WO2021055448A1 - Treatment of disc degenerative disease and stimulation of proteoglycan synthesis by fibroblast conditioned media and formulations thereof - Google Patents
Treatment of disc degenerative disease and stimulation of proteoglycan synthesis by fibroblast conditioned media and formulations thereof Download PDFInfo
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- WO2021055448A1 WO2021055448A1 PCT/US2020/051036 US2020051036W WO2021055448A1 WO 2021055448 A1 WO2021055448 A1 WO 2021055448A1 US 2020051036 W US2020051036 W US 2020051036W WO 2021055448 A1 WO2021055448 A1 WO 2021055448A1
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Classifications
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Definitions
- Embodiments of the disclosure include at least the fields of cell biology, molecular biology, and medicine.
- Intervertebral discs are made of highly organized matrices of collagen, water, and proteoglycans. Proteoglycan production in the discs is believed to occur by differentiated chondrocytes.
- Each intervertebral disc comprises a central highly hydrated and gelatinous nucleus pulposus (nucleus) surrounded by an elastic and highly fibrous annulus fibrosus (annulus).
- Cartilaginous endplates provide a connection to the vertebrae inferiorly and superiorly to the intervertebral disc. This cushioned arrangement within the intervertebral discs allows the discs to facilitate movement and flexibility within the spine while dissipating hydraulic pressure through the spine.
- the intervertebral disc may begin to degenerate. It is known that with aging, the matrix of the disc undergoes substantial structural, molecular, and mechanical changes.
- the present disclosure satisfies a long felt need in the art of compositions and methods for treatment of disc degeneration.
- compositions of the present disclosure comprise one or more components from fibroblasts cultured with one or more opioid receptor antagonists and one or more toll-like receptor (TLR) agonists.
- TLR toll-like receptor
- Some embodiments pertain to isolation of fibroblast regenerative cells from a population of cells and, optionally, using components in the media in which the cultured fibroblasts for a therapeutic purpose.
- a composition comprising one or more components derived from fibroblast cells cultured with one or more opioid receptor antagonists and one or more TLR agonists.
- the one or more components may be derived from media from the culture of the fibroblast cells.
- the one or more components may comprise one or more growth factors, for example, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-l, FGF-2., FGF-5, FGF-15, insulin like growth factor (IGF), placental growth factor, and hepatocyte growth factor (HGF), and in particular embodiments the one or more growth factors derive from fibroblasts that have been cultured under particular conditions.
- the one or more components comprise exosomes.
- the exosomes may comprise one or more markers, for example, CD9.
- the exosome is capable of binding to a dendritic cell and/or a mesenchymal stem cell.
- the one or more components were derived from fibroblast cells cultured with one or more opioid receptor antagonists and one or more TER agonists in a proliferative state for the cells.
- the opioid receptor antagonist is naltrexone, 6B-naltrexol, nalmefene, naloxone, N-methylnaltrexone, alvimopan, diprenorphine, nalorphine, nalorphine dinicotinate, levallorphan, samidorphan, nalodeine, naloxegol, axelopran, bevenopran, methylsamidorphan, naldemedine, or a combination thereof.
- the TER agonist is Pam3CSK4, LPS, CpG DNA, Poly (ic), flagellin, MALP-2, imiquimod, resmiquimod, zymosan, or a combination thereof.
- the fibroblast cell expresses a marker selected from the group consisting of Oct-4, Nanog, Sox-2, KLF4, c-Myc, Rex-1, GDF-3, LIF receptor, CD105, CD117, CD344, Stella, and a combination thereof.
- the fibroblast cell expresses a marker selected from the group consisting of CD10, CD13, CD44, CD73, CD90, CD 141, PDGFr- alpha, HLA-A, HLA-B, HLA-C, and a combination thereof.
- the fibroblast cell does not express a marker from the group consisting of MHC class I, MHC class II, CD45, CD13, CD49c, CD66b, CD73, CD105, CD90, and a combination thereof.
- the fibroblast cell does not express a marker selected from the group consisting of CD31, CD34, CD45, CD 117, CD 141, HLA-DR, HLA-DP, HLA-DQ, and a combination thereof.
- a method of promoting disc regeneration in an individual comprising providing to the individual an effective amount of one or more components derived from fibroblast cells cultured with one or more opioid receptor antagonists and one or more toll-like receptor (TLR) agonists.
- a method for promoting disc regeneration comprises providing to the individual an effective amount of fibroblast cells (and/or components derived therefrom) previously cultured with one or more opioid receptor antagonists and one or more TLR agonists.
- Fibroblast cells cultured with one or more opioid receptor antagonists and one or more TLR agonists, and/or one or more components (e.g ., one or more regenerative factors) therefrom, may be provided to an individual in any suitable delivery route, including at least locally (such as intradiscally) or systemically.
- a method for improving efficacy of a tolerogenic therapy comprising (a) providing the tolerogenic therapy to an individual and (b) providing to the individual an amount of one or more opioid receptor antagonists sufficient to enhance the efficacy of the tolerogenic therapy.
- the tolerogenic therapy may comprise autoantigen administration, which may be administered intravenously and/or orally.
- the autoantigen administration comprises providing immature antigen presenting cells comprising the autoantigen, providing tolerogenic antigen presenting cells comprising the autoantigen, providing mesenchymal stem cells comprising the autoantigen, providing hematopoietic stem cells comprising the autoantigen, and/or providing allogenic mesenchymal stem cells.
- the tolerogenic antigen presenting cells may be dendritic cells, in some cases.
- FIG. 1 shows epidermal growth factor (EGF) production from neonatal foreskin cells cultured with naltrexone and the indicated toll-like receptor (TLR) agonists.
- EGF epidermal growth factor
- nucleic acid includes a plurality of nucleic acids, including mixtures thereof.
- Some embodiments of the disclosure may consist of or consist essentially of one or more elements, method steps, and/or methods of the disclosure. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different embodiments may be combined.
- the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 25, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
- the terms “about” or “approximately” when preceding a numerical value indicates the value plus or minus a range of 15%, 10%, 5%, or 1%.
- the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. Unless otherwise stated, the term 'about' means within an acceptable error range for the particular value.
- administering refers to any method of providing a composition to an individual such that the composition has its intended effect on the patient.
- one method of administering is by an indirect mechanism using a medical device such as, but not limited to a catheter, applicator gun, syringe etc.
- a second exemplary method of administering is by a direct mechanism such as, local tissue administration, oral ingestion, transdermal patch, topical, inhalation, suppository etc.
- allogeneic refers to tissues or cells or other material from another body that in a natural setting are immunologic ally incompatible or capable of being immunologically incompatible, although from one or more individuals of the same species.
- allotransplantation refers to the transplantation of organs, tissues, and/or cells from a donor to a recipient, where the donor and recipient are different individuals, but of the same species. Tissue transplanted by such procedures is referred to as an allograft or allotransplant.
- alio stimulatory and “alloreactive” refer to stimulation and reaction of the immune system in response to an allologous antigens, or “alloantigens” or cells expressing a dissimilar HLA haplotype.
- autologous refers to tissues or cells or other material that are derived or transferred from the same individual's body (i.e ., autologous blood donation; an autologous bone marrow transplant).
- autotransplantation refers to the transplantation of organs, tissues, and/or cells from one part of the body in an individual to another part in the same individual, i.e., the donor and recipient are the same individual. Tissue transplanted by such “autologous” procedures is referred to as an autograft or autotransplant.
- biological activity refers to any molecule having structural, regulatory or biochemical functions. For example, biological activity may be determined, for example, by restoration of wild-type growth in cells lacking protein activity. Cells lacking protein activity may be produced by many methods ( i.e ., for example, point mutation and frame-shift mutation).
- Complementation is achieved by transfecting cells that lack protein activity with an expression vector that expresses the protein, a derivative thereof, or a portion thereof.
- a fragment of a gene product (such as a protein) may be considered biologically active (or it may be referred to as functionally active) if it retains the activity of the full-length gene product, although it may be at a reduced but detectable level of the activity of the full-length gene product.
- Cell culture is an artificial in vitro system containing viable cells, whether quiescent, senescent or (actively) dividing.
- cells are grown and maintained at an appropriate temperature, typically a temperature of 37°C and under an atmosphere typically containing oxygen and CO2, although in other cases these are altered.
- Culture conditions may vary widely for each cell type though, and variation of conditions for a particular cell type can result in different phenotypes being expressed.
- the most commonly varied factor in culture systems is the growth medium. Growth media can vary in concentration of nutrients, growth factors, and the presence of other components.
- the growth factors used to supplement media are often derived from animal blood, such as calf serum.
- drug refers to any pharmacologically active substance capable of being administered that achieves a desired effect.
- Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides, or nucleotides (DNA and/or RNA), polysaccharides or sugars.
- individual refers to a human or animal that may or may not be housed in a medical facility and may be treated as an outpatient of a medical facility. The individual may be receiving one or more medical compositions via the internet.
- An individual may comprise any age of a human or non-human animal and therefore includes both adult and juveniles ( i.e ., children) and infants. It is not intended that the term "individual” connote a need for medical treatment, therefore, an individual may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies.
- subject refers to any organism or animal subject that is an object of a method or material, including mammals, e.g., humans, laboratory animals (e.g., primates, rats, mice, rabbits), livestock (e.g ., cows, sheep, goats, pigs, turkeys, and chickens), household pets (e.g., dogs, cats, and rodents), horses, and transgenic non-human animals.
- mammals e.g., humans, laboratory animals (e.g., primates, rats, mice, rabbits), livestock (e.g ., cows, sheep, goats, pigs, turkeys, and chickens), household pets (e.g., dogs, cats, and rodents), horses, and transgenic non-human animals.
- mammals e.g., humans, laboratory animals (e.g., primates, rats, mice, rabbits), livestock (e.g ., cows, sheep, goats, pigs, turkeys, and chickens), household pets (e.g., dogs, cats,
- x, y, and/or z can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.” It is specifically contemplated that x, y, or z may be specifically excluded from an embodiment.
- pharmaceutically or “pharmacologically acceptable”, as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
- pharmaceutically acceptable carrier includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
- the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
- “Therapeutic agent” means to have "therapeutic efficacy” in modulating angiogenesis and/or wound healing and an amount of the therapeutic is said to be a "angiogenic modulatory amount", if administration of that amount of the therapeutic is sufficient to cause a significant modulation ( i.e ., increase or decrease) in angiogenic activity when administered to a subject (e.g., an animal model or human patient) needing modulation of angiogenesis.
- an effective amount is synonymous with “effective amount”, “therapeutically effective dose”, and/or “effective dose” and refers to the amount of compound that will elicit the biological, cosmetic or clinical response being sought by the practitioner in an individual in need thereof.
- an effective amount is the amount sufficient to reduce immunogenicity of a group of cells.
- an effective amount is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
- an effective amount is an amount sufficient to promote formation of new blood vessels and associated vasculature (angiogenesis) and/or an amount sufficient to promote repair or remodeling of existing blood vessels and associated vasculature.
- an effective amount can be extrapolated from in vitro and in vivo assays as described in the present specification.
- an effective amount can be extrapolated from in vitro and in vivo assays as described in the present specification.
- One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a compound or composition disclosed herein that is administered can be adjusted accordingly.
- Treatment means a method of reducing the effects of a disease or condition.
- Treatment can also refer to a method of reducing the disease or condition itself rather than just the symptoms.
- the treatment can be any reduction from pre-treatment levels and can be but is not limited to the complete ablation of the disease, condition, or the symptoms of the disease or condition. Therefore, in the disclosed methods, treatment” can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease or the disease progression, including reduction in the severity of at least one symptom of the disease.
- a disclosed method for reducing the immunogenicity of cells is considered to be a treatment if there is a detectable reduction in the immunogenicity of cells when compared to pre-treatment levels in the same subject or control subjects.
- the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.
- treatment does not necessarily refer to a cure of the disease or condition, but an improvement in the outlook of a disease or condition.
- treatment refers to the lessening in severity or extent of at least one symptom and may alternatively or in addition refer to a delay in the onset of at least one symptom.
- the disclosure relates to components obtained from culture of fibroblast cells.
- Such components may be or may be obtained from cell culture media from fibroblasts cultured with one or more compounds that stimulate the production of regenerative factors from the fibroblasts.
- Components obtained from fibroblast cell culture may be useful in one or more of the methods disclosed herein including, for example, promoting disc regeneration or repair, treatment of a disc degenerative disease, and stimulation of proteoglycan synthesis.
- fibroblast cells in the culture are in a proliferative state, said proliferative state being described as the cells not reaching confluency.
- said fibroblast cells are growing in a 25%-75% confluent state.
- One or more components e.g., regenerative factors may be obtained from fibroblast cells growing in a proliferative state.
- an opioid receptor antagonist as a modulator of immune responses to self-antigens through stimulation of regulatory cell expansion by modification of fibroblast activity is disclosed. Stimulation of fibroblast production of regenerative factors may be accomplished through the treatment of fibroblasts with one or more opioid receptor antagonists.
- opioid receptor antagonists include, but are not limited to, naltrexone, 6B-naltrexol, nalmefene, naloxone, N-methylnaltrexone, alvimopan, diprenorphine, nalorphine, nalorphine dinicotinate, levallorphan, samidorphan, nalodeine, naloxegol, axelopran, bevenopran, methylsamidorphan, and/or naldemedine.
- Treatment of fibroblasts with an opioid receptor antagonist e.g ., naltrexone
- an opioid receptor antagonist e.g ., naltrexone
- upregulation of regenerative factor production is further disclosed by combination of opioid receptor antagonist (e.g., naltrexone) administration together with agonists of the toll like receptor (TLR) family such as the toll like receptor 2 agonist Pam3CSK4, the toll like receptor 4 agonist lipopolysaccharide (LPS), and the toll like receptor 9 agonist CpG.
- opioid receptor antagonist e.g., naltrexone
- TLR toll like receptor
- TLR-4 antagonist is used to stimulate fibroblasts instead of an opioid receptor antagonist.
- Example TLR-4 antatonists which may be used to stimulate fibroblasts include LPS and lipid A from Rhodobacter sphaeroides LOS from Bartonella Quintana, LPS from Oscillatoria Planktothrix FP1; curcumin from Curcuma longa, sulforaphane and iberin from cruciferous vegetables; xanthohumol from hops and beer, and celastrol from Tripterygium wilfordii.
- LPS and lipid A from Rhodobacter sphaeroides LOS from Bartonella Quintana, LPS from Oscillatoria Planktothrix FP1; curcumin from Curcuma longa, sulforaphane and iberin from cruciferous vegetables; xanthohumol from hops and beer, and celastrol from Tripterygium wilfordii.
- TLRs can bind with damage-associated molecular patterns (DAMP) produced under stress or by tissue damage or cell apoptosis. It is believed that TLRs build a bridge between innate immunity and autoimmunity. There are five adaptors to TLRs including MyD88, TRIF, TIRAP/MAL, TRAM, and SARM. Upon activation, TLRs recruit specific adaptors to initiate the downstream signaling pathways leading to the production of inflammatory cytokines and chemokines. Under certain circumstances, ligation of TLRs drives to aberrant activation and unrestricted inflammatory responses, thereby contributing to the perpetuation of inflammation in autoimmune diseases.
- DAMP damage-associated molecular patterns
- TLR4 is associated with hepatocytes and non-parenchymal cells, including Kupffer cells, myeloid dendritic cells, stellate cells, T-cells, NK cells, and sinusoidal endothelial cells.
- TLR-4 autoimmune liver diseases
- Monocytes from patients with PBC produce increased levels of proinflammatory cytokines such as IL-l.beta., IL-6, etc. when challenged with a variety of ligands, particularly those signaling through TLR4 and TLR5 (Mao et al 2005). Endogenous DAMPs are released subsequent to tissue damage.
- TLR- 2 and TLR-4 such as heat-shock proteins, HMGB1, hyaluronan, fibronectin, heparan sulfate and biglycan are produced to mediate sterile inflammation (Moreth et al 2014).
- the biological characteristics, signaling mechanisms of TLR2/4, the negative regulators of TLR2/4 pathway, and the pivotal function of TLR2/4 in the pathogenesis of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes were recently reviewed by Liu Y, et al. [Clin Rev Allergy Immunol. 47(2): 136-47(2014)].
- compositions of the present disclosure may be obtained from isolated fibroblast cells or a population thereof (including from a culture thereof) capable of proliferating and differentiating into ectoderm, mesoderm, or endoderm.
- an isolated fibroblast cell expresses at least one of Oct-4, Nanog, Sox-2, KLF4, c-Myc, Rex-1, GDF-3, LIF receptor, CD105, CD117, CD344 or Stella markers.
- an isolated fibroblast cell does not express at least one of MHC class I, MHC class II, CD45, CD13, CD49c, CD66b, CD73, CD105, or CD90 cell surface proteins.
- Such isolated fibroblast cells may be used as a source of conditioned media. The cells may be cultured alone, or may by cultured in the presence of other cells in order to further upregulate production of growth factors in the conditioned media.
- Fibroblasts may be expanded and utilized by administration themselves, or may be cultured in a growth media in order to obtain conditioned media that may then be used (or that components thereof may be used).
- the term Growth Medium generally refers to a medium sufficient for the culturing of fibroblasts.
- one particular medium for the culturing of the cells of the disclosure herein comprises Dulbecco's Modified Essential Media (DMEM).
- DMEM Dulbecco's Modified Essential Media
- DMEM-low glucose also DMEM-LG herein
- the DMEM-low glucose may be supplemented with 15% (v/v) fetal bovine serum (e.g.
- fetal bovine serum defined fetal bovine serum, HycloneTM, Logan Utah
- antibiotic s/antimycotic s such as penicillin (100 Units/milliliter), streptomycin (100 milligrams/milliliter), and amphotericin B (0.25 micrograms/milliliter), (Invitrogen ® , Carlsbad, Calif.)), and 0.001% (v/v) 2-mercaptoethanol (Sigma ® , St. Louis Mo.).
- different growth media are used, or different supplementations are provided, and these are normally indicated as supplementations to Growth Medium.
- standard growth conditions refers to culturing of cells at 37°C, in a standard atmosphere comprising 5% CO2, where relative humidity is maintained at about 100%. While the foregoing conditions are useful for culturing, it is to be understood that such conditions are capable of being varied by the skilled artisan who will appreciate the options available in the art for culturing cells, for example, varying the temperature, CO2, relative humidity, oxygen, growth medium, and the like.
- Fibroblast cells used in the disclosed methods for obtaining conditioned media and/or regenerative factors can undergo at least 25, 30, 35, or 40 doublings prior to reaching a senescent state, in specific embodiments.
- fibroblast cells used for the generation of conditioned media are isolated and expanded, and possess one or more markers selected from the group consisting of CD10, CD13, CD44, CD73, CD90, CD141, PDGFr-alpha, HLA-A, HLA-B, HLA-C, and a combination thereof.
- the fibroblast cells do not produce one or more of CD31, CD34, CD45, CD 117, CD 141, HLA-DR, HLA-DP, or HLA-DQ.
- fibroblast cells are obtained from a biopsy, and the donor providing the biopsy may be either the individual to be treated (autologous), or the donor may be different from the individual to be treated (allogeneic). In cases wherein allogeneic fibroblast cells are utilized for an individual, the fibroblast cells may come from one or a plurality of donors.
- the fibroblasts may be obtained from a source selected from the group consisting of dermal fibroblasts; placental fibroblasts; adipose fibroblasts; bone marrow fibroblasts; foreskin fibroblasts; umbilical cord fibroblasts; hair follicle derived fibroblasts; nail derived fibroblasts; endometrial derived fibroblasts; keloid derived fibroblasts; and a combination thereof.
- components obtained from culture of fibroblasts include one or more regenerative factors.
- Regenerative factors produced from fibroblasts cultured with an opioid receptor antagonist and a TLR agonist include, for example, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-l, FGF-2., FGF-5, FGF-15, insulin like growth factor (IGF), placental growth factor, and hepatocyte growth factor (HGF).
- Regenerative factors may be isolated from cell culture media prior to use in the disclosed methods (e.g., stimulation of disc regeneration or repair). Alternatively, cell culture media may be used without isolating regenerative factors.
- components obtained from culture of fibroblasts include exosomes.
- Fibroblasts may produce exosomes comprising one or more regenerative factors (e.g., growth factors), which may be used in the disclosed methods (e.g., promotion of disc regeneration).
- Exosomes may be isolated from fibroblasts cultured with one or more opioid receptor antagonists and one or more TLR agonists, thereby obtaining one or more regenerative factors.
- Exosomes may be purified and concentrated from fibroblast cell culture media.
- exosomes obtained from fibroblasts are between 60 and 200 nanometers in size.
- exosomes obtained from fibroblasts stimulated with one or more opioid receptor antagonists and one or more TLR agonists are capable of inducing production of anti inflammatory mediators (e.g., IL-10, IL-20, TGF-beta, etc.) from dendritic cells.
- exosomes obtained from fibroblasts stimulated with an opioid receptor antagonist and a TLR agonist are capable of binding to mesenchymal stem cells and, in at least some cases, capable inducing production of TGF-beta from mesenchymal stem cells.
- Culture conditioned media obtained from fibroblasts may be concentrated by filtering and/or desalting means.
- Amicon ® filters, or substantially equivalent means, with specific molecular weight cut-offs are utilized. Said cut-offs may select for molecular weights higher than 1 kDa to 50 kDa.
- the cell culture supernatant may alternatively be concentrated using means known in the art such as solid phase extraction using C18 cartridges (Mini-Spe-ed Cl 8- 14%, S.P.E. Limited, Concord ON). Said cartridges are prepared by washing with methanol followed by deionized-distilled water. Up to 100 ml of stem cell or progenitor cell supernatant may be passed through each of these specific cartridges before elution, although it is understood by one of skill in the art that larger cartridges may be used. After washing the cartridges material adsorbed is eluted with 3 ml methanol, evaporated under a stream of nitrogen, redissolved in a small volume of methanol, and stored at 4°C.
- C18 cartridges Mini-Spe-ed Cl 8- 14%, S.P.E. Limited, Concord ON.
- Said cartridges are prepared by washing with methanol followed by deionized-distilled water. Up to 100 ml of stem cell or progenitor cell supern
- the methanol is evaporated under nitrogen and replaced by culture medium.
- the C18 cartridges are used to adsorb small hydrophobic molecules from the stem or progenitor cell culture supernatant, and allows for the elimination of salts and other polar contaminants. It may, however be desired to use other adsorption means in order to purify certain compounds from said fibroblast cell supernatant.
- Said fibroblast concentrated supernatant may be assessed directly for biological activities useful for the practice of this invention, or may be further purified.
- said supernatant of fibroblast culture is assessed for ability to stimulate proteoglycan synthesis using an in vitro bioassay.
- the in vitro bioassay allows for quantification and knowledge of which molecular weight fraction of supernatant possesses biological activity.
- Bioassays for testing ability to stimulate proteoglycan synthesis are known in the art. Production of various proteoglycans can be assessed by analysis of protein content using techniques including mass spectrometry, column chromatography, immune based assays such as enzyme linked immunosorbent assay (ELISA), immunohistochemistry, and flow cytometry.
- Further purification may be performed using, for example, gel filtration using a Bio-Gel P-2 column with a nominal exclusion limit of 1800 Da (Bio-Rad ® , Richmond Calif.).
- Said column may be washed and pre-swelled in 20 mM Tris-HCl buffer, pH 7.2 (Sigma ® ) and degassed by gentle swirling under vacuum.
- Bio-Gel P-2 material be packed into a 1.5x54 cm glass column and equilibrated with 3 column volumes of the same buffer.
- Amniotic fluid stem cell supernatant concentrates extracted by C18 cartridge may be dissolved in 0.5 ml of 20 mM Tris buffer, pH 7.2 and run through the column. Fractions may be collected from the column and analyzed for biological activity.
- Other purification, fractionation, and identification means are known to one skilled in the art and include anionic exchange chromatography, gas chromatography, high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry.
- Embodiments of the disclosure include means of augmenting regeneration of discs, which have undergone one or more degenerative processes, through introduction of components from fibroblasts which have been stimulated by one or more opioid receptor antagonists (e.g ., naltrexone) alone and/or together with one or more toll like receptor (TLR) agonists.
- Components from fibroblasts may include conditioned media from culture of fibroblasts with one or more opioid receptor antagonists and one or more TLR agonists.
- Conditioned media may be used as a source of regenerative factors.
- Conditioned media may be concentrated.
- Components from fibroblasts may be administered to an individual in need of disc regeneration or repair (e.g., an individual with degenerative disc disease).
- Components may be administered intradiscally or systemically.
- microvesicles and/or exosomes from stimulated fibroblasts are used as a source of regenerative factors.
- this disclosure relates to methods for treating or preventing pathological intervertebral disc disorders by delivering one or more components from (e.g., secreted by, released by, etc.) fibroblasts stimulated with one or more opioid receptor antagonists and one or more TLR agonists.
- Stimulated fibroblasts may generate one or more regenerative factors suitable for administration to a disc and capable of stimulating disc regeneration.
- one or more of these regenerative factors are provided to an individual in need thereof.
- stimulated fibroblasts capable of producing regenerative factors may be delivered to an individual directly.
- Embodiments of the disclosure encompass particular conditioned media, including for therapeutic use.
- the conditioned media is useful for stimulation of disc regeneration or repair in an individual, including one suffering from disc degenerative disease or at risk for disc degenerative disease (an individual at risk is an individual over the age of about 40, 45, 50, 55, 60, 65, 70, 75, 80, and so forth; an individual that is or was an athlete; an individual with a vocation that requires physical activity; an individual with a spinal injury; or a combination thereof, for example).
- disc degeneration is prevented utilizing methods encompassed by the disclosure or the disc degeneration may be delayed in onset and/or reduced in severity.
- Conditioned media may be generated by stimulation of fibroblast cells that may be any kind of fibroblast cells.
- Such stimulation includes, in some embodiments, treatment with an effective amount of one or more opioid receptor antagonists and one or more TLR agonists sufficient to stimulate production of regenerative factors (e.g., one or more growth factors) by the fibroblast cells.
- Fibroblast cells may be stimulated with any opioid receptor antagonist including, for example, naltrexone, 6B-naltrexol, nalmefene, naloxone, N-methylnaltrexone, alvimopan, diprenorphine, nalorphine, nalorphine dinicotinate, levallorphan, samidorphan, nalodeine, naloxegol, axelopran, bevenopran, methylsamidorphan, or naldemedine.
- opioid receptor antagonist including, for example, naltrexone, 6B-naltrexol, nalmefene, naloxone, N-methylnaltrexone, alvimopan, diprenorphine, nalorphine, nalorphine dinicotinate, levallorphan, samidorphan, nalodeine, naloxegol, axelopran, beven
- Fibroblast cells may be stimulated with any TLR agonist including, for example, Pam3CSK4, LPS, CpG DNA, Poly (ic), flagellin, MALP-2, imiquimod, resmiquimod, zymosan, or a combination thereof.
- TLR agonist including, for example, Pam3CSK4, LPS, CpG DNA, Poly (ic), flagellin, MALP-2, imiquimod, resmiquimod, zymosan, or a combination thereof.
- Conditioned media generated from stimulation of fibroblast cells may be obtained, in some cases concentration, and provided to an individual in need thereof.
- fibroblast conditioned media is utilized as part of a formulation with other therapeutic compounds where the formulation is administered intradiscally or systemically to an individual in order to induce proteoglycan production from the disc.
- Compounds can be vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, choline, vitamin Bl, vitamin B2, vitamin B5, vitamin B6, vitamin B 12, biotin, nicotinamide, betacarotene, coenzyme Q, selenium, superoxide dismutase, glutathione peroxide, uridine, creatine succinate, pyruvate, dihydroxy acetone), acetyl-L-camitine, alpha- lipoic acid, cardiolipin, omega fatty acid, lithium carbonate, lithium citrate, calcium, or any combination thereof.
- the compounds are anti-inflammatory agents.
- the anti-inflammatory agents include one or more of Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Alpha-lipoic acid; Alpha tocopherol; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Ascorbic Acid; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Chlorogenic acid; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; De
- the compounds are bioactive compounds including but not limited to growth factors, cytokines, antibodies, antibody fragments, and/or organic molecules of a mass of less than 5000 daltons.
- the compounds may be administered concurrently with a composition of the current disclosure. Alternatively, the compounds may be administered before and/or after the composition is administered to a subject.
- Embodiments of the disclosure include methods for obtaining or isolating regenerative fibroblast cells.
- Obtaining regenerative fibroblast cells may comprise enriching a population of regenerative fibroblast cells from a tissue having regenerative activity.
- regenerative fibroblast cells are obtained from a tissue having regenerative activity by enriching for cells that are about 6-12 pm in size, which express at least one of Oct-4, Nanog, Sox-2, KLF4, c-Myc, Rex-1, GDF-3, LIF receptor, CD105, CD117, CD344 and Stella, and which do not express at least one of MHC class I, MHC class II, CD45, CD13, CD49c, CD66b, CD73, CD105, or CD90 cell surface proteins.
- cell types such as granulocytes, T- cells, B-cells, NK-cell, red blood cells, or any combination thereof, are separated from fibroblast regenerative cells. In some aspects, separating the cell types is done by cell depletion. In some embodiments, fibroblast regenerative cells are enriched by flow cytometry.
- a vector comprising a fibroblast cell-specific promoter coupled to at least one selectable marker gene is introduced into a cell.
- the selectable marker gene may be expressed from the cell-specific promoter in the cell and detected, thereby identifying the fibroblast regenerative cell.
- the fibroblast regenerative cell does not express at least one of MHC class I, MHC class II, CD44, CD45, CD13, CD34, CD49c, CD66b, CD73, CD105, and CD90 cell surface proteins.
- the fibroblast regenerative cell expresses at least one of Oct-4, Nanog, Sox-2, Rex-1, GDF-3, Stella, FoxD3, or Polycomb embryonic transcription factors. In some embodiments, the fibroblast regenerative cell does not express CD13, CD44, CD90, or a combination thereof.
- the vector is a retroviral vector.
- the selectable marker gene encodes a fluorescent protein (e.g., Green Fluorescent Protein (GFP)).
- the vector comprises two selectable marker genes, where the two selectable marker genes comprise a fluorescent protein, a protein sensitive to drug selection, a cell surface protein or any combination thereof.
- the fibroblast cell- specific promoter is an Oct-4 promoter, a Nanog promoter, a Sox-2 promoter, a Rex-1 promoter, a GDF-3 promoter, aStella promoter, a FoxD3 promoter, a Polycomb Repressor Complex 2 promoter, or aCTCF promoter.
- the fibroblast cell-specific promoter is flanked by loxP sites.
- the fibroblast regenerative cell is capable of differentiating into mesoderm, ectoderm, and/or endoderm.
- the fibroblast regenerative cell further comprises a rhodamine 123 efflux activity.
- the fibroblast regenerative cell has enhanced expression of GDF-11 as compared to a control.
- the disclosed methods comprise transfecting a fibroblast regenerative cell with a transcription factor capable of enhancing the regenerative activity of the fibroblast regenerative cell.
- the fibroblast regenerative cell is transfected with an OCT-4 transcription factor.
- regenerative fibroblast cells are fused with cells having a pluripotent ability, thereby generating fibroblasts with enhanced regenerative activity.
- the disclosed methods comprise isolating a fibroblast regenerative cell from a mammal.
- the fibroblast regenerative cell is derived from bodily fluid of the mammal.
- the fibroblast regenerative cell is derived from tissue of the mammal.
- the mammal is a human.
- fibroblasts are enriched by contacting cells with a detectable compound that enters the cells, the compound being selectively detectable in proliferating and non-proliferating cells, and proliferating cells enriched based on detection of the compound.
- the detectable compound is carboxyfluorescein diacetate, succinimidyl ester, or AldefluorTM.
- fibroblasts expressing one or more markers may be selected.
- fibroblast cells expressing CD 105 and/or CD 117 are selected. Fibroblast cells expressing CD 105 and/or CD117 may be transfected with a NANOG gene.
- Cells expressing cell surface markers or MHC proteins may be separated or depleted from a population of fibroblast cells, thereby isolating a population of stem cells.
- the cell to be depleted express MHC class I, CD66b, glycophorin a, or glycophorin b.
- Cells may be transfected with a stem cell-specific promoter operably linked to a reporter or selection gene.
- a stem cell-specific promoter may be, for example, an Oct-4, Nanog, Sox-9, GDF3, Rex-1, or Sox-2 promoter.
- any of the cellular and/or non-cellular compositions described herein or similar thereto may be comprised in a kit.
- one or more reagents for use in methods for preparing fibroblasts may be comprised in a kit.
- Such reagents may include cells, vectors, one or more growth factors, vector(s) one or more costimulatory factors, media, enzymes, buffers, nucleotides, salts, primers, compounds, and so forth.
- the kit components are provided in suitable container means.
- kits may be packaged either in aqueous media or in lyophilized form.
- the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted. Where there are more than one component in the kit, the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a vial.
- the kits of the present disclosure also will typically include a means for containing the components in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained.
- the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly useful.
- the container means may itself be a syringe, pipette, and/or other such like apparatus, or may be a substrate with multiple compartments for a desired reaction.
- kits may be provided as dried powder(s).
- the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
- the kits may also comprise a second container means for containing a sterile acceptable buffer and/or other diluent.
- reagents and materials include primers for amplifying desired sequences, nucleotides, suitable buffers or buffer reagents, salt, and so forth, and in some cases the reagents include apparatus or reagents for isolation of a particular desired cell(s).
- the kit suitable for extracting one or more samples from an individual.
- the apparatus may be a syringe, fine needles, scalpel, and so forth.
- the present example characterizes the use of naltrexone and a TLR agonist to stimulate EGF production in foreskin fibroblasts as an example of a type of fibroblasts.
- Neonatal foreskin fibroblasts were obtained from ATCC and cultured in typical DMEM culture media containing 10% fetal calf serum and antibiotics. After 3 days of culture, fibroblasts where plated in 12 well plates and cultured at 50% confluent conditions. Addition of naltrexone (Sigma Aldrich ® ) and the indicated TLR agonists was performed for 12 hours of culture. Pam3CSK4 was added at a total concentration of 1 ug/ml. LPS was added at 0.5 ug/ml. CpG was added at 0.2 ug/ml. Concentration of EGF was assessed using ELISA (R&D Systems). Results are shown in FIG. 1.
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AU2020349481A AU2020349481A1 (en) | 2019-09-16 | 2020-09-16 | Treatment of disc degenerative disease and stimulation of proteoglycan synthesis by fibroblast conditioned media and formulations thereof |
JP2022516641A JP2022547619A (en) | 2019-09-16 | 2020-09-16 | Treatment of degenerative disc disease and stimulation of protein glycan synthesis by fibroblast conditioned medium and formulations thereof |
CA3154063A CA3154063A1 (en) | 2019-09-16 | 2020-09-16 | Treatment of disc degenerative disease and stimulation of proteoglycan synthesis by fibroblast conditioned media and formulations thereof |
EP20866096.9A EP4031167A4 (en) | 2019-09-16 | 2020-09-16 | Treatment of disc degenerative disease and stimulation of proteoglycan synthesis by fibroblast conditioned media and formulations thereof |
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CA3154063A1 (en) | 2021-03-25 |
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EP4031167A4 (en) | 2023-07-19 |
US20230407258A1 (en) | 2023-12-21 |
JP2022547619A (en) | 2022-11-14 |
US20210079350A1 (en) | 2021-03-18 |
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