Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1997-04-14
2002-09-24
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S325000, C435S320100, C435S252300, C536S023500
Reexamination Certificate
active
06455277
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to receptors for glial cell line-derived neurotrophic factor (GDNF) and provides nucleic acid and amino acid sequences encoding GDNF receptor (GDNFR). The present invention also relates to therapeutic techniques for the treatment of GDNF-responsive conditions.
BACKGROUND OF THE INVENTION
Glial Cell Line-Derived Neurotrophic Factor
Glial cell line-derived neurotrophic factor (GDNF) was initially isolated and cloned from rat B49 cells as a potent neurotrophic factor that enhances survival of midbrain dopaminergic neurons (Lin et al., Science, 260, 1130-1132, 1993). Recent studies have indicated that this molecule exhibits a variety of other biological activities, having effects on several types of neurons from both the central and peripheral nervous systems. In the central nervous system (CNS), GDNF has been shown to prevent the axotomy-induced death of mammalian facial and spinal cord motor neurons (Li et al., Proceedings Of The National Academy Of Sciences, U.S.A., 92, 9771-9775, 1995; Oppenheim et al., Nature, 373, 344-346, 1995; Yan et al., Nature, 373, 341-344, 1995; Henderson et al., Science, 266, 1062-1064, 1994; Zurn et al., Neuroreport, 6, 113-118, 1994), and to rescue developing avian motor neurons from natural programmed cell death (Oppenheim et al., 1995 supra). Local administration of GDNF has been shown to protect nigral dopaminergic neurons from axotomy-induced (Kearns and Gash, Brain Research, 672, 104-111, 1995; Beck et al., Nature, 373, 339-341, 1995) or neurotoxin-induced degeneration (Sauer et al., Proceedings Of The National Academy Of Sciences U.S.A., 92, 8935-8939, 1995; Tomac et al., Nature, 373, 335-339, 1995). In addition, local administration of GDNF has been shown to induce sprouting from dopaminergic neurons, increase levels of dopamine, noradrenaline, and serotonin, and improve motor behavior (Tomac et al., 1995 supra).
More recently, GDNF has been reported to be a potential trophic factor for brain noradrenergic neurons and Purkinje cells. Grafting of fibroblasts ectopically expressing GDNF prevented 6-hydroxydopamine-induced degeneration and promoted the phenotype of adult noradrenergic neurons in vivo (Arenas et al., Neuron, 15, 1465-1473, 1995), while exogeneously applied GDNF effectively promoted survival and morphological differentiation of embryonic Purkinje cells in vitro (Mount et al., Proceedings Of The National Academy Of Sciences U.S.A., 92, 9092-9096, 1995). In the peripheral nervous system, GDNF has been shown to promote the survival of neurons in nodose, ciliary, and sympathetic ganglia, as well as small populations of embryonic sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (Trupp et al., Journal Of Cell Biology, 130, 137-148, 1995; Ebendal et al., Journal Of Neuroscience Research, 40, 276-284, 1995; Oppenheim et al., 1995 supra; Yan et al., 1995 supra; Henderson et al., 1994 supra). GDNF has also been reported to enhance the expression of vasoactive intestinal peptide and preprotachykinin-A mRNA in cultured superior cervical ganglion (SCG) neurons, and thus effects the phenotype of SCG neurons and induces bundle-like sprouting (Trupp et al., 1995 supra).
Expression of GDNF has been observed in a number of different cell types and structures of the nervous system. In the CNS, GDNF mRNA expression has been observed by reverse transcriptase polymerase chain reaction (RT-PCR) in both developing and adult rat striatum, the major target of nigral dopaminergic innervation, and widely in other regions, including hippocampus, cortex, thalamus, septum, cerebellum, spinal cord, and medulla oblongata (Arenas et al., supra 1995; Poulsen et al., Neuron, 13, 1245-1252, 1994; Springer et al., Experimental Neurology, 127, 167-170, 1994; Stroemberg et al., Experimental Neurology, 124, 401-412, 1993; Schaar et al., Experimental Neurology, 124, 368-371, 1993). In human, GDNF transcripts have also been detected in striatum, with highest level in the caudate and lower levels in the putamen. Detectable levels are also found in hippocampus, cortex, and spinal cord, but not in cerebellum (Schaar et al., Experimental Neurology, 130, 387-393, 1994; Springer et al., 1994 supra). In the periphery, GDNF mRNA expression has been reported in DRG and SCG of postnatal day 1 rats, sciatic nerve, and primary cultures of neonatal Schwann cells (Trupp et al., 1995 supra; Hoffer et al., Neuroscience Letters, 182, 107-111, 1994; Henderson et al., 1994 supra; Springer et al., 1994 supra). In addition, recent studies have shown that GDNF transcripts are also widely expressed in peripheral non-neuronal organs, including postnatal testis and kidney, embryonic whisker pad, stomach, and skin. Expression can be detected at lower levels in embryonic muscle, adrenal gland and limb bud, and in postnatal lung, liver and ovary (Trupp et al., 1995 supra; Henderson et al., 1994 supra). So far, however, the biological significance of the non-neuronal expression of GDNF is not clear.
Detailed descriptions of the preparation and characterization of GDNF protein products may be found in U.S. patent application Ser. No. 08/182,183 filed May 23, 1994 and its parent applications (also see PCT/US92/07888, WO 93/06116 filed Sep. 17, 1992 and European Patent Application No. 92921022.7, Publication No. EP 610 254) the disclosures of which are hereby incorporated by reference. Additional GDNF protein products are described in pending U.S. patent application Ser. No. 08/535,681 filed Sep. 28, 1995, the disclosure of which is hereby incorporated by reference. As used herein, the term “GDNF protein product” includes biologically active synthetic or recombinant GDNF proteins and analogs, as well as chemically modified derivatives thereof. GDNF analogs include deletion variants such as truncated GDNF proteins, as well as insertion and substitution variants of GDNF. Also included are GDNF proteins that are substantially homologous to the human GDNF protein.
GDNF Therapy
GDNF therapy is helpful in the treatment of nerve damage caused by conditions that compromise the survival and/or proper function of one or more types of nerve cells. Such nerve damage may occur from a wide variety of different causes. Nerve damage may occur to one or more types of nerve cells by: (1) physical injury, which causes the degeneration of the axonal processes and/or nerve cell bodies near the site of injury; (2) temporary or permanent cessation of blood flow to parts of the nervous system, as in stroke; (3) intentional or accidental exposure to neurotoxins, such as chemotherapeutic agents (e.g., cisplatinum) for the treatment of cancer or dideoxycytidine (ddC) for the treatment of AIDS; (4) chronic metabolic diseases, such as diabetes or renal dysfunction; or (5) neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), which result from the degeneration of specific neuronal populations.
Several studies indicate that GDNF therapy is particularly helpful in the treatment of neurodegenerative conditions such as the degeneration of the dopaminergic neurons of the substantia nigra in Parkinson's disease. The only current treatments for Parkinson's disease are palliative, aiming at increasing dopamine levels in the striatum. The expected impact of GDNF therapy is not simply to produce an increase in the dopaminergic neurotransmission at the dopaminergic nerve terminals in the striatum (which will result in a relief of the symptoms), but also to slow down, or even stop, the progression of the degenerative processes and to repair the damaged nigrostriatal pathway and restore its function. GDNF may also be used in treating other forms of damage to or improper function of dopaminergic nerve cells in human patients. Such damage or malfunction may occur in schizophrenia and other forms of psychosis. The only current treatments for such conditions are symptomatic and require drugs which act upon dopamine receptors or dopamine uptake sites, consistent with the view that the improper fun
Fox Gary M.
Jing Shuqian
Wen Duanzhi
Amgen Inc.
Hayes Robert C.
Kunz Gary L.
Levy Ron K.
Odre Steven M.
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