WO2019222800A1 - Procédés pour le traitement ou la prévention de maladies auto-immunes ou auto-inflammatoires - Google Patents
Procédés pour le traitement ou la prévention de maladies auto-immunes ou auto-inflammatoires Download PDFInfo
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- WO2019222800A1 WO2019222800A1 PCT/AU2019/050492 AU2019050492W WO2019222800A1 WO 2019222800 A1 WO2019222800 A1 WO 2019222800A1 AU 2019050492 W AU2019050492 W AU 2019050492W WO 2019222800 A1 WO2019222800 A1 WO 2019222800A1
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- Prior art keywords
- inhibitor
- gap junction
- individual
- lupus erythematosus
- autoimmune
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Definitions
- the present invention relates to compositions and methods for the treatment or prevention of autoimmune or autoinflammatory diseases.
- autoinflammation The ability to distinguish foreign microorganisms from host cells is crucial to avoid detrimental localised damage to self during an inflammatory response.
- immune cells begin to target and damage host cells and tissues.
- adaptive cells break self-tolerance, the resulting condition is characterised as autoimmunity, where native host cells are recognised as foreign and the adaptive immune cells target them for destruction.
- autoinflammation When innate immune cells become activated, due to dysregulated secretion of pro-inflammatory cytokines and consequent damage to host tissues, it is termed autoinflammation
- Autoimmune diseases cause significant human morbidity and mortality. These diseases include approximately 80 diseases, such as rheumatoid arthritis, systemic lupus and multiple sclerosis, and affect approximately 5% of the population of the United States. Dysregulation of the immune system plays a critical underpinning role in conditions such as autoimmune diseases.
- Autoinflammatory diseases are a group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. From a pathogenetic point of view they are determined by a dysregulation of innate immunity, without involvement of specific immunity (auto reactive T cells and auto antibodies).
- a key element of the innate immune system is the cGAS/STING pathway responsible for sensing cytosolic DNA. Activation of the cGAS/STING pathway leads to the rapid stimulation of a potent inflammatory response. This response is characterised by strong induction of type I interferons and pro-inflammatory cytokines such as IL-6, TNF-a and IFN-beta.
- the inflammatory response is characterized by increased blood flow, increased capillary permeability, and the influx of phagocytic cells. These events result in swelling, redness, warmth (altered heat patterns), and pus formation at the site of injury.
- cGAS protein cyclic GMP-AMP Synthase
- STING Stimulator of Interferon Genes
- the present invention provides a method of treating an autoimmune or autoinflammatory disease in an individual, the method comprising, consisting essentially of or consisting of inhibiting a gap junction in the individual, thereby treating the autoimmune or autoinflammatory disease.
- the autoimmune or autoinflammatory disease may be any one described herein.
- the autoimmune disease is selected from the group consisting of lupus, arthritis and psoriasis.
- the autoimmune disease is systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE).
- SLE systemic lupus erythematosus
- CLE cutaneous lupus erythematosus
- the methods, uses or compositions of the invention find utility in treating or minimising the severity of a flare-up of the symptoms of SLE or of CLE.
- the flare-up may be induced following exposure to sunlight.
- the present invention provides a method of treating lupus erythematosus in an individual, the method comprising, consisting essentially of or consisting of inhibiting a gap junction in the individual, thereby treating lupus erythematosus in the subject.
- the method includes administering a gap junction inhibitor to the individual.
- the lupus erythematosus is cutaneous lupus erythematosus.
- the lupus erythematosus is systemic lupus erythematosus (SLE).
- the present invention thus also provides a method of treating or preventing, or reducing the severity of a sunlight-induced flare up of the symptoms of lupus erythematosus in an individual, the method comprising, consisting essentially of or consisting of inhibiting a gap junction in an individual who has been diagnosed with lupus erythematosus and is at risk of a sunlight-induced flare up of symptoms, thereby treating or preventing a sunlight-induced flare up of the symptoms of lupus erythematosus in the individual.
- the symptom of lupus erythematosus is preferably selected from: joint pain, joint swelling, weakness, fatigue, tingling, numbness, skin rash.
- the lupus erythematosus is cutaneous lupus erythematosus.
- the lupus erythematosus is systemic lupus erythematosus (SLE).
- SLE systemic lupus erythematosus
- the present invention also provides a method of treating photosensitivity in an individual diagnosed with or suspected of having lupus erythematosus, the method comprising, consisting essentially of or consisting of inhibiting a gap junction in an individual who has been diagnosed with lupus erythematosus, thereby treating photosensitivity in the individual.
- inhibiting a gap junction may be by administration of a small molecule, an antibody, a peptide, a protein, an antisense oligonucleotide or an interfering RNA to the individual.
- the inhibitor is a small molecule.
- Inhibition may be by genetic ablation of all or part of the gene encoding one or more gap junction proteins (e.g. connexins), introduction of an inactivating mutation of a gene encoding one or more gap junction proteins, inactivation of a regulator of gap junction gene transcription, inactivation of a regulator of gap junction mRNA translation or inactivation of an allosteric potentiator of gap junction activity. Any molecule that results in this inhibition is an inhibitor of a gap junction.
- inhibiting a gap junction may be by inhibiting one or more gap junction proteins. Typically, this involves administering an inhibitor of one of more gap junction proteins to an individual. Preferably, an inhibitor of one or more gap junction proteins inhibits the capacity of the gap junction proteins to form a functional intercellular channel.
- a functional intercellular channel is one that allows direct diffusion of ions or small molecules between adjacent cells.
- the adjacent cells are a non-immune cell and an immune cell. Examples of non-immune cells are an epithelial cell, a keratinocyte, a vascular cell, a neuron or a bone/cartilage cell.
- the non-immune cell is an epithelial cell, a keratinocyte, or a neuron, more preferably an epithelial cell.
- the immune cell is a monocyte.
- the gap junction protein may be a connexin.
- the inhibitor of one or more gap junction proteins directly inhibits the interaction between one connexin with another connexin, for example the inhibitor may prevent the formation of a homo- or heterohexameric connexon or hemichannel.
- the inhibitor may inhibit the association between hemichannels on adjacent cells thereby inhibiting, preventing or reducing formation of a functional intercellular channel.
- the inhibitor may inhibit, prevent or reduce the formation of, or level of, polymorphic maculae or plaques containing clusters of gap junctions.
- the inhibitor of one or more gap junction proteins inhibits the capacity of the gap junction to form a functional intercellular channel thereby inhibiting, preventing or reducing the transfer of cyclic guanosine monophosphate- adenosine monophosphate (herein referred to as either cyclic GMP-AMP or cGAMP), or other bacterial-derived cyclic di-nucleotides (e.g. cyclic dimeric adenosine monophosphate, or cyclic dimeric guanosine monophosphate) from one cell to another cell.
- the inhibitor binds to a site on a connexin that is involved in interaction with another connexin.
- the inhibitor may bind to one or both of the two extracellular loops of the connexin protein.
- peptide inhibitors are Gap26 and Gap27, which are identical to amino acid sequences on the first and second extracellular loop regions of connexin 43, respectively. Peptides that are identical to the first and second extracellular loop regions of the other connexins are also contemplated for use in the invention.
- the inhibitor is selective and binds to 1 , 2 or 3 different connexins.
- the inhibitor is non-selective and binds to greater than 3 different connexins.
- the inhibitor may be any one described herein, including in Table 1.
- the inhibitor of a gap junction may exhibit a K ⁇ value of less than 1 mM, preferably less than 100pM, less than 10mM, less than 1 mM, less than 100nM, less than 50nM, less than 40nM, less than 10nM as determined by an assay as described herein.
- the inhibitor of a gap junction may exhibit an ICso of less than 1 mM, preferably less than 100pM, less than 10pM, less than 1 pM, less than 100nM, less than 90nM, less than 80nM, less than 50nM, less than 40nM, less than 10nM as determined by an assay as described herein.
- the invention also provides a method of alleviating or ameliorating a symptom of an autoimmune or autoinflammatory disease in an individual in need thereof, the method comprising, consisting essentially of or consisting of administering to the individual in need thereof a therapeutically effective amount of an inhibitor of a gap junction, thereby alleviating or ameliorating a symptom of an autoimmune or autoinflammatory disease in the individual.
- the symptom of an autoimmune or autoinflammatory disease which is alleviated or ameliorated according to the present invention is a symptom of lupus erythematosus.
- the symptom of lupus erythematosus is a symptom of cutaneous lupus erythematosus (CLE).
- the symptoms of lupus erythematosus is a symptom of systemic lupus erythematosus (SLE).
- the symptom of SLE or of CLE is a symptom that is induced or occurs after exposure of the individual to sunlight or UV radiation.
- the present invention provides a method for the treatment of an autoimmune or autoinflammatory disease in an individual comprising, consisting essentially of or consisting of the steps of identifying a subject having an autoimmune or autoinflammatory disease; and administering to the individual in need thereof a therapeutically effective amount of an inhibitor of a gap junction, thereby treating the autoimmune or autoinflammatory disease in the individual.
- the invention provides a method for the treatment of lupus erythematosus in an individual comprising, consisting essentially of or consisting of the steps of: identifying a subject having lupus erythematosus; and administering to the individual in need thereof a therapeutically effective amount of an inhibitor of a gap junction, thereby treating the lupus erythematosus in the individual.
- the invention provides a method for the prevention or reduction of the severity of a flare-up of symptoms of lupus erythematosus in an individual comprising, consisting essentially of or consisting of the steps of identifying a subject having lupus erythematosus wherein the individual is at risk of prolonged exposure to sunlight; and administering to the individual in need thereof a therapeutically effective amount of an inhibitor of a gap junction, thereby preventing a flare-up of symptoms of lupus erythematosus in the individual.
- the present invention also provides a method for inhibiting or minimising the progression of a flare-up of symptoms of lupus erythematosus in an individual comprising, consisting essentially of or consisting of the steps of administering a therapeutically effective amount of an inhibitor of a gap junction to an individual who is experiencing a flare-up of symptoms of lupus erythematosus thereby inhibiting or minimising the progression of a flare-up of symptoms of lupus erythematosus in the individual.
- the method further comprises the step of providing or identifying an individual who is experiencing a flare-up of symptoms of lupus erythematosus.
- An individual may be identified as experiencing a flare-up of symptoms of lupus erythematosus by any biochemical or clinical method or test as described herein.
- the present invention also provides use of an inhibitor of a gap junction in the manufacture of a medicament for:
- the present invention also provides use of an inhibitor of a gap junction in the manufacture of a medicament for treating lupus erythematosus in an individual.
- the present invention also provides an inhibitor of a gap junction for use in treating an autoimmune or autoinflammatory disease in an individual. More particularly, the present invention also provides an inhibitor of a gap junction for use in:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising, consisting essentially of, or consisting of an inhibitor of a gap junction and a pharmaceutically acceptable carrier, diluent or excipient for use in treating an autoimmune or autoinflammatory disease in an individual.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising, consisting essentially of, or consisting of an inhibitor of a gap junction and a pharmaceutically acceptable carrier, diluent or excipient for use in treating lupus erythematosus in an individual, or for use in preventing a flare up of symptoms of lupus erythematosus in an individual exposed or at risk of exposure to sunlight.
- the invention provides a pharmaceutical composition for treating an autoimmune or autoinflammatory disease, preferably lupus erythematosus comprising an inhibitor of a gap junction and a pharmaceutically acceptable diluent, excipient or carrier.
- the only active ingredient present in the composition is an inhibitor of a gap junction.
- the invention provides a pharmaceutical composition for treating an autoimmune or autoinflammatory disease, preferably lupus erythematosus comprising as an active ingredient an inhibitor of an autoimmune or autoinflammatory disease and a pharmaceutically acceptable diluent, excipient or carrier.
- an autoimmune or autoinflammatory disease preferably lupus erythematosus
- a pharmaceutically acceptable diluent, excipient or carrier preferably a pharmaceutically acceptable diluent, excipient or carrier.
- the only active ingredient present in the composition is an inhibitor of a gap junction.
- the invention provides a pharmaceutical composition for treating an autoimmune or autoinflammatory disease, preferably lupus erythematosus comprising as a main ingredient an inhibitor of a gap junction and a pharmaceutically acceptable diluent, excipient or carrier.
- an autoimmune or autoinflammatory disease preferably lupus erythematosus
- a pharmaceutically acceptable diluent, excipient or carrier preferably a pharmaceutically acceptable diluent, excipient or carrier.
- the only active ingredient present in the composition is an inhibitor of a gap junction.
- an inhibitor of a gap junction may be administered system ically or directly to the site of disease.
- the inhibitor of a gap junction may be formulated for oral administration.
- the inhibitor of a gap junction may be formulated for topical administration, for example in the context of treating or treating or preventing symptoms of a sunlight-induced flare up of cutaneous lupus erythematosus.
- the present invention also provides a kit for use, or when used, in a method of the invention, the kit comprising, consisting essentially of or consisting of:
- FIG. 1 Gap junctions facilitate amplification of cGAMP signal by monocytes a- c) PMA-activated THP-1 (WT, cGASKO or STINGKO) (a, b) or primary monocytes (c) were co-cultured for 24 h with HEK293T WT or cGAS overexpressing (producing constitutive levels of cGAMP). Supernatants were collected and IP-10 levels analysed by ELISA. Carbenoxolone (CBX) at 100 mM was used to assess the impact of gap junction inhibition on the activation of IFN-I response by HEK cGAS (c). IP-10 was not detected in HEK WT or cGAS.
- CBX Carbenoxolone
- FIG. 2 Connexin expression in epithelial cells and monocytic cells is required for cGAMP transfer a) PMA-activated THP-1 cGAS-KO cells were co-cultured for 24 h with HEK293T WT or HEK293T lacking CX43/45, previously transfected with vectors encoding GFP or cGAS for 2 h (leading to cGAMP production). Supernatants were collected and IP-10 levels analysed by ELISA.
- THP-1 WT cells were pre-treated or not with PMA for 2 h, prior to co- culture for 24 h with HEK cGAS high cells, or direct stimulation with transfected cGAS (ISD 70) or STING (cGAMP) agonists. Supernatants were collected and IP 10 levels analysed by ELISA.
- THP-1 WT cells were pre-treated with 20 ng/ml PMA for indicated amount of time prior to lysis and western blot analysis of CX43 protein levels. CX43 levels were increased with time of treatment with PMA. All data shown are representative of a minimum of 2 independent experiments.
- FIG. 3 cGAMP transfer from HaCaT cells to monocytes after UV stimulation a) PMA differentiated WT THP-1 cells were co-cultured 24 h with HaCaT (WT, cGASKO or STINGKO) pre-treated with UV (7.5mJ/cm 2 ). IP10 were measured in supernatants by ELISA b) HEK293T (WT or cGAS overexpressing - producing constitutive levels of cGAMP) were co-cultured with HaCaT cells for 24 h, and IL-6 measured in supernatants by ELISA.
- IL-6 production confirms by-stander response to cGAMP in HaCaT cells - validating that HaCaT cGASKO are responsive to cGAMP.
- HaCaT cells did not make detectable IP 10 (not shown).
- Data shown is averaged of at least 2 independent experiments ( ⁇ sem). *p ⁇ 0.05.
- FIG. 4 cGAMP produced by joint fibroblast-like synoviocytes can transfer to activate STING in adjacent monocytes through gap junctions, resulting in positive feedback increasing further joint inflammation
- FLS primary Fibroblast-Like Synoviocytes
- ISD lipofectamine only
- Genistein inhibits cGAMP-mediated transactivation through its effect on connexins in either cGAMP donor or recipient cells a) HEK wild type or expressing low level of cGAS (cGAS l0W - making constitutive levels of cGAMP) were treated for 48 h with 30 or 50 mM Genistein for 48 h prior to being co-cultured (after replating the cells at similar densities for each condition) with mouse L929 cells expressing an Interferon Stimulated Responsive Element (ISRE)-Luciferase reporter (referred to as “LL171 cells”).
- ISRE Interferon Stimulated Responsive Element
- Data are averaged from 3 independent experiments in biological triplicate ( ⁇ s.e.m and unpaired Mann-Whitney U- tests shown) d) HEK expressing Sting and an IFN-beta Luciferase reporter and lacking connexin 43/45 (CXKO) or not (CXWT) were treated for 8 h with 50 mM Genistein prior rinsing and overnight co-culture with FIEK cGAS l0W . Data shown is averaged from 2 independent experiments in biological triplicate ( ⁇ s.e.m and unpaired Mann-Whitney U- tests shown).
- IFN-I receptor IFNAR
- anifrolumab IFN-I receptor
- aspects of the invention of inhibiting gap junctions allow retention of the capacity to sense pathogens and trigger an immune response, while also retaining the capacity to activate senescence in epithelial cells.
- An advantage of the aspects of the present invention is that only the positive feedback loop operated by the cell:cell communication of cGAMP, which favours autoimmunity or autoinflammation, is targeted.
- a“gap junction inhibitor” or“inhibitor of a gap junction” is any compound or molecule that inhibits, reduces or prevents the formation of a functional intercellular channel between adjacent cells. This may be by inhibiting the formation of a connexin in a cell, or inhibiting the interaction between connexins on adjacent cells. Inhibition, reduction or prevention of formation of a function intercellular channel between adjacent cells leads to a reduction in the direct diffusion of ions or small molecules, for example cGAMP, between adjacent cells. Inhibiting a gap junction may be by inhibiting one or more gap junction proteins. Preferably, an inhibitor of one or more gap junction proteins inhibits the capacity of the gap junction proteins to form a functional intercellular channel.
- a functional intercellular channel is one that allows direct diffusion of ions or small molecules between adjacent cells.
- the inhibitor of one or more gap junction proteins directly inhibits the interaction between one connexin with another connexin, for example the inhibitor may prevent the formation of a homo- or heterohexameric connexin or hemichannel.
- the compound may inhibit the interaction between two of the same connexins, e.g. inhibit the interaction between one Gx43 protein with another Gx43 protein, or may inhibit the interaction between two different connexins, e.g. inhibit the interaction between one Gx43 protein with Gx45 protein.
- the inhibitor may inhibit, prevent or reduce the formation of, or level of, polymorphic maculae or plaques containing clusters of gap junctions.
- the gap junction inhibitor may be an indirect inhibitor, for example, by acting directly on an agent which itself reduces expression or activity of a gap junction protein.
- an indirect inhibitor is Genistein, which is known to activate PKC and MAPK, and which in turn are thought to inactivate gap junctions via promoting the phosphorylation of connexins including Cx43.
- Non-limiting examples of compounds that may be a“gap junction inhibitor” or “inhibitor of a gap junction” include a small molecule, an antibody, a peptide, a protein, an antisense oligonucleotide, an interfering RNA or a synthetic oligonucleotide (e.g. antisense or aptamer).
- the inhibitor binds to a site on a connexin that is involved in interaction with another connexin.
- the inhibitor may bind to one or both of the two extracellular loops of the connexin protein.
- Examples of peptide inhibitors are Gap26 and Gap27, which are identical to amino acid sequences on the first and second extracellular loop regions of connexin 43, respectively. Peptides that are identical to the first and second extracellular loop regions of the other connexins are also contemplated for use in the invention.
- the inhibitor is selective and binds to 1 , 2 or 3 different connexins.
- the inhibitor is non-selective and binds to greater than 3 different connexins.
- the capacity for a compound to inhibit a gap junction may be measured by any method or assay described herein.
- small molecule denotes a generally low molecular weight compound and includes organic and inorganic compounds.
- a small molecule has a well- defined chemical formula with a single molecular weight.
- a small molecule has a molecular weight of less than 3000 daltons. More preferably, a small molecule has a molecular weight of less than 2000 daltons. In some embodiments of this invention, the small molecule has a molecular weight of less than 1000 daltons.
- Some non-limiting examples of small molecules include lipids such as fatty acids; saccharides (mono, di or poly); xenobiotics; organometallic compounds and natural products.
- An antibody inhibitor of a gap junction protein can be produced via techniques known in the art to generate an antibody against gap junction protein and then those antibodies can be screened for inhibitory activity using assays as described herein.
- monoclonal antibodies can be prepared as follows. Immunization of mice or other appropriate host animal by a connexin or fragment thereof. Immunization with a connexin or fragment thereof and/or adjuvant may be by multi-point injection usually subcutaneous injection or intraperitoneal injection. A connexin or fragment thereof may be conjugated to a carrier, such as serum albumin, or soybean trypsin on inhibitor, an antigen to enhance immunogenicity in the host.
- the preferred animal system for generating hybridomas is the murine system.
- Fusion cell partners e.g., murine myeloma cell lines SP2/0, NS0, NS1 , rat myeloma Y3, rabbit myeloma 240E 1 , human K6H6
- fusion and screening procedures are also well known in the art.
- the present invention also includes the use of functional analogs, variants and derivatives of the above-mentioned gap junction inhibitors.
- the present invention contemplates the use of Glycyrrhetinic acid and functional derivatives or analogues thereof.
- Glycyrrhetinic acid (CAS no 471 -53-4, also known as Enoxolone or glycyrrhetic acid) is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice.
- Carbenoxolone (CBX, CAS no: 5697-56-3) is a glycyrrhetinic acid derivative with a steroid-like structure, similar to substances found in the root of the licorice plant. Carbenoxolone reversibly inhibits the conversion of inactive cortisone to cortisol by blocking 11 b-hydroxysteroid dehydrogenase (I ⁇ b-HSD). I ⁇ b-HSD also reversibly catalyzes the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. Carbenoxolone is a modestly potent, reasonably effective, water-soluble blocker of gap junctions. Carbenoxolone is available as a topical cream such as Carbosan gel.
- Glycyrrhetinic acid is Acetoxolone.
- Retinoic acid ((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1 - yl)nona-2,4,6,8-tetraenoic acid, CAS no 302-79-4) is a metabolite of vitamin A1 (all- trans-retinol) that mediates the functions of vitamin A1 required for growth and development. Isomers include 13-cis- and 9-cis-retinoic acid. Other retinoid medications include Tretinoin and Isotretinoin.
- the present invention also contemplates the use of quinine and functional analogs and derivatives thereof obtained from the cinchona tree.
- Quinine (sold as Qualaquin, Quinate, Quinbisul, and others, CAS no: 130-95-0) is an alkaloid derived from the bark of the cinchona tree. Quinine is a basic amine and is usually provided as a salt. Various existing preparations include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin. All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR).
- IV intravenously
- quinine gluconate may also be given intramuscularly (IM) or rectally (PR).
- Quinidine (CAS no 56-54-2) is a stereoisomer of quinine, and is sold under the trade names Quinaglute, Quinidex. Quinidine acts as a blocker of voltage-gated sodium channels. Inhibition of the Nav1.5 channel is specifically involved in its antiarrhythmic effects as a class I antiarrhythmic agent. Quinidine also blocks certain voltage-gated potassium channels (e.g., Kv1.4, Kv4.2, hERG, among others), acts as an antimuscarinic and alpha-1 blocker, and is an antimalarial (as is quinine).
- voltage-gated potassium channels e.g., Kv1.4, Kv4.2, hERG, among others
- Mefloquine (sold under the brand names Lariam Mephaquin, Mefliam, others, CAS no: 53230-10-7).
- Melfoquine is also known as [(R*,S*)-2,8- bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol and alpha-2-Piperidinyl-2,8- bis(trifluoromethyl)-4-quinolinemethanol. It is available in tablets of 228mg base (250mg salt).
- Anandamide (CAS no 94421 -68-8, also known as N-arachidonoylethanolamine or AEA), is a fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid), an essential w-6 polyunsaturated fatty acid.
- Anandamide is also known as (5Z,8Z,11 Z, 14Z)-N-(2-hydroxyethyl)icosa-5, 8,11 ,14- tetraenamide).
- Oleamide (CAS no: 301 -02-0, also known as (Z)-Octadec-9-enamide, Oleylamide, and Cis-9,10-octadecenoamide) is the amide derived from the fatty acid oleic acid.
- the gap junction inhibitor is a member of the anthranilic acid derivatives class of NSAID drugs which include: meclofenamic acid (also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2), mefenamic acid, flufenamic acid (CAS no 530-78-9) and Niflumic acid (CAS no 4394- 00-7).
- meclofenamic acid also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2
- mefenamic acid also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2
- mefenamic acid also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2
- mefenamic acid also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2
- mefenamic acid also known as meclofenamate sodium, brand Meclomen, CAS no 644-62-2
- mefenamic acid
- 1 -Heptanol (CAS no 111 -70-6) is an alcohol with a seven carbon chain and the structural formula of CH3(CH2)60H. It is a clear colorless liquid that is very slightly soluble in water, but miscible with ether and ethanol. There are three other isomers of heptanol that have a straight chain, 2-heptanol, 3-heptanol, and 4-heptanol, which differ by the location of the alcohol functional group.
- Octanol (111 -87-5) is another alcohol that can be used to inhibit connexins in accordance with the present invention.
- Tonabersat SB-220405 is a benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. Tonabersat is a member of a family of novel benzoylamino-benzopyran compounds, typified by carabersat (SB-204269),
- the inhibitor of a gap junction or of a gap junction protein is Genistein, or a functional analog or derivative thereof.
- Genistein is an isoflavone, also known as 5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one or 4', 5, 7- Trihydroxyisoflavone (CAS no 446-72-0).
- Genistein has previously been implicated as a negative mediator of proliferation and angiogenesis in vitro, partially by down-regulating cell adhesion-related genes and impairing cell adhesions.
- Genistein acts to inhibit gap junctions is surprising given the previous reports that flavonoids increase expression of connexins including Cx 43.
- the present inventors are the first to demonstrate that Genistein acts differently to other isoflavonoid molecules, and inhibits the transfer of cGAMP between cells.
- the ability for Genistein to inhibit the transfer of cGAMP between cells was shown to be dependent upon connexins 43 and 45.
- the inventors have demonstrated that Genistein inhibits cGAMP-mediated transactivation through its effect on connexins.
- gap junction mimetic peptides which can be used to inhibit connexins are described, for example, in WO/2006/134494.
- the inhibitor of a gap junction may inhibit the function of the intercellular channel at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or preferably by up to 100%.
- the inhibitor inhibits the transfer of cGAMP, c-di- AMP, or c-di-GMP to an immune cell by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or preferably by up to 100%.
- the inhibitor of a gap junction may exhibit a K ⁇ value of less than 1 mM, preferably less than 100pM, less than 10mM, less than 1 mM, less than 100nM, less than 50nM, less than 40nM, less than 10nM.
- the K ⁇ is a measure of the transfer of cGAMP, c-di-AMP, or c-di-GMP to an immune cell, typically from an epithelial cell, using an assay or a method as described herein.
- the inhibitor of a gap junction may exhibit an IC50 of less than 1 mM, preferably less than 100pM, less than 10mM, less than 1 mM, less than 100nM, less than 90nM, less than 80nM, less than 50nM, less than 40nM, less than 10nM.
- the IC50 is a measure of the transfer of cGAMP, c-di-AMP, or c-di-GMP to an immune cell, typically from an epithelial cell, using an assay or a method as described herein.
- Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP; cyclic GMP-AMP; cGAMP(2'-5'); cyclic Gp(2'-5')Ap(3'-5')) is a cyclic di-nucleotide.
- cGAMP is synthesized by cyclic GMP-AMP synthase (cGAS) from ATP and GTP upon cytosolic DNA stimulation.
- cGAMP produced by cGAS contains mixed phosphodiester linkages, with one between 2'-OH of GMP and 5'- phosphate of AMP and the other between 3'-OH of AMP and 5'-phosphate of GMP.
- the structure of cGAMP is shown below:
- An exemplary assay to measure inhibition of gap junction intercellular communication may be any one described herein or any one described in Abacci et al. Biotechniques. 2008 Jul;45(1 ):33-52, 56-62.
- the method may be micro- injection, scrape Loading/electroporation, Gap-FRAP (Fluorescence Recovery after Photobleaching), Preloading Assay, LAMP (Local Activation of Molecular Fluorescent Probe), Radiolabeled Nucleotides Transfer, Intercellular Calcium Waves (ICW), Dual Whole-cell Patch Clamp.
- LAMP Local Activation of Molecular Fluorescent Probe
- Radiolabeled Nucleotides Transfer e.g. small molecule, peptide, antibody, RNAi or other molecule
- a compound e.g. small molecule, peptide, antibody, RNAi or other molecule, can inhibit, prevent or reduce gap junction mediated intercellular communication.
- autoinflammation When adaptive cells break self-tolerance, the resulting condition is characterised as autoimmunity, where native host cells are recognised as foreign and the adaptive immune cells target them for destruction.
- autoimmunity When innate immune cells become activated, due to dysregulated secretion of pro-inflammatory cytokines and consequent damage to host tissues, it is termed autoinflammation.
- autoimmune disease refers generally to those diseases characterized by the failure of one or more B- and/or T-cell populations, or gene products thereof, to distinguish between self and non-self antigenic determinants.
- autoinflammatory disease or“autoinflammatory diseases” (AIDs) refers generally to those diseases characterized by the dysregulated secretion of pro-inflammatory cytokines and consequent damage to host tissues.
- AIDs and systemic autoimmune diseases share some characteristics: they start with the prefix "auto" to define a pathological process directed against self; they are systemic diseases, frequently involving musculoskeletal system; both include monogenic and polygenic diseases. From the pathogenetic point of view, they are characterized by a chronic activation of immune system, which eventually leads to tissue inflammation in genetically predisposed individuals. Nevertheless, the specific effectors of the damage are different in the two groups of diseases: in AIDs the innate immune system directly causes tissue inflammation, whereas in ADs the innate immune system activates the adaptive immune system which, in turn, is responsible for the inflammatory process.
- Some conditions may be characterized as exhibiting both autoimmune and autoinflammatory features.
- autoimmune diseases are often characterized by the infiltration of the target cells with inflammatory lymphoid cells, for example, mononuclear phagocytes, lymphocytes and plasma cells as well as secondary lymphoid follicles.
- autoimmune diseases or disorders include, but are not limited to, inflammatory responses such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome; ARDS); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythe
- Both monogenic autoinflammatory diseases and multifactorial autoinflam matory diseases are contemplated. Examples of both are described in Ciccarelli et al. Curr Med Chem. 2013 Jan; 21 (3): 261-269, such as Familial Mediterranean Fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Flyperimmuno globulinemia W with periodic fever syndrome (H IDS), Cryopyrin associated periodic syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Neonatal onset multisystemic inflammatory disorder (NOMID), NALP12-associated periodic fever, Deficit of IL-1 receptor antagonist (DIRA), Majeed’s syndrome, Pyogenic arthritis pyoderma gangrenosum and acne syndrome (PAPA), Blau’s syndrome, Periodic fever, aphthous stomatitis, pharyngitis and adenopathy syndrome (PFAPA), Behcet’s Disease, Chron’s Disease, Still’s Disease, Adult-onset Still Disease,
- therapeutically effective amount generally refers to an amount of one or more inhibitors, or, if a small molecule inhibitor, a pharmaceutically acceptable salt, polymorph or prodrug thereof of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
- preventing or “prevention” is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e. , causing at least one of the clinical symptoms of the disease not to develop in a individual that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
- Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.
- the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimise progression, of a flare-up or symptom of a disease or condition as described herein.
- the methods of the present invention have utility as treatments as well as prophylaxes.
- treatment or “treating” of a subject includes the inhibition of a gap junction in an individual with the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
- treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.
- a “subject” herein is preferably human subject. Although the invention finds application in humans, the invention is also useful for veterinary purposes. The invention is useful for domestic or farm animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals. It will be understood that the terms“subject” and“individual” are interchangeable in relation to an individual requiring treatment according to the present invention.
- the therapeutically effective amount of a compound corresponds to preferably between about 0.01 to about 10% (w/w), or between about 0.1 to 10% (w/w), or between about 1.0 to about 10% (w/w), between about 0.1 to about 5% (w/w), or between about 1.0 to about 5% (w/w).
- the therapeutically effective amount of a compound corresponds preferably between about 1 to about 50 mg/kg, or between about 1 to 25 mg/kg, or between about 1 to about 10 mg/kg, between about 5 to about 25 mg/kg, or between about 10 to about 20 mg/kg.
- the proportion of the inhibitor described herein may be at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total active present in the composition, typically stored in solution for a suitable period of time under suitable conditions.
- Suitable periods of time and conditions include ranges of time and conditions under which a skilled practitioner might reasonably expect to keep a inhibitor in solution prior to use. For example, periods of time of about 24 hours, about 48 hours, or about 72 hours are typical, although some solutions may be kept for longer periods for example, at least a week, a month, 6 months, 1 year, 2 years, 3 years or more.
- Storage conditions may typically be room temperature and relative humidity, or typically 25° C. and 60% relative humidity, but could include any standard storage conditions encountered by the skilled person, for example approximately 4° C., -20° C., or -80° C.
- the frequency of administration may be once daily, or 2 or 3 time daily.
- the treatment period may be for the duration of the detectable disease.
- a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1 % up to about 50% or more, and all combinations and sub-combinations of ranges therein.
- the compositions can be formulated to contain one or more the inhibitors described herein in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1 %, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
- compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1 %, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%.
- the compositions can contain from greater than about 1 % for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
- the active agent can, for example, be present in a concentration of about 5%. In all cases, amounts may be adjusted to compensate for differences in amounts of active ingredients actually delivered to the treated cells or tissue.
- the autoimmune diseases are selected from the group consisting of lupus, arthritis and psoriasis.
- SLE Systemic lupus erythematosus
- SLE is a multi-system autoimmune disease. At least 5 million people worldwide have SLE; 90% of those diagnosed are female and most develop the disease between the ages of 15-44. In Australia, SLE is diagnosed in ⁇ 1 in 1000 people and is more prevalent and severe in Native Australians and Asian Australians. SLE patients suffer chronic immune-mediated inflammatory damage in the brain, kidneys, heart, lungs, joints, skin, and other organs, resulting in a marked loss of life expectancy, exemplified by a standardized mortality ratio above 3. In a British cohort, the average age of death of the 14% of patients who died during follow-up was only 52 years. Most often the clinical course is characterised by episodic flares, which are associated with accrual of irreversible organ damage and thereby mortality.
- lupus include discoid, drug-induced and neonatal lupus.
- systemic lupus erythematosus also known as SLE
- SLE systemic lupus erythematosus
- a more thorough categorization of lupus includes the following types: acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus (chronic cutaneous), childhood discoid lupus erythematosus, generalized discoid lupus erythematosus, localized discoid lupus erythematosus, chilblain lupus erythematosus (Hutchinson), lupus erythematosus-lichen planus overlap syndrome, lupus erythematosus panniculitis (lupus erythematosus profundus),
- Cutaneous lupus erythematosus (CLE) is seen in the majority of SLE cases and is most often observed in skin exposed to the sun, appearing as a variety of severe and in some cases disfiguring skin rashes. Lupus may also manifest as a purely cutaneous form, also known as incomplete lupus erythematosus. While all the factors leading to the development of SLE, and its pattern of intermittent flares, are not known, it is clear that sunlight exposure is important in systemic as well as cutaneous disease exacerbation.
- Inhibition of sunlight driven flares by gap junction inhibition has the potential to stop disease progression and increase life expectancy. Successful treatment may be determined by a decreased in the severity or frequency of flares and an increase in survival time.
- the present invention includes methods of preventing sunlight- induced symptoms of SLE and CLE such as joint pains, weakness, fatigue, fever, skin rashes, tingling, and numbness in an individual diagnosed with or suspected of having lupus.
- the methods of the present invention find utility in preventing or reducing the severity of a UV- or sunlight-exposure induced flare-up of the symptoms of SLE.
- administration of a gap junction inhibitor either before a period of sunlight-exposure, or alternatively, in the period following sunlight-exposure may be used to inhibit the progression of the cGAMP-mediated inflammatory process leading to expression or exacerbation of symptoms of lupus erythematosus in an individual.
- the methods of the invention can be used to prevent or reduce the severity of a flare-up of the symptoms of SLE and/or CLE.
- Psoriasis is an inflammatory skin condition relating to the hyper-proliferation of keratinocytes which affects ⁇ 2% of the general population, and involving T lymphocytes.
- Skin lesions are chronic red plaques often observed on elbows, knees, scalp, and umbilicus/lumbar areas. Eruptive guttate psoriasis is often the initial manifestation triggered by with a streptococcal infection.
- Psoriatic lesions can progress to erythroderma impacting the entire body surface. It may also associate with join inflammation. There is evidence that psoriatic lesions contain keratinocytes with increased connexin expression - with example of CX26.
- Successful treatment may be determined by a decrease of inflammatory plaques for a period of time (the duration of remission is a measure of treatment).
- RA Rheumatoid arthritis
- Sjogren Sjogren syndrome
- RA directly impacts the working life of patients, with 60% being unable to work 10 years after onset of their disease. RA also impacts life expectancy by 3-7 years for females/males. There is evidence that increased gap junction intercellular communication mediated by Cx43 contributes to the development of RA, and that this could result to increased levels of joint pro-inflammatory cytokines such as TNFa.
- Successful treatment may be determined by a decrease in joint inflammation, bone destruction, pain and increased life expectancy.
- compositions comprising, formulations and modes of administration
- compositions of the invention typically include a therapeutically effective amount of an inhibitor of one or more in admixture with one or more pharmaceutically and physiologically acceptable formulation materials.
- suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants.
- a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
- compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as
- Various dosage units are each preferably provided as a discrete dosage tablet, capsules, lozenge, dragee, gum, or other type of solid formulation.
- Capsules may encapsulate a powder, liquid, or gel.
- the solid formulation may be swallowed, or may be of a suckable or chewable type (either frangible or gum-like).
- the present invention contemplates dosage unit retaining devices other than blister packs; for example, packages such as bottles, tubes, canisters, packets.
- the dosage units may further include conventional excipients well-known in pharmaceutical formulation practice, such as binding agents, gellants, fillers, tableting lubricants, disintegrants, surfactants, and colorants; and for suckable or chewable formulations.
- compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations.
- Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
- excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
- an oil medium such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate.
- Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl p-hydroxybenzoate
- colouring agents for example ethyl, or n-propyl p-hydroxybenzoate
- flavouring agents such as sucrose or saccharin.
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations.
- Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
- compositions may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
- Suitable emulsifying agents include naturally- occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
- An emulsion may also comprise one or more sweetening and/or flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
- Compositions or particles of the invention may be formulated for local or topical administration, such as for topical application to the skin. Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
- Topical vehicles include organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerine, lipid- based materials such as fatty acids, acylglycerols including oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, protein- based materials such as collagen and gelatine, silicone-based materials (both nonvolatile and volatile), and hydrocarbon-based materials such as microsponges and polymer matrices.
- organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixture
- a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
- stabilizing agents such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
- a topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches.
- the physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation.
- Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form.
- Solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
- Creams and lotions are often similar to one another, differing mainly in their viscosity. Both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
- Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels, and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
- Emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
- Suitable viscosity adjusting agents include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
- a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
- a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
- Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
- dimethicone copolyol polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocam idopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
- Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
- Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol.
- Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
- Suitable fragrances and colours include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
- Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
- Typical modes of delivery for topical compositions include application using the fingers, application using a physical applicator such as a cloth, tissue, swab, stick or brush, spraying including mist, aerosol or foam spraying, dropper application, sprinkling, soaking, and rinsing.
- Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration (for example, as a transdermal patch).
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvant
- compositions and particles of the invention may be administered orally, nasally, intravenously, intramuscularly, ocularly, transdermally, intraperitoneally, or subcutaneously.
- the particles of the invention are administered intravenously.
- injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the effective amounts and method of administration of the present invention for modulation of an immune response can vary based on the individual, what condition is to be treated and other factors evident to one skilled in the art. Factors to be considered include route of administration and the number of doses to be administered.
- compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration.
- sustained release formulations such as a capsule that creates a slow release of modulator following administration.
- Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
- Carriers for use within such formulations are biocompatible, and may also be biodegradable.
- the formulation provides a relatively constant level of modulator release.
- the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
- kit or article of manufacture including one or more compositions, peptides and/or pharmaceutical compositions as described above.
- kit for use in a therapeutic or prophylactic application mentioned above including:
- the kit may contain one or more further active principles or ingredients for treatment of an autoimmune disease, particularly a demyelination disorder such as multiple sclerosis.
- the kit or“article of manufacture” may comprise a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- the label or package insert indicates that the therapeutic composition is used for treating the condition of choice.
- the label or package insert includes instructions for use and indicates that the therapeutic or prophylactic composition can be used to treat an inflammatory disease or condition described herein.
- the kit may comprise (a) a therapeutic or prophylactic composition; and (b) a second container with a second active principle or ingredient contained therein.
- the kit in this embodiment of the invention may further comprise a package insert indicating the composition and other active principle can be used to treat a disorder or prevent a complication stemming from an autoimmune disease described herein.
- the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- the therapeutic composition may be provided in the form of a device, disposable or reusable, including a receptacle for holding the therapeutic, prophylactic or pharmaceutical composition.
- the device is a syringe.
- the device may hold 1 -2 ml_ of the therapeutic composition.
- the therapeutic or prophylactic composition may be provided in the device in a state that is ready for use or in a state requiring mixing or addition of further components.
- compositions of the invention typically include a therapeutically effective amount of an inhibitor of a gap junction in admixture with one or more pharmaceutically and physiologically acceptable formulation materials.
- suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants.
- a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
- the primary solvent in a vehicle may be either aqueous or non-aqueous in nature.
- the vehicle may contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation.
- the vehicle may contain still other pharmaceutically-acceptable excipients for modifying or maintaining the rate of release of an inhibitor of a gap junction, or for promoting the absorption or penetration of an inhibitor of a gap junction, for example, across the skin or intestinal lining.
- the therapeutic composition may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder.
- Such formulations may be stored either in a ready to use form or in a form, e.g., lyophilized, requiring reconstitution prior to administration.
- the optimal pharmaceutical formulations will be determined by one skilled in the art depending upon considerations such as the route of administration and desired dosage. See for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712, the disclosure of which is hereby incorporated by reference. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the gap junction inhibitor.
- Topical vehicles include organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerine, lipid- based materials such as fatty acids, acylglycerols including oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, protein- based materials such as collagen and gelatine, silicone-based materials (both nonvolatile and volatile), and hydrocarbon-based materials such as microsponges and polymer matrices.
- organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixture
- an inhibitor of a gap junction which is administered in this fashion may be encapsulated and may be formulated with or without those carriers customarily used in the compounding of solid dosage forms.
- the capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional excipients may be included to facilitate absorption of an inhibitor of a gap junction. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
- compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations.
- Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
- excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
- an oil medium such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate.
- Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl p-hydroxybenzoate
- colouring agents for example ethyl, or n-propyl p-hydroxybenzoate
- flavouring agents such as sucrose or saccharin.
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations.
- Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
- compositions may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
- Suitable emulsifying agents include naturally- occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
- An emulsion may also comprise one or more sweetening and/or flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
- sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
- Additional formulation components may include materials which provide for the prolonged residence of an inhibitor as described herein so as to maximize the topical contact and promote absorption. Suitable materials include polymers or gel forming materials which provide for increased viscosity of the preparation.
- the suitability of the formulations of the instant invention for controlled release (e.g., sustained and prolonged delivery) of an inhibitor as described herein can be determined by various procedures known in the art..
- the specific dose of a gap junction inhibitor may be calculated according to considerations of body weight, body surface area or organ size. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed, especially in light of the dosage information and assays disclosed herein. Appropriate dosages may be ascertained through use of the established assays for determining dosages utilized in conjunction with appropriate dose-response data.
- the final dosage regimen involved in a method for treating the above-described conditions will be determined by the attending physician, considering various factors which modify the action of drugs, e.g., the age, condition, body weight, sex and diet of the patient, the severity of any infection, time of administration and other clinical factors. As studies are conducted, further information will emerge regarding the appropriate dosage levels for the treatment of various diseases and conditions.
- an inhibitor of a gap junction may be advantageous for a given treatment. While continuous administration may be accomplished via a mechanical means, such as with an infusion pump, it is contemplated that other modes of continuous or near continuous administration may be practiced. For example, chemical derivatization or encapsulation may result in sustained release forms of the inhibitor which have the effect of continuous presence, in predictable amounts, based on a determined dosage regimen.
- an inhibitor of a gap junction includes inhibitors derivatized or otherwise formulated to effectuate such continuous administration.
- a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
- stabilizing agents such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
- Emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
- Suitable viscosity adjusting agents include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
- a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
- a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
- Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
- dimethicone copolyol polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocam idopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
- Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
- Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol.
- Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
- Suitable fragrances and colours include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
- Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
- Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
- Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water.
- the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
- Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
- compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration.
- sustained release formulations such as a capsule that creates a slow release of modulator following administration.
- Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
- Carriers for use within such formulations are biocompatible, and may also be biodegradable.
- the formulation provides a relatively constant level of modulator release.
- the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
- kit or article of manufacture including one or more inhibitors of a gap junction, as described herein, or a pharmaceutically acceptable salt, polymorph or prodrug thereof and/or pharmaceutical composition as described above.
- kits for use in a therapeutic or prophylactic application mentioned above including:
- the kit may contain one or more further active ingredients for treatment or prevention of an autoimmune or autoinflammatory disease.
- the kit or“article of manufacture” may comprise a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- the label or package insert indicates that the therapeutic composition is used for treating the condition of choice.
- the label or package insert includes instructions for use and indicates that the therapeutic or prophylactic composition can be used to treat or prevent an autoimmune or autoinflammatory disease as described herein.
- the kit may comprise (a) a therapeutic or prophylactic composition; and (b) a second container with a second active principle or ingredient contained therein.
- the kit in this embodiment of the invention may further comprise a package insert indicating the composition and other active principle can be used to treat a disorder or prevent a complication stemming from an autoimmune disease as described herein.
- the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
- BWFI bacteriostatic water for injection
- the therapeutic composition may be provided in the form of a device, disposable or reusable, including a receptacle for holding the therapeutic, prophylactic or pharmaceutical composition.
- the device is a syringe.
- the device may hold 1 -2 ml_ of the therapeutic composition.
- the therapeutic or prophylactic composition may be provided in the device in a state that is ready for use or in a state requiring mixing or addition of further components.
- cGAMP made by an epithelial cell constitutively producing it can be transferred to co-cultured 24 h with PMA activated THP-1 monocytes, where it activates production of the cytokine IP-10 through STING, independently of cGAS ( Figure 1A).
- THP-1 cells genetically lacking cGAS were still able to respond to cGAMP producing cells, demonstrating that it is not engagement of cGAS in the THP-1 cells which is at play in the transactivation by the HEK cGAS cells.
- STING deficiency in the THP-1 cells ablated IP-10 production, in line with the direct role of cGAMP from the HEK cGAS cells in the transactivation by the HEK cGAS cells.
- THP-1 cells required a 2 h PMA pre-treatment to produce IP-10 when co-cultured with HEK cGAS high cells (Figure 2C).
- This requirement for PMA differentiation of the THP-1 cells did not relate to their basal capacity to respond to cGAS or STING, since liposome based transfection of 70 nt double stranded DNA or synthetic cGAMP activated IP-10 production in un-primed cells ( Figure 2C).
- FLSs human joint fibroblast-like synoviocytes
- ISD immunostimulatory DNA
- the experiments described in Figure 5C show that pre-treatment of human TERT immortalised BJ fibroblasts (referred to as“hTERT”) with Genistein (75 mM) for 48h reduces their capacity to transfer cGAMP to LL171 cells, after transfection of the hTERT with 1 pg/ml ISD.
- the experiments described in Figure 5D show that 8h pre-treatment of HEK expressing mouse Sting (referred to as“HEK Sting CX WT”) and an Interferon (IFN)-p- Luciferase reporter with 50 pM Genistein, inhibits their capacity to respond to cGAMP generated by co-cultured HEK cGAS l0W cells.
- HEK Sting lacking connexins 43 and 45 (referred to as“HEK Sting CX KO”), do not respond to co-cultured HEK cGAS l0W cells and are not impacted on by Genistein.
- Genistein can inhibit cGAMP-mediated transactivation, through its effect on connexins in either cGAMP donor or recipient cells.
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Abstract
La présente invention concerne des compositions et des procédés pour le traitement ou la prévention de maladies auto-immunes ou auto-inflammatoires. Dans un aspect, la présente invention concerne un procédé de traitement d'une maladie auto-immune ou auto-inflammatoire chez un individu, le procédé comprenant, consistant essentiellement ou consistant à inhiber une jonction lacunaire chez l'individu, traitant ainsi la maladie auto-immune ou auto-inflammatoire. De préférence, la maladie auto-immune ou auto-inflammatoire est le lupus érythémateux.
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AU2018901775 | 2018-05-21 | ||
AU2018901775A AU2018901775A0 (en) | 2018-05-21 | Method of treatment |
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