductases, which are collectively known as aldehyde reductases.
In tissues which take up glucose independently of insulin and contain aldose reductase, the flux through the pathway under normal glycemic conditions is limited by the relatively low cellular glucose concentration and the low affinity of aldose reductase for glucose. Under these conditions glucose is metabolized predominantly by hexokinase. In hyperglycemia, however, glucose levels are elevated within these tissues, hexokinase is saturated and the fraction of glucose metabolized by aldose reductase increases.
Exaggerated flux through the polyol pathway has been implicated in the pathogenesis of biochemical, functional and structural nerve abnormalities associated with experimental diabetes (Tomlinson et al. (1992)
Pharmacol. and Therapeutics
54:154-194). In peripheral nerve, aldose reductase (AR), the first enzyme of the polyol pathway, is localized to the Schwann cells of myelinated fibers. (Powell et al. (1991)
Acta Neuropathol
. 81:529-539) The ability of aldose reductase inhibitors (ARIs) to prevent structural and functional abnormalities of myelinated fibers (Yagihashi et al. (1990)
Diabetes
39:690-696; Mizisin et al. (1993)
J. Neuropathol Exp. Neurol
. 52:78-86) suggests that flux through AR and/or polyol accumulation in Schwann cells may precipitate a variety of the nerve disorders reported in experimental diabetes. Aldose reductase inhibitors (ARI) have been studied extensively in the context of co
Longo Frank
Mizisin Andrew
Morrison & Foerster / LLP
Nichols Christopher James
The Regents of the University of California
LandOfFree
Huntington's disease treatment comprising administering... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Huntington's disease treatment comprising administering..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Huntington's disease treatment comprising administering... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3303792