Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-07-01
1998-11-17
LeGuyander, John L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
435 6, 435 911, 435325, 435366, 435375, 536 231, 536 2431, 536 245, A61K 4800, C07H 7104, C12Q 168, C12N 1585
Patent
active
058376941
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/AU94/00631, filed Oct. 18, 1994.
The present invention relates generally to neurones and more particularly to a method for increasing or enhancing survival of same. The present invention further contemplates agents in the form of compositions of matter useful for facilitating survival of neurones.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide sequences referred to in the specification are defined following the bibliography.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
A number of soluble trophic factors have been shown to exhibit an effect on neuronal survival in vivo. Many of these factors act directly on the developing neurone within, for example, the dorsal root ganglia (DRG). One factor of particular importance is Nerve Growth Factor (NGF; 1). The effects of NGF are mediated at least in part by trkA, the high affinity NGF receptor. Another receptor, the low affinity NGF receptor p75.sup.NGFR, is a receptor, the function of which, is incompletely characterised. The p75.sup.NGFR receptor has been shown to increase affinity of trkA for NGF (12) and work by Lee et al (2) suggests that p75.sup.NGFR, is required for development of sensory neurones. Notwithstanding that administration of NGF may have therapeutic potential in facilitating survival of neurones, NGF is a multifunctional molecule affecting a range of target cells. There is a need, therefore, to specifically target neuronal cells.
In work leading up to the present invention, the inventors sought to further characterise the function of p75.sup.NGFR by down regulating the receptor in sensory neurones from DRG at various stages of development. The inventors surprisingly discovered that lowering levels of p75.sup.NGFR, expression in sensory neurones increases the survival of postnatal (P) day 2 (P2) sensory neurones in the absence of exogenous NGF notwithstanding that the down regulation of p75.sup.NGFR expression prevents NGF-mediated survival of sensory neurons at the embryonic (E) stage of target innervation.
Accordingly, one aspect of the present invention contemplates a method of facilitating neuronal survival in an animal, said method comprising down regulating expression of a receptor on said neurones for a neurotrophic factor capable of neurotrophic factor-mediated survival of neurones.
The present invention is exemplified and described herein with reference to the receptor, p75.sup.NGFR and to one of its effector molecules, i.e. NGF. This is done, however, with the understanding that the present invention extends to all neurotrophic receptors which act in a manner functionally analogous to p75.sup.NGFR and its effector molecules which include NGF and Brain Derived Neurotrophic Factor (BDNF) in promoting neurone survival as determined in accordance with the present invention. Neurones contemplated by the present invention are those which express or have the ability to express p75.sup.NGFR. By "facilitating neuronal survival" is meant to include increasing or enhancing survival of neurones or rescuing neurones following, during or prior to neurodegenerative conditions such as associated with disease and/or trauma. "Rescuing neurones" includes maintenance of the differentiated state of a neurone such as, for example, maintaining the cholinergic differentiated state of a neurone. In this regard, therefore, a related aspect of the present invention provides a method of facilitating neuronal rescue in an animal, said method comprising down regulating expression of a receptor on said neurones for a neurotrophic factor capable of neurotrophic factor-mediated rescue of neurones.
Accordingly
REFERENCES:
patent: 5585479 (1996-12-01), Hoke et al.
Westermann et al., Inhibition of expression of SV-40 virus large T-antigen by antisense oligodeoxyribonucleotides, Biomed. Biochim. Acta, vol. 48(1), pp. 85-93, 1989.
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Barrett et al., The p75 nerve growth factor receptor mediates survival of death depending on the stage of sensory neuron development, Proc. Natl. Acad. Sci., vol. 91, pp. 6501-6505, Jul. 1994.
Chao, M.V. et al. (1986) "Gene Transfer and Molecular Cloning of the Human NGF Receptor", Science 232:518-521.
Ross, Alonzo H. et al. (1991) "Nerve Growth Factor--Induced Differentiation of Human Neuroblastoma Cell Lines" Chem. Abstracts115:229, Abstract No. 151785d.
Wagner, R.W. (1994) "Gene Inhibition Using Antisense Oligodeoxynucleotides " Nature(372):333-335.
International Patent Application PCT/US93/08446 (Int. Publication No. Wo 94/06935).
LeGuyander John L.
The Walter and Eliza Hall Institute of Medical Research
Wang Andrew
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