WO2012004611A1 - Therapeutic use of neural stem cells - Google Patents
Therapeutic use of neural stem cells Download PDFInfo
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- WO2012004611A1 WO2012004611A1 PCT/GB2011/051289 GB2011051289W WO2012004611A1 WO 2012004611 A1 WO2012004611 A1 WO 2012004611A1 GB 2011051289 W GB2011051289 W GB 2011051289W WO 2012004611 A1 WO2012004611 A1 WO 2012004611A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/30—Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
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- 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
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0618—Cells of the nervous system
- C12N5/0623—Stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses
Definitions
- the present invention relates to the use of neural stem cells in the treatment of psychiatric disorders.
- Depression is a debilitating disorder that affects millions of people worldwide (Lopez AD and Murray C, 1998) and imposes a significant cost upon society (Gumnick and Nemeroff, 2000). It is a common psychiatric disorder with a lifetime prevalence of 10-20% (Wong and Lucinio, 2001). Recurrent symptoms are common, with more than 50% of patients experiencing more than one depressive episode. Depression is widespread in patients with co-existing illness, such as diabetes, cancer and stroke, and is particularly prevalent after experiencing heart attack. There are multiple symptoms of depression, including mood alteration, loss of appetite and fatigue; often the sufferer's day to day life is disrupted by lack of concentration, disturbed sleep and feelings of worthlessness. In the most severe cases, patients experience psychotic symptoms such as hallucinations, delusions, morbid and even suicidal thoughts.
- HPA hypothalamic pituitary adrenal
- chronic stress results in atrophy of the vulnerable neurones in the hippocampus in rats and non-human primates (Watanabe et al., 1982; Saplosky et al., 1985; Uno et al., 1989; Sapolsky et al., 1990; Wooley et aladmi 1990; Stein-Behrens et al., 1994; Mararinos et al., 1996).
- pro-inflammatory cytokines have been shown to activate the HPA axis and innate immune system in depressed patients (Schiepers et al., 2005). Additionally patients with immune disorders have been shown to exhibit a higher incidence of depression (Dunn et al., 2005). Changes in cytokine profiles have also been demonstrated in depressed patients (Kim et al., 2007; Brambilla et al., 2004).
- SSRIs serotonin re-uptake inhibitor drugs
- the present invention is directed to an isolated cell obtainable from the CTX0E03 neural stem cell line for use in the treatment of a disorder associated with elevated levels of pro-inflammatory cytokines, particularly a disorder selected from unipolar and bipolar depression, schizophrenia, obsessive compulsive disorder, autism and autistic syndrome disorders.
- a disorder associated with elevated levels of pro-inflammatory cytokines particularly a disorder selected from unipolar and bipolar depression, schizophrenia, obsessive compulsive disorder, autism and autistic syndrome disorders.
- the present invention provides a method for determining the potential effectiveness of cells of the CTX0E03 stem cell line for use as a therapy in the treatment of a psychiatric disorder, comprising the steps of: contacting a sample of peripheral blood cells from a patient suffering from a psychiatric disorder with cells of the cell line; and determining the effect of the cells on the pro-inflammatory cytokine response of the peripheral blood cells.
- the psychiatric disorder is selected from unipolar and bipolar depression, schizophrenia, obsessive compulsive disorder, autism and autistic syndrome disorders.
- Figure 1 shows fluorescent images of microglial and astrocytic responses in the mouse brain at 7 days post vehicle (1A, 1C, 1 E) and 7 days post CTX0E03 treatment (1 B, 1 D, 1 F);
- Figure 2A(i) is a graph showing a reduction in total GFAP fluorescent signal with CTX0E03-treated mouse brains compared with HTS vehicle-treated mouse brains.
- Figures 2A(ii)-2A(v) are representative low (ii, iii) and high (iv, v) fluorescent images showing GFAP expression in HTS, vehicle-treated (ii, iv) and CTX0E03-treated (iii, v) brains;
- Figure 2B(i) is a graph showing a significant reduction in TGF- ⁇ fluorescent signal with CTX0E03-treated mouse brains compared with HTS vehicle-treated mouse brains.
- Figures 2B(ii)-2B(iii) are representative fluorescent images showing TGF- ⁇ positive microglia (ii) and microglia stained with haematoxylin and eosin (iii);
- Figure 5 is a graph showing the dose-dependent effect of IFN - ⁇ on CTX0E03-mediated production of IDO;
- Figure 7 shows images of (i) high expression of IDO by CTX0E03 drug product prior to implantation, and (ii & iii) up-regulation of IDO expression by CTX0E03 cells 24 hours post implantation;
- Figure 8 shows images of (i) no expression of CD274 (PDL-1) by CTX0E03 drug product prior to implantation and (ii & iii) up-regulation and sustained expression of CD274 (PDL-1) by CTX0E03 up to 7 days post implantation;
- Figure 9 are graphs showing that CTX0E03 cells inhibit the LPS release of IFN-y from human PBMCs in a concentration-dependent manner
- Figure 10 illustrates the expression profiling of CTX0E03 cells
- Figure 11A is an image showing that the addition of the pro-inflammatory cytokine IFN- ⁇ in vitro induces CTX0E03 cells to express CD27
- Figure 10B is a graph showing that pre-incubation of CTX0E03 cells with a blocking antibody raised against human CD274 (10pg/ml for 2 hours) prior to co-culture with LPS stimulates PBMCs and restores the inhibition induced by CTX0E03 cells
- Figure 1 1C shows the proposed mechanism of action illustrating the requirement of an inflammatory environment to activate the cells' immunosuppressive function.
- the present invention is based on the surprising discovery that cells of the CTX0E03 cell line, are able to reduce, modulate or inhibit pro-inflammatory cytokines in vivo, and are therefore able to modulate or inhibit activation of T cells and other cells of the immune system. As such, these cells are useful in the treatment of disorders associated with elevated levels of pro-inflammatory cytokines, compared with a control, and disorders characterised by elevated levels of one or more inflammatory marker, compared with a control. These cells provide an industrially scalable, safe and potent allogeneic treatment.
- the present invention is directed to the use of cells obtained from the CTX0E03 cell line in the treatment of psychiatric disorders, including unipolar and bipolar depression, stress-induced depression, obsessive compulsive disorder, bipolar disorder, schizophrenia and autism or autistic syndrome disorders.
- the cells of the CTX0E0E cell line have the following characteristics:
- the present invention relates to the treatment of depressed patients with depressive symptoms that do not respond to common antidepressant medication.
- pro-inflammatory cytokine has its usual meaning in the art and refers to a cytokine which promotes systemic inflammation.
- pro-inflammatory cytokines include interleukin-1 (IL-1), tumour necrosis factor- alpha (TNF-a), necrosis factor -beta (TNF- ⁇ ) and interferon-gamma (IFN- ⁇ ).
- the neural stem cell line CTX0E03 has been deposited at the European Collection of Animal Cultures (ECACC), Vaccine Research and Production laboratories, Public Health Laboratory Services, Porton Down, Salisbury, Wiltshire, SP4 OJG, UK.
- ECACC Accession No. is 04091601.
- the derivation of this cell line is described in European Patent No. 1645626 the content of which is incorporated herein by reference.
- the cells of the CTX0E03 cell line may be cultured in the following culture conditions;
- the cells can be differentiated by removal of the 4-hydroxytamoxifen, which will occur on administration of the cells to the patient.
- CTX0E03 cell line has allowed the scale-up of a consistent product for clinical use. Production of cells from banked materials allows for the generation of cells in quantities for commercial application.
- psychiatric disorder refers to chronic behavioural disorders typically involving systemic and brain inflammation. Disorders include unipolar and bipolar depression, schizophrenia, obsessive compulsive disorder, autism and autistic syndrome disorders.
- the term 'patient' refers to a mammal including a non- primate (e.g. a cow, pig, horse, dog, cat, rat and mouse) and primate (e.g. a monkey and human), and more preferably a human.
- a non- primate e.g. a cow, pig, horse, dog, cat, rat and mouse
- primate e.g. a monkey and human
- Suitable routes of administration of cells according to the invention include direct intra-venous, intra-arterial, intra-muscular or intra-cerebral injection.
- the cells will be administered preferably in the undifferentiated state.
- the cells for transplantation are suspended in a composition comprising Trolox, Na + , K ⁇ Ca 2+ , mg 2 ⁇ CI " , H 2 P0 4 ( HEPES, lactobionate, sucrose, mannitol, glucose, dextron-40, adenosine and glutathione.
- the composition will not include a dipolar aprotic solvent, e.g. D SO.
- Suitable compositions are available commercially, e.g. HypoThermasol ® -FRS. Such compositions are preferred as they allow the cells to be stored at 4°C to 25°C for extended periods (hours to days) or preserved at cryothermic temperatures, i.e. temperatures below -20 ° C. The cells may then be administered in this composition after thawing.
- the present invention is directed to a method for determining the potential effectiveness of the cells the CTX0E03 cell line for use as a therapy in the treatment of a psychiatric disorder, said method comprising the steps of: contacting a sample of peripheral blood cells from a patient suffering from a psychiatric disorder with cells of the cell line; and determining the effect of the cells of the cell line on the pro-inflammatory cytokine response of the peripheral blood cells.
- the psychiatric disorder is selected from unipolar and bipolar depression, schizophrenia, obsessive compulsive disorder, autism and autistic syndrome disorders. If the cells reduce or modulate pro-inflammatory cytokines, this indicates a potential for use in treating said disorders.
- CTX0E03 cells inhibit or modulate pro-inflammatory cytokines, and thereby inhibit or reduce inflammation, including microglial and T cell activation, involves the cell-surface expression of the programmed cell death ligand CD274.
- Up-regulation of CD274 requires IFN- ⁇ which, as shown in the data described above, results in abrogation of PBMC IFN- Y production. Therefore, it appears that the immunosuppressive activity of CTX0E03 cells is driven by the presence of pro-inflammatory cytokines (such as IFN- ⁇ ) and the immuno-modulatory activity of CTX0E03 cells following implantation in vivo is mediated in part by CD274 upregulation which is triggered by the inflammatory microenvironment surrounding the cells.
- Example 1 - CTX0E03 cells reduce host astrocyte and microglia responses in the mouse brain
- CTX0E03 treatment afforded a reduction in GFAP, CD1 1 b and TGF- ⁇ expression in the striatum, at the site of implantation, compared with vehicle control-treated brains.
- Example 2 - CTX0E03 cells reduce host astrocyte and microglia responses in the mouse brain
- mice were implanted with CTX0E03 cells, or control vehicles in the striatal region of the brain. At 4, 24, 48, 72 hours and 7 days post- implantation, brains were collected and subjected to histological analysis.
- Fluorescence immunohistochemistry using specific markers to detect astrocytes (GFAP) and microglia (TGF- ⁇ ) was performed. Host astrocytes and microglia responses were quantified by measuring GFAP and TGF- ⁇ fluorescent signals by image analysis.
- GFAP astrocytes
- TGF- ⁇ microglia
- CTX0E03 treatment reduced GFAP host responses at 72 hours post-implantation, compared with vehicle-treated brains.
- the reactive morphology demonstrated by vehicle treated brains at this time point was not observed in CTX0E03-treated brains.
- CTX0E03 treatment significantly reduced TGF- ⁇ host responses at 72 hours post implantation compared with vehicle-treated brains.
- Example 3 - CTX0E03 cells significantly reduce the production of IFN-v when cultured with lipopolvsaccharide (LPS)-stimulated mixed human peripheral blood mononuclear cells (PBMCs) compared with control PBMCs
- LPS lipopolvsaccharide
- PBMCs mixed human peripheral blood mononuclear cells
- CTX0E03 cells were cultured in 96 well plates with LPS stimulated human PBMCs for 24 hours at 37°C. After 24 hours, culture plates were centrifuged at 1500rpm and the cell supernatants analysed for interferon-gamma (IFN gamma) by ELISA.
- IFN gamma interferon-gamma
- CTX0E03 demonstrated a significant and dose-dependent reduction of PBMC IFN- ⁇ production, with complete abrogation of the response as demonstrated with CTX0E03 at 25K and 50K (see Figure 4).
- Example 4 Microarrav and quantitative polymerase chain reaction (QPCR) demonstrate significant up-requlation of indoleamine2. 3-dioxyqenase (IPO) and Programmed Death Liqand-1 (PDL-1) in response to IFN- v
- Table 1 shows the CTX0E03 inflammation genes significantly up- or down- regulated by IFN- ⁇ treatment.
- CTX0E03 cells were cultured in 96 well plates with LPS stimulated human PBMCs for 24 hours at 37°C with the addition of an anti-CD274 (PDL-1 ) functional blocking antibody. After 24 hours, culture plates were centrifuged at 1500rpm and the cell supernatants analysed for interferon-gamma (IFN gamma) by ELISA.
- IFN gamma interferon-gamma
- CTX0E03 Cell smears of CTX0E03 drug product were produced on glass microscope slides and were subjected fluorescence immunohistochemistry, using specific markers to detect IDO and CD274 (PDL-1).
- PDL-1 specific markers to detect IDO and CD274
- CTX0E03 did not demonstrate CD274 (PDL-1) expression prior to implantation. A significant up-regulation of this protein was observed in CTX0E03 cells post intracerebral implantation. Cytoplasmic expression of this protein was present on CTX0E03 cells up to 7 days post implantation and appeared to be more prominent in CTX0E03 with mature neuronal like morphology at the later time points, see Figure 8.
- Lymphocyte reactions were performed with 7 day growth-arrested CTX0E03 cells combined with 100,000 human peripheral blood mononuclear cells (PBMC) per well of a 96 well plate for 24 hours. Where stated, LPS was added at 50ng/ml. Functional experiments using a blocking antibody (eBioscience) was added to CTX0E03 cells 2 hours prior to PBMCs (10pg/ml).
- PBMC peripheral blood mononuclear cells
- Figure 9 (A-E) shows that CTX0E03 cells inhibit the LPS release of IFN-y from human PBMCs, isolated from a variety of donors.
- the IFN-y levels within a co-culture of CTX0E03 cells with unstimulated (no LPS) human PBMCs are shown in Figure 9A.
- Figures 9B-E demonstrate IFN-y levels within a co-culture of LPS stimulated human PBMCs and CTX0E03 cells from different donors (p ⁇ 0.01). These data show that CTX0E03 cells inhibit IFN- ⁇ release in a concentration-dependent manner.
- Figure 10 illustrates the expression profiling of CTX0E03 cells.
- Real-time PCR illustrates the relative expression levels of known immune modulators in the presence of absence (control) of IFN-y.
- the expression level of each gene was dependent upon the concentration of IFN- ⁇ .
- IFN- ⁇ had no effect on the expression level of certain genes, even at 50ng/ml. A fold increase greater than 4 was considered significant.
- Figure 11 A shows that the addition of the pro-inflammatory cytokine IFN-y In vitro induced CTX0E03 cells to express CD274.
- Pre-incubation of CTX0E03 cells with a blocking antibody raised against human CD274 (10Mg/ml for 2 hours) prior to co-culture with LPS stimulated PBMCs (n 3) and restored an average of 8.3% of the inhibition induced by CTX0E03 cells.
- Figure 11 B shows the proposed mechanism of action illustrating the requirement of an inflammatory environment to activate the cells' immunosuppressive function.
- Heuser I (1998) The hypothalamic-pituitary-adrenal system in depression. Pharmacopsychiatry 31 :10-13.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11738783.7A EP2590660B1 (en) | 2010-07-09 | 2011-07-11 | Therapeutic use of neural stem cells |
AU2011275493A AU2011275493B2 (en) | 2010-07-09 | 2011-07-11 | Therapeutic use of neural stem cells |
CA2803961A CA2803961C (en) | 2010-07-09 | 2011-07-11 | Therapeutic use of neural stem cells |
JP2013519155A JP6151181B2 (en) | 2010-07-09 | 2011-07-11 | Therapeutic use of neural stem cells |
US13/701,932 US9629879B2 (en) | 2010-07-09 | 2011-07-11 | Therapeutic use of neural stem cells |
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GB1011589.7 | 2010-07-09 | ||
GBGB1011589.7A GB201011589D0 (en) | 2010-07-09 | 2010-07-09 | Therapeutic cells |
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US (1) | US9629879B2 (en) |
EP (1) | EP2590660B1 (en) |
JP (3) | JP6151181B2 (en) |
AU (1) | AU2011275493B2 (en) |
CA (1) | CA2803961C (en) |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013150303A1 (en) | 2012-04-03 | 2013-10-10 | Reneuron Limited | Stem cell microparticles |
WO2014013258A1 (en) | 2012-07-19 | 2014-01-23 | Reneuron Limited | Stem cell microparticles |
WO2014125277A1 (en) | 2013-02-12 | 2014-08-21 | Reneuron Limited | Method of producing microparticles |
WO2014125276A1 (en) | 2013-02-12 | 2014-08-21 | Reneuron Limited | Stem cell microparticles and mirna |
US8932577B2 (en) | 2009-02-06 | 2015-01-13 | Reneuron Limited | Treatment of limb ischemia |
WO2015052527A1 (en) | 2013-10-09 | 2015-04-16 | Reneuron Limited | Microparticles, mirna and wound therapy |
WO2015052526A1 (en) | 2013-10-09 | 2015-04-16 | Reneuron Limited | Stem cell microparticles and mirna |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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GB201011589D0 (en) * | 2010-07-09 | 2010-08-25 | Reneuron Ltd | Therapeutic cells |
PL3496730T3 (en) | 2016-08-14 | 2022-09-26 | Ramot At Tel-Aviv University Ltd. | Mesenchymal cell-derived exosomes to treat neurological disorders |
CN112236131A (en) | 2018-03-29 | 2021-01-15 | 技术研究及发展基金有限公司 | Vesicles comprising PTEN inhibitors and uses thereof |
US20200108100A1 (en) * | 2018-10-08 | 2020-04-09 | Reneuron Limited | Neural stem cell therapy for stroke |
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EP1645626A1 (en) | 2004-09-30 | 2006-04-12 | Reneuron Limited | Cell line |
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GB9518606D0 (en) * | 1995-09-12 | 1995-11-15 | Inst Of Psychiatry | Neural transplantation |
US7785601B2 (en) * | 2002-12-31 | 2010-08-31 | Sygnis Bioscience Gmbh & Co. Kg | Methods of treating neurological conditions with hematopoietic growth factors |
GB0514300D0 (en) * | 2005-07-12 | 2005-08-17 | Fond Ct San Raffaele | Imflammation |
US20080219955A1 (en) * | 2007-03-08 | 2008-09-11 | Sekula Raymond F | Method of Producing Purified Neural Stem Cells and Related Methods of Treating a Patient |
EP2543380B1 (en) * | 2008-01-29 | 2016-11-23 | Kyowa Hakko Kirin Co., Ltd. | Neural stem cells proliferation promoting agent |
GB201011589D0 (en) * | 2010-07-09 | 2010-08-25 | Reneuron Ltd | Therapeutic cells |
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EP1645626A1 (en) | 2004-09-30 | 2006-04-12 | Reneuron Limited | Cell line |
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