Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1995-09-28
2001-02-06
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S300000, C530S350000, C530S399000
Reexamination Certificate
active
06184200
ABSTRACT:
FIELD OF THE INVENTION
In general, the present invention relates to proteins, referred to herein as glial cell line-derived neurotrophic factors (also referred to as glial derived neurotrophic factor or GDNF), that are characterized by the ability to promote dopamine uptake by dopaminergic neurons and support the survival of the neurons that die in Parkinson's Disease. The present invention more specifically relates to a novel truncated GDNF proteins.
BACKGROUND OF THE INVENTION
Neurotrophic factors are proteins, found in the nervous system or in non-nerve tissues innervated by the nervous system, whose function is to promote the survival and maintain the phenotypic differentiation of nerve and/or glial cells (Varon et al.,
Ann. Rev. Neuroscience
1:327, 1979; Thoenen et al., Science 229:238, 1985). Because of this physiological role, neurotrophic factors are useful in treating the degeneration of nerve cells and the loss of differentiated function that occurs in a variety of neurodegenerative diseases.
In order for a particular neurotrophic factor to be potentially useful in treating nerve damage, the class or classes of damaged nerve cells must be responsive to the factor. Different neurotrophic factors typically affect distinctly different classes of nerve cells. Therefore, it is advantageous to have on hand a variety of different neurotrophic factors to treat each of the classes of damaged neurons that may occur with different forms of disease or injury.
Neurotrophic factors can protect responsive neurons against a variety of unrelated insults. For example, nerve growth factor (NGF) will rescue a significant portion of sensory neurons from death caused by cutting their axonal processes (Rich et al.,
J. Neurocytol
16:261, 1987; Otto et al.,
J. Neurosci.
83:156, 1987), from ontogenetic death during embryonic development (Hamburger et al.,
J. Neurosci.
4:767, 1984), and from damage caused by the administration of taxol or cisplatin (Apfel et al.,
Ann. Neurol.
29: 87, 1991). This apparent generality of protection has led to the concept that if a neurotrophic factor protects responsive neurons against experimental damage, it may be useful in treating diseases that involve damage to those neurons in patients, even though the etiology may be unknown.
A given neurotrophic factor, in addition to having the correct neuronal specificity, must be available in sufficient quantity to be used as a pharmaceutical treatment. Since neurotrophic factors are typically present in small amounts in tissues (e.g., Hofer and Barde
Nature
331:261, 1988; Lin et al.,
Science
246:1023, 1989), it would be inconvenient to prepare pharmaceutical quantities of neurotrophic factors directly from animal tissues. As an alternative, it is desirable to use a recombinant expression system to produce the desired protein.
Lin et al. previously described a method for screening biological samples for neurotrophic activity on the embryonic precursors of the substantia nigra dopaminergic neurons (see U.S. patent application Ser. No. 08/182,183 filed May 23, 1994 and its parent applications; PCT/US92/07888 filed Sep. 17, 1992 (WO 93/06116); and European Patent Application No. 92921022.7 (Publication No. EP 610 254); the disclosures of which are hereby incorporated by reference). This bioassay is useful in identifying neurotrophic factors which may be used in treating Parkinson's disease (Friedman et al.,
Neuro. Sci. Lett.
79:65-72, 1987) as the disease is characterized by the degeneration of dopaminergic neurons in the midbrain that innervate the striatum.
Lin et al. further described the characterization of a new neurotrophic factor that was purified from one such source, the conditioned culture medium from a glioblastoma cell line, B49 (Schubert et al.,
Nature
249:224-27, 1974). The conditioned medium from this cell line was previously reported to contain dopaminergic neurotrophic activity (Bohn et al.,
Soc. Neurosci. Abs.
15:277, 1989). Prior to the disclosure of Lin et al., glial cell line-derived neurotrophic factor (GDNF) had not been identified as a discrete biologically active substance or isolated as a substantially pure protein. In addition, Lin et al. described processes for cloning human genes encoding GDNF, the nucleic acid sequence of the human genes that encode GDNF and the amino acid sequences of the GDNF protein. The GDNF gene was subcloned into an expression vector, and the vector was used to express biologically active GDNF. The GDNF protein is a homodimer composed of two 134 amino acid, 22 kDa, subunits joined by disulfide bond. The description further included the use of GDNF for preventing and treating nerve damage and nerve related diseases such as Parkinson's disease.
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.
GDNF therapy could be particularly helpful in the treatment of neurodegenerative conditions involving the degeneration of the dopaminergic neurons of the substantia nigra, such as 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 functioning of the dopaminergic neurons which innervate these receptor-bearing neuronal populations may be involved in the disease process.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel truncated glial cell line-derived neurotrophic factor (GDNF) protein products. In one embodiment, truncated GDNF proteins are produced by recombinant genetic engineering techniques. In an alternative embodiment, the truncated GDNF proteins are synthesized by chemical techniques, or a combination of the recombinant and chemical techniques.
The truncated GDNF protein products of the present invention include the proteins represented by the amino acid sequence X-[Cys
41
-Cys
133
]-Y. The amino acid residue numbering scheme of
FIG. 1
(SEQ ID NO:2) is used to facilitate comparison to the mature GDNF protein. [Cys
41
-Cys
133
] represents the amino acid sequence of Cys
41
through Cys
133
as depicted in
FIG. 1
(SEQ ID NO:2). Y represents the carboxy terminal group of Cys
133
or a carboxy-terminus amino acid residue of Ile
134.
X represents a methionylated or nonmethionylated amine group of Cys
41
or amino-terminus amino acid residue(s) selected from the group:
&e
Amgen Inc.
Curry Daniel R.
Gucker Stephen
Kunz Gary L.
Levy Ron K.
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