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
1998-10-29
2001-05-29
Priebe, Scott D. (Department: 1632)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S254110, C435S320100, C435S325000, C435S455000, C435S471000, C536S023100, C536S023500
Reexamination Certificate
active
06238883
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in therapy and in identifying compounds which may be agonists, antagonists and /or inhibitors which are potentially useful in therapy, and to production of such polypeptides and polynucleotides.
BACKGROUND OF THE INVENTION
The drug discovery process is currently undergoing a fundamental revolution as it embraces ‘functional genomics’, that is, high throughput genome- or gene-based biology. This approach as a means to identify genes and gene products as therapeutic targets is rapidly superceding earlier approaches based on ‘positional cloning’. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on high-throughput DNA sequencing and the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery.
In the central and peripheral nervous system, reliable neurotransmission depends on rapid termination of transmitter action following postsynaptic activation. In some cases this is achieved by metabolism of the neurotransmitter, as in the case of acetycholine and neuropeptides. In many cases, however, including catecholamines, serotonin and some amino acids (e.g. GABA, glycine and glutamate), the neurotransmitter is efficiently removed into the presynaptic terminal or surrounding glial cells by neurotransmitter transporters, membrane-bound polypeptides located in the plasma membrane.
Recently, cDNAs encoding a number of Na/Cl-dependent neurotransmitter transporters (e.g. for serotonin, catecholamine, amino acid (glycine, GABA)) have been described. The general structure of this class of transporter is very similar, containing twelve potential transmembrane helices and an external loop with 3-4 glycosylation sites between transmembrane segments 3 and 4. In GABA and catecholamine transporter subfamilies, the amino acid sequence is about 60-80% identical to other members within a subfamily and about 40% identical to members between two subfamilies (Liu et al., Proc. Natl. Acad. Sci. USA, (1992), 89:6639-6643). Transporters of amino acids such as glycine share about 40-50% homology with all members of the neurotransmitter transporter superfamily. Two classes of glycine transporter, GlyT-1 and GlyT-2, have been identified (Liu et al, J. Biol. Chem. (1992),268,22802-22808). Rat GlyT-2 has about 50% amino acid sequence identity with either human or rat GlyT-1.
Glycine is a major transmitter in the nervous system. Glycine can have both inhibitory and excitatory functions, which are mediated by two different types of receptor, each associated with a different class of glycine transporter. The excitatory function of glycine is mediated by “strychnine-insensitive” glycine receptors, which are part of the NMDA receptor complex which mediates some of the actions of glutamate, the major excitatory transmitter in the central nervous system. This type of glycine receptor is widely distributed throughout the brain, and is associated with the GlyT-1 transporter. Conversly, the inhibitory action of glycine is mediated by “strychnine-sensitive” glycine receptors. These receptors are found mainly in the spinal cord, brainstem and cerebellum, and are associated with the GlyT-2 transporter.
Modulation of neurotransmitter transport enables synaptic transmission to be increased or decreased by altering the levels of neurotransmitter in the synaptic cleft, and blockade of transport is an established approach to the treatment of psychiatric and neurological illness. Drugs which act by this mechanism include the tricyclic antidepressants, which act on monamine transporters in general, and the selective serotonin uptake inhibitors (SSRIs) (Lesch K P and Bengel D, CNS Drugs 4(1995), 302-322). A GABA transport inhibitor, tiagabine, has recently been identified as a potential therapy for epilepsy (Lesch K P and Bengel D, CNS Drugs 4(1995), 302-322. Compounds which modulate glycine transporter function would be expected to alter synaptic levels of glycine and thus affect receptor function. In the case of the GlyT-2 transporter, inhibition of transporter function would produce increased activation of strychnine-sensitive glycine receptors. In the spinal cord, activation of these receptors would be expected to reduce transmission of pain-related information, so inhibition of the GlyT-2 transporter could alleviate neuropathic or other pain sensation (e.g. Simpson R K et al, Neurochem. Res. (1996) 21, 1221-1226). In addition, activation of strychnine-sensitive glycine receptors can reduce muscle hyperactivity, which can be related to conditions such as myoclonus, epilepsy and spasticity (e.g. Simpson R K et al, J. Spinal Cord Med. (1996) 19, 215-224). Therefore, inhibition of the glycine transporter could alleviate spasticity or other muscle hyperactivity associated with epilepsy, stroke, head trauma, spinal cord injury, dystonia, multiple sclerosis amyotrophic lateral sclerosis, Huntington's Disease or Parkinson's Disease
SUMMARY OF THE INVENTION
The present invention relates to SC6, in particular SC6 polypeptides and SC6 polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for using such polypeptides and polynucleotides, including the treatment of neuropathic pain, other pain, spasticity, myoclonus, epilepsy, stroke, head trauma, spinal cord injury, dystonia, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's Disease or Parkinson 's Disease, hereinafter referred to as “the Diseases”, amongst others In a further aspect, the invention relates to methods for identifying agonists and antagonists/inihibitors using the materials provided by the invention, and treating conditions associated with SC6 imbalance with the identified compounds. In a still further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate SC6 activity or levels.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to SC6 polypeptides. Such peptides include isolated polypeptides comprising an amino acid sequence which has at least 97% identity, preferably at least 99% identity, to that of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include those comprising the amino acid of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides in which the amino acid sequence has at least 97% identity, preferably at least 99% identity, to the amino acid sequence of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include the polypeptide of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides encoded by a polynucleotide comprising the sequence contained in SEQ ID NO: 1.
Polypeptides of the present invention are believed to be members of the Neurotransmitter transporter family of polypeptides. They are therefore of interest because of the established, proven history of neurotransmitter transporters as therapeutic targets for the treatment of neurological or psychiatric diseases. In particular, glycine transporters would be expected to modulate activation of glycine receptors by glycine, and there is evidence that strychnine-sensitive glycine receptors can regulate transmission of pain information and modulate muscle activity. Therefore, a therapeutic target for treatment of diseases associated with altered muscle activity or pain transmission could be provided by a polypeptide which has the properties of a glycine transporter, in particular of the GlyT-2 type which is associated with strychnine-sensitive glycine receptors. These properties are hereinafter referred to as “SC6 acti
Brown Anthony M
Cairns William
Chapman Conrad Gerald
Evans Joanne Rachel
Gloger Israel Simon
Han William T.
King William T.
Priebe Scott D.
Ratner & Prestia
SmithKline Beecham Plc
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