WO1994000494A1 - Improvements in or relating to neuroregeneration - Google Patents
Improvements in or relating to neuroregeneration Download PDFInfo
- Publication number
- WO1994000494A1 WO1994000494A1 PCT/GB1993/001343 GB9301343W WO9400494A1 WO 1994000494 A1 WO1994000494 A1 WO 1994000494A1 GB 9301343 W GB9301343 W GB 9301343W WO 9400494 A1 WO9400494 A1 WO 9400494A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycoprotein
- activity
- antibody
- grey matter
- collapse
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to neuroregeneration.
- CNS central nervous system
- PNS peripheral nervous system
- Parkinson's Disease Alzheimer's Disease
- various motor neurone diseases include Parkinson's Disease, Alzheimer's Disease and various motor neurone diseases.
- Alzheimer's Disease lesions occur in cerebral cortex neurons, in particular cholinergic neurons projecting from the substantia innominata to the cortex. Treatment regimes are aimed at enhancing the activity of the remaining neurons.
- Motor neurone disease in which there is a chronic degeneration of CNS and PNS motor neurons resulting in a loss of muscle strength and control, can be treated in similar ways.
- Acute conditions involving brain injury include the following:
- axotomy for example, penetrating brain injury and spinal cord transection
- a disadvantage common to the known treatments of the diseases and conditions outlined above is that the treatment is aimed at enhancing the activity of remaining neurons rather than in replacing lost neurons or halting the degeneration that causes the disease. As a result, higher doses of relevant drugs are required as the disease progresses. Further, it is likely that in time the disease goes beyond the point at which treatment can be effective.
- a further disadvantage is that there are side effects associated with the drugs used for treating the diseases.
- the present invention aims to mitigate at least some of these disadvantages.
- the present invention is based on the extraction from grey matter of one or more glycoproteins that have been implicated in neurodegeneration.
- the present invention provides glycoprotein obtainable from grey matter, and capable of inducing growth cone collapse.
- the glycoprotein is further characterised by dye binding properties, and in particular is capable of binding to the commercially available dye Mimetic Green (obtained from Affinity Chromatography Limited) but does not bind to the dye Mimetic Blue 2.
- the glycoprotein is retained by a membrane of 100,000 molecular weight cut off, e.g. an Amicon Diaflow (Trade Mark) YM type membrane with 100,000 molecular weight cut off used in an Amicon Centriprep Concentrator or an Amicon Centricon Concentrator (Centriprep and Centricon are Trade Marks) .
- a membrane of 100,000 molecular weight cut off e.g. an Amicon Diaflow (Trade Mark) YM type membrane with 100,000 molecular weight cut off used in an Amicon Centriprep Concentrator or an Amicon Centricon Concentrator (Centriprep and Centricon are Trade Marks) .
- Glycoprotein in accordance with the invention has been extracted from grey matter from a wide range of sources, including mammalian sources such as human, sheep, rat, pig, avian sources such as chicken, and fish sources such as carp.
- mammalian sources such as human, sheep, rat, pig, avian sources such as chicken, and fish sources such as carp.
- Cross-reactivity of material from different sources has been tested e.g. with chicken-derived glycoprotein being tested for the effect on rat nerve cell growth cones, and vice versa, and similarly for chicken and human material, and in all cases growth cone collapse is induced.
- chicken nerve cells are generally used to test growth cone collapse activity of human-derived glycoprotein.
- glycoprotein of the invention is conveniently extracted from grey matter by chromatography on immobilsed dyes, e.g. Mimetic Green 1 as mentioned above.
- glycoprotein has yet to be fully characterised.
- the cleanest preparations of inhibitory glycoprotein isolated from avian grey matter as a single band on a non-denaturing gel, show 2 bands to be present at approximate molecular weights of 75K and 62K when examined by SDS-PAGE under reducing conditions .
- the lower of these 2 bands is derived from the biologically-active material.
- glycoprotein The ability of the glycoprotein to induce growth cone collapse, e.g. as determined by the growth cone collapse assay described in Cook et al, 1991, suggests it may be implicated in the failure of CNS regeneration as well as neurodegeneration, so that it can be used as the basis of attempts to stimulate nerve regeneration by interfering (up or down regulating) with the functioning of the glycoprotein. This view is substantiated by experimental evidence obtained by the present inventors.
- AD Alzheimer's disease
- CHAPS detergent extracts of cerebral cortex from 4 normal brains (4-30 hours post-mortem delay; tissue obtained collectively from the frontal, parietal, temporal and occipital lobes ) were incorporated into liposomes and added to cultures of chick embryo sensory neurons extending on a laminin substratum.
- a mean of 70% of the growth cones had collapsed, changing from a typical spread morphology (with filopodia and lamellipodia) to a needle-like morphology.
- Nerve sprouting has been noted in a number of studies of AD (for example: Scheibel and Tomiyasu, 1978; Probst et al., 1983; Ihara, 1988; McKee et al., 1989; Geddes and Cotman, 1991; Masliah et al., 1991), and could be secondary to partial deaffe antation of neurons (resulting from a primary process of cell death).
- AD brain An alternative, however, is that it might result from a primary reduction (from whatever cause) in the levels of expression of the molecule suppressing nerve growth, for example on astrocytes surrounding synaptic terminals, leading to aberrant nerve growth and alteration of normal synaptic connectivity. Associated with such a change, neurons could lose normal trophic support, leading secondarily to cell death. Dementia could then result from sprouting and/or cell death. In sum, while the loss of growth cone collapse-inducing activity in AD brain may be secondary to cell death, it is equally plausible that it lies upstream of cell death in the chain of events that leads to full AD pathology.
- One approach to stimulate nerve regeneration involves use of antibodies (monoclonal or polyclonal) to the glycoprotein(s) : by binding to the glycoprotein(s) , • biochemical activity may be affected.
- the invention thus provides a method of inhibiting neurodegeneration or promoting neuroregeneration comprising administering to a patient a substance that interferes with the functioning of glycoprotein of the invention.
- an antibody preferably a monoclonal antibody, to glycoprotein of the invention.
- the invention also provides an antibody preferably a monoclonal antibody to the glycoprotein of the invention, which antibody is for use in a method of treatment of the human or animal body.
- the antibody is for use in treating neurodegenerative diseases, or in promoting neuroregeneration.
- the invention provides a method of inhibiting neurodegeneration or promoting neuroregeneration, comprising administering to a patient antibodies to glycoprotein of the invention.
- the invention finds applicablility in the treatment of conditions and diseases such as acute brain injury, Alzheimer's Disease or motor neurone disease.
- Two logical developments from the invention concern the purification of the receptor(s) for the biologically- active glycoprotein, and the cloning of the genes for both the glycoprotein and its receptor(s).
- the identification of the receptor(s) would provide another entry point for molecular manipulation of the system for the clinical purposes described herein, for example using suitable blocking antibodies or chemical agonists and antagonists.
- Cloning the genes for both the glycoprotein and its receptor(s), via partial sequence determination of the purified molecules, would enable the production of large quantities of the molecules by insertion of appropriate cDNA in suitable expression vectors. In turn, this would provide a more efficient means of production of antigen for the generation of further antibodies.
- antibodies and cDNA probes would be for diagnostic purposes, where extracts of mammalian brain biopsy could be subjected to immunoassays (such as ELISA, enzyme-linked immunoadsorbent assay) and/or RNA assay (such as Northern blot analysis or RNAase protection).
- immunoassays such as ELISA, enzyme-linked immunoadsorbent assay
- RNA assay such as Northern blot analysis or RNAase protection
- Figure 1 is a photograph of an acrylamide gel, illustrating growth cone collapse activity isolated from chicken grey matter by affinity chromatography
- Figure 2 shows histograms representing the level of growth cone collapse activity obtained from various extracts of grey matter
- Figure 3 shows histograms representing the level of growth cone collapse activity of various products of dye chromatography
- Figure 4 shows histograms representing the level of growth cone collapse activity obtained from extracts grey matter of various different species.
- Freshly dissected grey matter e.g. mammalian (human, sheep, rat, mouse etc) or avian (chicken) is homogenized in 2% (w/v) CHAPS (Sigma) (CHAPS is a zwitterionic detergent, 3-[ (3-cholamidopropyl) dimethyl ammonio]-l- propanesulphonate) in phosphate-buffered saline, pH 7.4, at 4°C, centifuged at 100,000g for 1 hour at 4°C, and the supernatant fluid harvested as source material.
- CHAPS Sigma
- the active material present in the second peak can be worked up by one of two protocols: a) use of further dye-affinity chromatography, or b) by hydrophobic interaction chromatography.
- protocol (a) material from the second peak is dialyzed against excess 0.2% CHAPS, 25mM phosphate, pH 6.6 It is then passed successively through immobilized Brown-10 (a procion dye obtained in immobilized form from Sigma Chemical Co; the batches used by us normally have more that 5mgm dye per ml of gel) followed by Mimetic Blue-2 marketed by Affinity Chromatography Ltd.
- immobilized Brown-10 a procion dye obtained in immobilized form from Sigma Chemical Co; the batches used by us normally have more that 5mgm dye per ml of gel
- Mimetic Blue-2 marketed by Affinity Chromatography Ltd.
- the filtrates from these columns are adsorbed onto immobilized Green-19 (marketed in immobilized form by Sigma Chemical Co.), washed extensively with 0.2% CHAPS 25mM phosphate, pH 6.65, followed by elution with 0.5M KCl, 50 mM phosphate, pH 8.0, 0.2% CHAPS followed by 0.7M KCl, 50mM phosphate, pH 8.0, 0.2% CHAPS, followed by IM KCl, 50mM phosphate, pH 8.0, 0.2% CHAPS. The bulk of the biological activity is recovered in the latter elution. After extensive dialysis against 0.2% CHAPS 25mM phosphate (pH 7.0), the material is fractioned on a non-denaturing slab gel (10% acrylamide; Ha es and Rickwood, 1981).
- FIG. 1 illustrates how biologically-active material isolated from Mimetic Green 19 may be fractionated on a non-denaturing gel (10% acrylamide) and detected by silver-staining reagent.
- the 2 tracks on the left on the figure are standard marker proteins, ovalbumin and BSA; the track on the right is material which has been purified from Green 19 affinity column chromatography.
- the biologically-active material runs principally as a single band, which in the case of chicken grey matter runs in the same position as BSA monomer as shown, and from which it may be electroeluted and shown to possess growth cone collapse-inducing activity.
- This material shows 2 components of M 62,000 and 75,000 as determind by SDS- PAGE.
- the sample used in Figure 1 corresponds to approximtely lug protein.
- An alternative procedure is to adsorb the active material from Mimetic Green directly to a suitable hydrophobic matrix. From a survey of propyl, butyl, hexyl, octyl and phenyl ligands we have evidence that activity is best adsorbed to the propyl and butyl matrices. Biological activity may be recovered by eluting these matrices with 0.2% CHAPS, 25mM phosphate, pH 7.0. Such material, when subjected to non-denaturing gel electrophoresis (see above), results in a similar co-migration of the active material with the BSA marker.
- the histograms of Figure 2 illustrate the fractionation of collapse-inducing activity from extracts of human grey matter on a 5ml column of Mimetic Green. Each histogram represents the level of collapse activity present in the column fractions, which correspond to 0.2 column volumes.
- the histograms marked RG through to Di are various controls. RG represents the level of collapse found in
- CHAPS extracts of rat grey matter, and HG the same found in extracts of human grey matter.
- PL and PBS are control values, showing that liposomes (PL) used as a vehicle for the collapse-inducing molecules have themselves no effect on growth cones, and that saline alone (PBS) is likewise without effect.
- the dye affinity purification protocol requires that the extracts are dialysed against excess 0.2% CHAPS, 25mM phosphate, pH 6.65, before addition to the Mimetic Green.
- the histogram Di shows the extracts of human grey matter (HG) so treated retain biological activity.
- Histograms Fl, F5 and F8 show the loading of dialysed material onto Mimetic Green. It will be seen that after 8x0.2 column volumes the Mimetic Green column is fully saturated.
- the column may then be thoroughly washed and, as seen by comparison of l with 22, any excess activity can be washed off. Note that by washing fraction 22, collapse activity has reached control levels (cf. PL and PBS).
- the adsorbed biological activity is then elutable using IM KCl, 50mM phosphate (pH 8.0), 0.2% CHAPS, as shown by histograms El to E4.
- the Mimetic Blue 2 may also be used to remove contaminating proteins from biologically- active material eluted from Mimetic Green (see Figure 3).
- a 1ml Mimetic blue 2 column was used and the fractions represented by individual histograms of Figure 3 correspond to 0.4 column volumes.
- the 1st KCl elution fraction from the experiment illustrated in Figure 2 (El) has been brought back to 0.2% CHAPS, 25 mM phosphate (pH 6.65) by dialysis.
- the histogram shows that most of the collapse-inducing activity passes straight through the column (MBF) and in the 1st washing (Wl) .
- the biological activity obtained from chicken grey matter at least may be adsorbed by interaction with immobilized peanut agglutinin (PNA), a property associated with the collapse-inducing molecules isolated from chicken somites (Davies et al. , 1990). This is prima facie evidence that the molecules encountered here are glycoproteins carrying O-linked carbohydrate groups (Cook and Keynes, 1992. Relations between mesodermal and neural segmentation. - in Formation and Differentiation of Early Embryonic Mesoderm; eds. R Bellairs & J W Lash, Plenum Press.).
- PNA peanut agglutinin
- Extracts from a variety of species have been prepared under standard conditions (ie. lgm wet weight grey matter to 2.5 ml homogenisation medium) and tested for their ability to induce collapse of chicken sensory axon growth cones extending on a laminin substratum.
- the results are shown in Figure 4.
- Controls for plain liposomes (PL) and phosphate buffered saline (PBS) are shown, along with extracts from carp (CB), chicken (CG), rat (RG), sheep (SG) and human (HG) grey matter.
- CB plain liposomes
- CB carp
- CB chicken
- CG rat
- SG sheep
- HG human
- mammalian activity causes avian (chicken) growth cones to collapse, and the latter source of growth cones is used as the regular test material.
- Avian activity also causes mammalian (rat) growth cones to collapse.
- Glycoproteins purified as described above on preparative gels are either electroeluted or directly excised by razor blade and act as antigen.
- the antigen in sterile phosphate-buffered saline (0.145M NaCl, lOmM phosphate, pH 7.4) is made into an emulsion with Freund's complete adjuvant using a Berlin adaptor. Emulsion is admistered at several sites across the back of the rabbit by subcutaneous injection, as well as by intramuscular injection into the thigh. Booster injections are given every 10 days using the above procedure, with the major exception that Freund's incomplete adjuvant is used. As an alternative vehicle to Freund's adjuvant we use Hunter's TiterMax, available from Stratech Scientific Limited.
- Serum is harvested by low speed centrifugation. Serum is used either directly, or an IgG fraction is isolated by immoblized protein A (alternatively Spectragel is used. This is a low molecular weight non-protein, non-carbohydrate synthetic affinity ligand, marketed by Spectrum Medical Industries Inc., Houston, Texas, U.S.A. and has the advantage that the IgG preparation is not contaminated with protein A).
- immobilized immune IgG is used to test whether collapse- inducing activity can be removed from extracts of mammalian grey matter.
- antibodies to the glycoprotein antigens can be administered directly to the site of the neuronal lesion or into the cerebrospinal fluid via a cerebral ventricle. This could be accomplished by surgical infusion following craniotomy (the blood brain barrier may preclude systemic administration of immunoglobulins) .
- the induction of transient leakiness of the blood brain barrier for example by infusion of a hyperosmotic solution, with simultaneous systemic administration of antibodies, may provide an alternative therapeutic strategy.
- Conditions most readily suited to such procedures comprise: 1) acute mechanical trauma with axotomy (for example, penetrating brain injury and spinal cord transection) ; 2) cerebrovascular accident due to haemorrhage, thrombosis or embolism; 3) as an adjunct therapy to the treatment of brain and spinal cord damage due to bacterial or viral infection, and tumour or abscess expansion.
- axotomy for example, penetrating brain injury and spinal cord transection
- cerebrovascular accident due to haemorrhage, thrombosis or embolism 3) as an adjunct therapy to the treatment of brain and spinal cord damage due to bacterial or viral infection, and tumour or abscess expansion.
- the antibodies can also be used in treatment of diseases involving chronic neurodegeneration such as Alzheimer's Disease and motor neurone disease.
- glycoproteins in purified form can also be used in treating humans, preferably in treating diseases caused by excessive neuronal growth.
- Neuritic plaques in senile dementia of Alzheimer type a Golgi analysis in the hippocampal region. Brain Res. 268, 249-254.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6502169A JPH07508729A (en) | 1992-06-27 | 1993-06-25 | Improvements in or relating to nerve regeneration |
AU43511/93A AU4351193A (en) | 1992-06-27 | 1993-06-25 | Improvements in or relating to neuroregeneration |
EP93913439A EP0648227A1 (en) | 1992-06-27 | 1993-06-25 | Improvements in or relating to neuroregeneration |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9213694.4 | 1992-06-27 | ||
GB929213694A GB9213694D0 (en) | 1992-06-27 | 1992-06-27 | Improvements in or relating to neuroregeneration |
Publications (1)
Publication Number | Publication Date |
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WO1994000494A1 true WO1994000494A1 (en) | 1994-01-06 |
Family
ID=10717836
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/GB1993/001343 WO1994000494A1 (en) | 1992-06-27 | 1993-06-25 | Improvements in or relating to neuroregeneration |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0648227A1 (en) |
JP (1) | JPH07508729A (en) |
AU (1) | AU4351193A (en) |
GB (1) | GB9213694D0 (en) |
WO (1) | WO1994000494A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998004197A1 (en) * | 1996-07-26 | 1998-02-05 | Karolinska Innovations Ab | Medical device for treatment of a gap or defect in the central nerve system |
US7998986B2 (en) | 2001-12-21 | 2011-08-16 | Exelixis Patent Company Llc | Modulators of LXR |
US8013001B2 (en) | 2001-12-21 | 2011-09-06 | Exelixis, Inc. | Modulators of LXR |
-
1992
- 1992-06-27 GB GB929213694A patent/GB9213694D0/en active Pending
-
1993
- 1993-06-25 AU AU43511/93A patent/AU4351193A/en not_active Abandoned
- 1993-06-25 JP JP6502169A patent/JPH07508729A/en active Pending
- 1993-06-25 WO PCT/GB1993/001343 patent/WO1994000494A1/en not_active Application Discontinuation
- 1993-06-25 EP EP93913439A patent/EP0648227A1/en not_active Withdrawn
Non-Patent Citations (5)
Title |
---|
BIOCHEMICAL SOCIETY TRANSACTIONS, Vol. 20, No. 2, May 1992, London, GB, pages 399-401, R.J. KEYNES et al., "Contact Inhibition of Growth-Cone Motility During Peripheral Nerve Segmentation". * |
BIOLOGICAL ABSTRACTS, Vol. BR44, 1993, Philadelphia, PA, US, Abstract No. 71190, G.M.W. COOK et al., "Purification of Growth Cone Collapse-Inducing Glycoprotein From Adult Chicken Grey Matter"; & SOCIETY FOR NEUROSCIENCE ABSTRACTS (22ND ANNUAL MEETING OF THE SOCIETY FOR NEUROSCIENCE, ANAHEIM, CA, US, 25-30 October 1992), Vol. 18, No. 1-2, 1992, page 944. * |
CELL, Vol. 62, 24 August 1990, Cambridge, MA, US, pages 609-610, R. KEYNES et al., "Cell-Cell Repulsion: Clues From the Growth Cone?". * |
CHEMICAL ABSTRACTS, Vol. 113, No. 17, 22 October 1990, Columbus, Ohio, US, Abstract No. 149420w, J.A. DAVIES et al., "Isolation From Chick Somites of A Glycoprotein Fraction That Causes Collapse of Dorsal Root Ganglion Growth", page 491; & NEURON, Vol. 4, No. 1, 1990, pages 11-20. * |
CHEMICAL ABSTRACTS, Vol. 113, No. 17, 22 October 1990, Columbus, Ohio, US, Abstract No. 149421x, J.A. RAPER et al., "The Enrichment of A Neuronal Growth Cone Collapsing Activity From Embryonic Chick Brain", page 492; & NEURON, Vol. 4, No. 1, 1990, pages 21-29. * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998004197A1 (en) * | 1996-07-26 | 1998-02-05 | Karolinska Innovations Ab | Medical device for treatment of a gap or defect in the central nerve system |
AU732199B2 (en) * | 1996-07-26 | 2001-04-12 | Swenora Biotech Ab | Medical device for treatment of a gap or defect in the central nerve system |
US6808530B2 (en) | 1996-07-26 | 2004-10-26 | Karolinska Innovations Ab | Medical device for treatment of a gap or defect in the central nerve system |
US7998986B2 (en) | 2001-12-21 | 2011-08-16 | Exelixis Patent Company Llc | Modulators of LXR |
US8013001B2 (en) | 2001-12-21 | 2011-09-06 | Exelixis, Inc. | Modulators of LXR |
Also Published As
Publication number | Publication date |
---|---|
AU4351193A (en) | 1994-01-24 |
EP0648227A1 (en) | 1995-04-19 |
GB9213694D0 (en) | 1992-08-12 |
JPH07508729A (en) | 1995-09-28 |
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