Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-05-11
2001-01-16
Yucel, Remy (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S091100, C435S325000, C435S366000, C435S375000, C536S023100, C536S024500
Reexamination Certificate
active
06174869
ABSTRACT:
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 indusion 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
NGFR
, is a receptor, the function of which, is incompletely characterised. The p75
NGFR
receptor has been shown to increase affinity of trkA for NGF (12) and work by Lee et al. (2) suggests that p75
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
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
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
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
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
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
NGFR
. By “facilitating neuronal survival” is meant to include increasing or enhancing survival of neurones 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, in a preferred aspect of the present invention, there is provided a method of facilitating survival of neurones which express receptor p75
NGFR
in an animal, said method comprising down regulating p75
NGFR
expression in said neurones.
Neurones which express or have the ability to express p75
NGFR
and which are encompassed by the present invention include, but are not limited to, sensory neurones, sympathetic neurones, central cholinergic neurones (and in particular basal forebrain neurones which are affected in Alzheimer's disease), motor neurones and cerebellar neurones and neurones at the substantia nigia and stinatum, involved in Parkinson's Disease.
Preferably, the animal is a mammal such as a human, livestock animal (e.g. sheep, pig, cow, horse or goat), companion animal (e.g. dog or cat), laboratory test animal (e.g. mouse, rat, rabbit or guinea pig) or captive wild animal. Most preferably, the animal is a human.
The term “down regulating” is used in its most general sense and includes decreasing the number of receptors per cell, decreasing the number of functional receptors per cell and/or blocking existing receptors on a cell. In each case, the down regulated expression results in increased survival of sensory neurones. Analysis of p75
NGFR
receptor expression may be monitored by any convenient means such as, but not limited to, use of labelled antibodies and/or through analysis of gene expression.
Preferably, the facilitation of neuronal survival is at the stage of or after target innervation.
In its most preferred embodiment, down regulation is at the genetic level through use of antisense nucleic acid molecules. In a particular exemplified embodiment, the antisense nucleic acid molecules are antisense oligonucleotides. Generally, short oligonucleotides are used having from about 5 to about 50 nucleotides depending on their target. Preferably, the oligonucleotides are from about 10 to less than about 26 nucleotides in length. Preferably, the antisense oligonudeotides target the 5′ end portion of the p75
NGFR
gene or a region comprising and/or adjacent to the termination codon on the p75
NGFR
gene.
The present invention extends, however, to larger nucleic acid molecules capable of targeting mRNA of the structural p75
NGFR
genetic sequence or a gene regulating p75
NGFR
expression.
A related embodiment is directed to a method of down regulating expression of the low affinity nerve growth factor (NGF) receptor, p75
NGFR
on a neurone, said method comprising contacting said neurone with an effective amount of an antisense oligonucleotide to the gene encoding p75
NGFR
for a time and under conditions sufficient to reduce expression of p75
NGFR
such that neurone survival is facilitated.
More particularly, there is provided a method of down regulating expression of the low affinity nerve growth factor (NGF) receptor, p75
NGFR
on a neurone, said method comprising contacting said neurone with an effective amount of an antisense oligonucleotide to the gene encoding p75
NGFR
for a time and under conditions sufficient to reduce expression of p75
NGFR
such that in the absence of exogenously added NGF, neurone survival is increased, enhanced or otherwise facilitated.
The oligonucleotides are preferably chemically modified to facilitate improved or increased stability in vitro and/or in vivo (e.g. against the action of nucleases) and/or to allow oral bioavailability, to permit transfer across the blood-brain barrier and/or to increase the therapeutic index. Furthermore, the chemical modification may facilitate administration into the target animal or, following administration, passage of the oligonucleotides to the target tissue. For example, the oligonucleotides may carry linkers, tags or other effector molecules such as transferrin receptor antibody. Particularly preferred oligonucleotides are phosphorothioate oligonucleotides since phosphorothioates exhibit resistance to nucleases contributing to high stability both in vitro and in vivo (3). Alternatively, the oligonucleotides may be conjugated to lipophilic groups (13), conjugated to meso-tetr
Scully Scott Murphy & Presser
The Walter and Eliza Hall Institute of Medical Research
Wang Andrew
Yucel Remy
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