WO2014013014A1 - Inhibiteurs de jak pour l'activation de populations de cellules souches épidermiques - Google Patents

Inhibiteurs de jak pour l'activation de populations de cellules souches épidermiques Download PDF

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WO2014013014A1
WO2014013014A1 PCT/EP2013/065177 EP2013065177W WO2014013014A1 WO 2014013014 A1 WO2014013014 A1 WO 2014013014A1 EP 2013065177 W EP2013065177 W EP 2013065177W WO 2014013014 A1 WO2014013014 A1 WO 2014013014A1
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jak
jak inhibitor
cells
stem cells
hair
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PCT/EP2013/065177
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English (en)
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William Keyes
Jason DOLES
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Fundació Privada Centre De Regulació Genòmica (Crg)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to the fields of aging and age-associated changes in stem cells.
  • the invention provides methods to activate epidermal stem cells and/or progenitor cells by interfering with the JAK/STAT signalling pathway.
  • JAK inhibitors are provided for use in epidermal stem cell activation and cosmetic or pharmaceutical applications derived thereof, such as promoting hair growth, treatment of hair-loss disorder, repair and regeneration of the skin.
  • the skin is one of the most obvious tissues to undergo aging-associated phenotypic and functional changes, including decreased hair cycling, epidermal thinning, diminished sebaceous gland function and an impaired wound response (Balin and Pratt 1989).
  • the cellular regeneration of the skin is maintained by different adult stem/progenitor cell subpopulations localized within the specialized microenvironments, niches in interfollicular epidermis (IFE), sebaceous gland and hair follicle bulge region (Mimeault and Batra 2010).
  • Stem cell therapy is one of the current strategies to promote tissue growth in vivo or to generate cultured tissues for transplantation (reviewed by Vogel 1999).
  • Methods for skin regeneration using mesenchymal stem cells are, for example, disclosed in EP0953040.
  • extrinsic stem cells raises concerns regarding tumorigenicity caused by undifferentiated pluripotent cells as well as immunogenicity caused by allogenecity.
  • agents capable of maintaining, increasing and/or activating the pool of endogenous (pre-existing) epidermal stem cells and/or progenitor cells thus avoiding the many drawbacks involved in current stem cell therapies, in order to promote epidermal renewal and prevent and/or combat cutaneous signs of aging.
  • hair follicle stem cells are susceptible to age- associated changes that may contribute to aging phenotypes. Novel unexpected alterations in hair follicle stem cells during skin aging were identified, including increased numbers, decreased function and an inability to tolerate stress. That these cells retain stem-like properties while simultaneously being repressed by the external environment implies a degree of reversibility, which the inventors show is feasible with chemical compounds.
  • inhibitors of the JAK/STAT signalling pathway can be used to activate a population of epidermal stem cells and/or progenitor cells.
  • this may lead to several applications in the cosmetics and/or pharmaceutical field, including but not limited to regeneration and repair of skin, promotion of hair growth and treatment of hair-loss disorders.
  • the present invention thus provides methods for activation of adult epidermal stem cells in situ to undergo differentiation into the many cell types required to generate tissue, by localized delivery of inhibitors of the JAK/STAT signalling pathway.
  • the population of epidermal stem cells and/or progenitor cells is a population of hair follicle stem cells and/or progenitor cells.
  • the population of epidermal stem cells and/or progenitor cells is a human stem cell population.
  • the JAK inhibitor is an inhibitory agent or a small molecule.
  • the JAK inhibitor for use according to the invention is an inhibitor of JAK3.
  • the JAK inhibitor for use in hair follicle regeneration (i) the JAK inhibitor for stimulating hair growth and/or for use in treatment of a hair-loss disorder; (iii) the JAK inhibitor for use in skin repair and regeneration; (iv) the JAK inhibitor for use in wound healing.
  • the JAK inhibitor for use according to the invention will be formulated in a physiologically acceptable medium.
  • the cosmetic and pharmaceutical compositions utilized in this invention may be administered by any number of routes including oral, transdermal, subcutaneous and topical.
  • the JAK inhibitors for use according to the invention will be formulated in a physiologically acceptable medium that is suitable for topical application.
  • the invention relates to a method for activating a population of epidermal stem cells and/or progenitor cells, the method comprising contacting epidermal tissue or cells with an effective amount of a JAK inhibitor, in particular a JAK inhibitor that inhibits JAK3.
  • a JAK inhibitor in particular a JAK inhibitor that inhibits JAK3.
  • a JAK inhibitor in particular a JAK3 inhibitor
  • the invention further envisages a method for skin regeneration or for wound healing, the method comprising applying to a site in need thereof an effective amount of a JAK inhibitor, in particular a JAK3 inhibitor, formulated in a physiological acceptable medium.
  • Krt-15-GFP hair follicle stem cell number increases with age.
  • a Whole-mount co-immunofluorescence of aged tail epidermis stained with antibodies targeting Keratin 15 (red) and GFP (green).
  • FIG. 1 Age-associated functional decline in Krt-15-GFP stem cells.
  • a Clonogenic colony forming assays of FACS-sorted GFP + and GFP " cells from 3- and 18-month old epidermis. Pictured are duplicate wells of each condition, representative of n>3 independent experiments.
  • b,c Quantification of colony number (b) and normalized colony size (c) of data depicted in (a),
  • d Colony assays using FACS-sorted GFP + /CD34 + /CD49f + cells,
  • e Aged Krt-15-GFP mice were exposed to 5Gy whole-body irradiation and sacrificed 24h post IR.
  • f Absolute GFP + cell number per hair follicle in shaved, back skin epidermis treated with 20nM TPA every other day for one week
  • g Representative histological images of back skin sections stained with antibodies against Ki67, GFP and CD34. p-values were determined using unpaired, two- tailed student t-tests. *p ⁇ 0.05, **p ⁇ 0.001. Error bars for bar graphs represent +/- s.d.
  • FIG. 3 Heatmaps of epidermal, lineage-associated transcripts (3m vs. 18m). a-c, Heat maps depicting relative gene expression changes for transcripts associated with interfollicular epidermis (a), core hair follicle bulge (b), and sebaceous gland (c). Individual transcript values for each time point (row) are shown as the log2(fold change [time point]) with respect to the mean expression value.
  • Figure 4 Selected qPCR of epidermal stem cell transcripts (3m vs. 18m).
  • p-values were determined using unpaired, two-tailed student's t-tests. *p ⁇ 0.05.
  • FIG. 5 Dynamic changes in cytokine signaling networks in aging epidermis.
  • a A balloon graph depicting RNA-seq-determined individual transcript changes of aged, Krt-15-GFP stem cells. Red data points represent significantly up or down regulated transcripts
  • b Differential expression values of transcripts associated with positive (+) or negative regulation (-) of selected signalling pathways
  • c qRT-PCR validation of selected Jak-Stat signalling transcripts.
  • FIG. 6 Gene ontology analysis of significant differentially expressed transcripts.
  • a,b Gene ontology analysis of significant differentially expressed genes between 3- and 18- month Krt- 15-GFP cells. Transcripts were analysed using Gene Ontology enrichment analysis and visualization (GOrilla) software (http://cbl-gorilla.cs.technion.ac.il/). Shown are the top 20 GO processes enriched in up-regulated (a) and down-regulated (b) gene sets.
  • a Clonogenic colony formation assays of aged (18m) keratinocytes cultured in the presence of Jak, Wnt, or Notch pathway inhibitors
  • b Colony assays of FACS-sorted GFP + or GFP + /CD34 + /CD49f + cells treated with 500nM Jak inhibitor
  • d Quantification of anagen hair follicles in Jak-inhibitor treated tail hair follicles compared to vehicle controls.
  • FIG. 8 Colony immunofluorescence (JAK inhibitor), colony assays: additional pathway modifying drugs.
  • b Clonogenic colony forming assays of drug- treated 18-month old epidermis. Epidermal cell preparations were generated from wild type C57BI6/J mice, allowed to attach to a fibroblast feeder layer, and then treated with the Wnt-agonist BIO (500nM-luM) or Cyclopamine (1UM-5UM).
  • FIG. 10 Sorted CD34/GFP subpopulation colony assays +/- IR- a, Clonogenic colony forming assays of FACS-purified progenitor cell subpopulations.
  • Aged (3m and 18m) CD49f+-gated cells were sorted, split into 3 groups (bulge+/GFP+, bulge+/GFP-, and bulge-/GFP+), and treated +/- 500nM Jak inhibitor, b, Colony assays (as described in [a]) instead using tissue sourced from mice exposed to 5Gy whole-body irradiation for 24h.
  • stem cell is a cell that can divide and differentiate into diverse specialized cell types and that can self-renew.
  • stem cells can divide without limit and are totipotent.
  • the role of stem cells in vivo is to replace cells that are destroyed during the normal life of a multicellular organism. After division, the stem cell may remain a stem cell, become a precursor cell, or proceed to terminal differentiation.
  • embryonic stem cells found in blastocysts
  • adult stem cells found in various tissues.
  • the stem cells as referred to in the present invention are meant to be adult stem cells.
  • adult stem cells are cells that have the ability to self-renew throughout adult life and to generate progeny that undergo further differentiation.
  • a "progenitor cell” is a cell that, like a stem cell, has the capacity to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its target cell. The most important difference between stem cells and progenitor cells is that stem cells can replicate indefinitely, whereas progenitor cells can divide only a limited number of times.
  • "JAK” or Janus Activated Kinases are cytoplasmic tyrosine kinases that are either constitutively associated with cytokine receptors or recruited to receptors after ligand binding.
  • stimulation with the ligand results in the catalytic activation of receptor-associated JAKs.
  • This activation results in the phosphorylation of cellular substrates, including the JAK-associated cytokine receptor chains.
  • Some of these phosphorylated tyrosines can serve as coding sites for "STAT" proteins or Signal Transducer and Activator of Transcription proteins, which bind to the phosphotyrosines by their S C-homology 2 (SH2) domains.
  • STAT proteins are also phosphorylated on a conserved tyrosine residue, resulting in their dimerization and acquisition of high-affinity DNA-binding activity, which facilitates their action as nuclear transcription factors.
  • JAK/STAT pathway is one of the most rapid cytoplasmic to nuclear signalling mechanisms. There are a total of four JAK (JAK1-3 and tyrosine kinase 2) and seven STAT proteins (STAT 1-4, STAT5a, STAT5b and STAT6) (for review see Rawlings et al. 2004).
  • skin appendages in particular means the hair follicles, the sebaceous glands and the nails.
  • AA Alopecia Areata
  • AA a skin disease which leads to hair loss on the scalp and elsewhere. In some severe cases, it can progress to complete loss of the hair on the head or body.
  • androgenetic alopecia is known in the art and refers to an inherited condition, caused by a genetically determined sensitivity to the effects of dihydrotestosterone, which is believed to shorten the anagen phase of the hair cycle, causing miniaturisation of the follicles, and producing progressively finer hairs.
  • alopecia can also be induced by chemical agents or physical agents (e.g. during anti-cancer chemotherapy), and the condition also results from specific disease states and factors (emotional distress).
  • Alopecia typically is attributable to a disturbance in the hair renewal cycle leading to acceleration of the frequency of the cycles, which results in a shift in the population of follicles from the anagen phase to telogen.
  • the hair follicles degenerate and a decrease in the number of hairs in the affected area of the scalp or skin is observed.
  • the population of epidermal stem cells and/or progenitor cells is from mammalian origin, preferably human origin.
  • Epidermal stem cells and its progenitor cells are localized in the skin epidermis, which forms one of the two tissues of the skin (the other being the dermis, which gives the epidermis a solid support).
  • the skin epidermis is the stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections.
  • the epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behaviour.
  • the epidermis undergoes a constant turnover and distinct epidermal stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments.
  • SCs epidermal stem cells
  • epidermal stem cells and/or progenitor cells refers to one or more of the multiple populations of adult stem cells and/or progenitor cells (as defined herein) residing in different locations within epidermal tissue and are well-characterized. Under normal homeostatic conditions the stem cells in different locations maintain the differentiated lineages that are appropriate for those locations.
  • an epidermal stem cell population includes hair follicle stem cells that will maintain the hair lineages, sebaceous gland stem cells that will produce differentiated sebocytes and stem cells in the interfollicular epidermis (IFE) that will give rise to the outermost barrier layers of the epidermis.
  • IFE interfollicular epidermis
  • epidermal stem cells are multipotent and may give rise to all cell types of the hair, the epidermis and the sebaceous gland.
  • stem cells in the interfollicular epidermis can be reprogrammed to become hair follicle stem cells on sustained activation of the WNT pathway.
  • a population of epidermal stem cells as used herein includes such reprogrammed epidermal stem cells.
  • a population of epidermal stem cells and/or progenitor cells is characterized by the expression of specific markers, preferably molecular markers that distinguish them from other cell types in the epidermal tissue and allow their isolation.
  • the expression "activation of a population of epidermal stem cells and/or progenitor cells", as used herein, means, in particular maintaining, promoting and/or increasing (i) the capacity of said population of cells for self-renewal and/or their capacity to proliferate, and/or (ii) their capacity to regenerate a stratified epidermis and/or all or some of the skin appendages (sebaceous glands, hair follicle, nails, etc.).
  • Measurable parameters and/or evaluation criteria for the maintaining, promoting and/or increasing of the properties of a population of epidermal stem cells can be expressed both in a quantitative and/or qualitative way, and are known by the person skilled in the art, for example, as described in Barrandon and Green 1987, Morris et al. 2004.
  • the expression "capacity of a cell for self-renewal”, as used herein, means a cell capable of dividing so as to give two daughter cells, at least one of which is identical to the mother cell.
  • the notion of self-renewal implies the maintenance of a compartment of cells having phenotypic and functional characteristics that are constant in the course of the successive cell divisions. According to the invention, this will involve the maintenance of a compartment made up of epidermal stem cells and/or epidermal progenitors, in particular characterized by a strong proliferative potential and a capacity to generate a stratified epidermis.
  • the expression "capacity of a cell to proliferate”, as used herein, means a cell capable of multiplying to give two daughter cells, without there being necessarily transmission of the characteristics and of the potential of the mother cell to at least one of the two daughter cells.
  • the proliferation which may or may not be associated with the self-renewal phenomenon, is liable to result in the gradual decrease or the disappearance of the cellular compartment of interest within the cell population that multiplies.
  • the cell proliferation can be accompanied by a gradual decrease in and/or by the disappearance of the compartment of epidermal stem cells and/or epidermal progenitors, in particular characterized by a strong proliferative potential and a capacity to generate a stratified epidermis.
  • a JAK inhibitor is provided for use in activation of a population of hair follicle stem cells and/or progenitor cells.
  • a "population of hair follicle stem cells and/or progenitor cells” refers to a population of epidermal stem cells and/or progenitor cells that primarily resides in the bulge of the hair follicle - the bulge is defined as the attachment site of the arrector pili muscle, but may also reside above the bulge, in the isthmus, as well as in the junctional zone.
  • Hair follicle stem cells are multipotent and are able to give rise to all cell types of the hair, the epidermis and the sebaceous gland. Hair follicle stem cells, like other adult stem cells, are thought to be slow-cycling cells, with a superior clonogenicity and proliferative capacity.
  • the first marker that was used to identify stem cells in the bulge was long-term retention of a DNA label, such as tritiated thymidine or 5-bromodeoxyuridine (BrdU).
  • the first molecular marker of the bulge to be identified was keratin 15 (K15; also known as K T15).
  • markers of the bulge include CD34, SOX9, LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5), and GUI. It will be understood by the person skilled in the art that, although there is substantial overlap in the expression of the different bulge markers, the ultimate fate or function of a given cell type might differ according to the presence of one or more particular markers.
  • Molecular markers of the isthmus include LGR6 and/or PLET1 (placenta-expressed transcript 1; also known as C110RF34 and MTS24).
  • Molecular markers of the junctional zone include LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1).
  • a STAT inhibitor, a JAK inhibitor, and a JAK/STAT inhibitor are used to refer to any agent capable of down-regulating or otherwise decreasing or suppressing the amount and/or activity of JAK- STAT interactions.
  • JAK inhibitors down-regulate the quantity or activity of JAK molecules.
  • STAT inhibitors down-regulate the quantity or activity of STAT molecules. Inhibition of these cellular components can be achieved by a variety of mechanisms known in the art, including, but not limited to binding directly to JAK (for example, a JAK-inhibitor compound binding complex, or substrate mimetic), binding directly to STAT, or inhibiting the expression of the gene, which encodes the cellular components.
  • JAK/STAT inhibitors are well known in the art and are described further herein.
  • the inhibitor is a JAK inhibitor, such as a JAKl inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor.
  • the inhibitor is a STAT inhibitor, such as a STAT1 inhibitor, a STAT2 inhibitor.
  • the inhibitor is an antisense RNA that specifically inhibits the expression of the gene that encodes the JAK protein or the STAT protein; or the inhibitor is an siRNA that specifically targets the gene that encodes the JAK protein or the STAT protein; or the inhibitor is an antibody that inhibits the JAK protein or the STAT protein; or the inhibitor is a vaccine that inhibits the JAK protein or the STAT protein.
  • the inhibitor is a small molecule compound that inhibits the JAK protein or the STAT protein.
  • JAK inhibitors include any small molecule compound, antibody, siRNA or vaccine that inhibits JAK (including JAKl, JAK2, JAK3 and TYK2).
  • JAK inhibitor means any small molecule compound, antibody, siRNA or vaccine that inhibits JAK (including JAKl, JAK2 and JAK3).
  • JAK inhibitor means any small molecule compound, antibody, si NA or vaccine that inhibits JAKl.
  • JAK inhibitor means any small molecule compound, antibody, siRNA or vaccine that inhibits JAK2.
  • “JAK inhibitor” means any small molecule compound, antibody, siRNA or vaccine that inhibits JAK3. In another embodiment, “JAK inhibitor” means any small molecule compound, antibody, siRNA or vaccine that inhibits JAK1/2. In a further embodiment, the term “JAK inhibitor” means any small molecule compound that inhibits JAK (including JAKl, JAK2, JAK3 and TYK2). In an embodiment, “JAK inhibitor” means any small molecule compound that inhibits JAK (including JAKl, JAK2 and JAK3). In another embodiment, “JAK inhibitor” means any small molecule compound that inhibits JAKl. In another embodiment, “JAK inhibitor” means any small molecule compound that inhibits JAK2. In another embodiment, “JAK inhibitor” means any small molecule compound that inhibits JAK3. In another embodiment, “JAK inhibitor” means any small molecule compound that inhibits JAK 1/2.
  • JAK inhibitors include phenylaminopyrimidine compounds (WO2009/029998), substituted tricyclic heteroaryl compounds (WO2008/079965), cyclopentyl-propanenitrile compounds (WO2008/157208 and WO2008/157207), indazole derivative compounds (WO2008/114812), substituted ammo- thiophene carboxylic acid amide compounds (WO2008/156726), naphthyridine derivative compounds (WO2008/112217), quinoxaline derivative compounds (WO2008/148867), pyrrolopyrimidine derivative compounds (WO2008/119792), purinone and imidazopyridinone derivative compounds (WO2008/060301 ), 2,4-pyrimidinediamine derivative compounds (WO2008/118823), deazapurine compounds (WO2007/117494) and tricyclic heteroaryl compounds (WO2008/079521).
  • JAK inhibitors include compounds disclosed in the following publications: US2004/176601, US2004/038992, US2007/135466, US2004/ 102455, WO2009/054941, US2007/134259, US2004/265963, US2008/194603, US2007/207995, US2008/260754, US2006/063756, US2008/261973, US2007/142402, US2005/159385, US2006/293361, US2004/205835, WO2008/148867, US2008/207613, US2008/279867, US2004/09799, US2002/055514, US2003/236244, US2004/097504, US2004/147507, US2004/ 176271, US2006/217379, US2008/092199, US2007/043063, US2008/021013, US2004/ 152625, WO2008/079521, US2009/186815, US2007/203142, WO2008/144011, US2006/270694 and US2001/044442.
  • JAK inhibitors further include compounds disclosed in the following publications: WO2003/011285, WO2007/145957, WO2008/156726, WO2009/035575, WO2009/054941, and WO2009/075830. JAK inhibitors further include compounds disclosed in the following patent applications: US Serial Nos. 61/137475 and 61/134338. Specific JAK inhibitors include Jak2-IA, AG490, Pyridone 6, WP1066, LS104, TG101209, TG101348, CP690,550, CP352,664, INCB18424, WHI-PI 54, CMP6, SB1518, XLOI 9, CEP-701 , INCB20, AUB-6-96 and AZ960.
  • the present invention envisages a JAK inhibitor that inhibits JAK3 for use in the activation of a population of epidermal stem cells and/or progenitor cells.
  • a JAK inhibitor that inhibits JAK3 for use in the activation of a population of epidermal stem cells and/or progenitor cells.
  • Pyrimidine derivatives exhibiting JAK3 kinase inhibiting activities are described in WO2008/009458.
  • Pyrimidine compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3 are described in WO2008/118822 and WO2008/118823.
  • Fluoro-substituted pyrimidine compounds as JAK3 inhibitors are described in WO 2010/118986.
  • a particularly preferred example of a JAK3 inhibitor includes CP690,550 (tofacitinib, also called tasocitinib).
  • JAK inhibitors for stimulating the regenerative power of the epidermal stem cells and/or progenitor cells capable of generating a stratified epidermis and/or all or some of the skin appendages, in "anti-aging” or “anti-hair loss” cosmetic compositions, and/or for preparing pharmaceutical compositions suited for skin regeneration and/or wound healing, is therefore apparent.
  • the JAK inhibitors as described herein that are capable of activating epidermal stem cells and/or progenitor cells are particularly suited to: i. Stimulate the renewal of the epidermis and/or of all or some of the skin appendages; in particular the treatment of burns;
  • ii. Prevent and/or combat cutaneous signs of aging, in particular thinning of the skin and/or loss of firmness, of elasticity and/or of tonicity of the skin, and/or the formation of wrinkles and fine lines; and/or smooth out the microrelief of the skin in order to give it once again a young, smooth and firm appearance;
  • JAK inhibitors as described herein for use in cosmetic and/or pharmaceutical applications, preferably dermatological applications such as skin repair and regeneration, promoting hair growth, treatment of hair-loss disorders, wound repair, and other skin-related conditions.
  • the JAK inhibitors as described herein can be useful for stimulating hair growth, and/or for the treatment of a hair-loss disorder, thus for retaining hair or reducing hair loss.
  • the anagen phase is a period of growth lasting for two to six years. During this time, the follicle is long and deep, and produces thick, well-pigmented hair. Usually, about 90% of all scalp hairs are in the anagen phase at a given time.
  • This growth phase is followed by the catagen phase for few weeks, which corresponds to the follicle base shrinking.
  • the resting period, or telogen phase lasts for two to four months. In this phase, the follicle withers even further. Following the telogen phase, the next anagen phase begins, and old hair is dislodged and falls out to make room for a new hair.
  • hair-loss disorder refers herein to alopecia such as alopecia areata and androgenetic alopecia as well as hair loss caused by other factors (all as defined herein).
  • the uses of JAK inhibitors as described herein embrace promoting new hair growth, promoting hair growth before, during or after chemotherapy, promoting hair growth in hair transplant patients, preventing, stopping or minimizing hair fall out.
  • the JAK inhibitors as described herein are particularly useful for hair follicle regeneration.
  • hair follicle regeneration refers to the renewal and/or activation of one or more regions and/or cell populations of the hair follicle so that the regenerated hair follicles can repeat the hair cycle. In particular, the regeneration occurs through the activity of epidermal stem cells.
  • the JAK inhibitors for use according to the invention will be in any of the pharmaceutical forms normally used in the cosmetics and dermatological fields, suitable for oral, transdermal, subcutaneous or topical administration to a site in need thereof, such as epidermal tissue, in particular the skin, the hair, or the scalp.
  • compositions of JAK inhibitors as described herein and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the condition or disease to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the condition or disease state is achieved.
  • a formulation suitable for oral administration may be in the form of pills, gelatine capsules, gels, emulsions, tablets, capsules or liquid solutions, in particular oral ampoules, for example.
  • the active agent(s) according to the invention may be incorporated into any other forms of food supplements or enriched foods, for example food bars, or compacted or non-compacted powders.
  • the effective amount of JAK inhibitor present in the composition ranges from 10 "12 % to 1% of the total weight of the composition, preferably from 10 "9 % to 0.1%, and even more preferably from 10 "7 % to 0.01% of the total weight of the composition.
  • the invention features compositions comprising JAK inhibitors suitable for topical application to a site in need thereof, such as epidermal tissue, in particular the skin or the scalp, comprising, in a physiologically acceptable medium, at least an effective amount of a JAK inhibitor as described herein.
  • physiologically acceptable medium means a medium which is compatible with epidermal tissue, in particular the skin or the scalp, and/or its integuments (eyelashes, nails, hair) and/or the mucous membranes (lips).
  • compositions according to the invention are cosmetic compositions or pharmaceutical compositions.
  • the pharmaceutical compositions will preferably be dermatological compositions.
  • the effective amount of a JAK inhibitor as described herein present in the composition preferably ranges from 10 "12 % to 1% of the total weight of the composition, 10 "9 % to 0.1%, and even more preferably from 10 "7 % to 0.01% of the total weight of the composition.
  • the composition may in particular be in the form of an aqueous, optionally gelled, solution, of a dispersion of the lotion type, optionally two-phase lotion, of an emulsion obtained by dispersion of a fatty phase in an aqueous phase (O/W) or conversely (W/O), or of a triple emulsion (W/O/W or 0/W/O) or of a vesicular dispersion of the ionic and/or non-ionic type.
  • a dispersion of the lotion type optionally two-phase lotion
  • W/O triple emulsion
  • W/O/W or 0/W/O a vesicular dispersion of the ionic and/or non-ionic type.
  • the JAK inhibitor for use according to the invention may also be formulated in compositions suitable for targeting to the deep layers of the epidermis, in particular for targeting to the basal layers of the epidermis or to the pilosebaceous unit.
  • the JAK inhibitor may be (i) encapsulated in a coating such as microspheres, nanospheres, oleosomes or nanocapsules, or (ii) compartmentalized in a fatty phase containing the main constituents of sebum (squalene, triglycerides, aliphatic waxes, cholesterol waxes and free cholesterol), or structural constituents present in proportions similar to those present in sebum.
  • Particles called nanoparticles are in fact capable of crossing the superficial layers of the stratum corneum and/or of the follicular ostium, and of penetrating into the layers of the epidermis.
  • the advantage of a composition in which the fatty phase mimics the composition of sebum is to allow better availability of the active agent at the target organ, i.e., at the sebaceous gland.
  • the composition may have, for example, the appearance of a white or coloured cream, of an ointment, of a milk, of a lotion, of a gel, of a serum, of a paste or of a foam, or may be in solid form (for example: stick) for application to the skin and/or the mucous membranes, such as the lips. It may also be in the form of a lotion of the aqueous, aqueous-alcoholic or oily solution type, of an oil-in-water or water-in- oil or multiple emulsion, or of an aqueous or oily gel, or any other form suitable for application to skin, the mucous membranes or the scalp.
  • compositions according to the invention may also contain the adjuvants that are usual in the cosmetics or dermatological field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, fragrances, fillers, screening agents, pigments, odour absorbers and dyestuffs.
  • the amounts of these various adjuvants are those conventionally used in the field under consideration, and are, for example, from 0.01 to 20% of the total weight of the composition.
  • These adjuvants depending on their nature, can be introduced into the fatty phase, into the aqueous phase or into the lipid vesicles. In any event, these adjuvants, and also the proportions thereof, will be chosen so as not to harm the desired properties of the JAK inhibitor.
  • the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition.
  • the oils, the emulsifiers and the co-emulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration.
  • the emulsifier and the co-emulsifier are present, in the composition, in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.
  • oils that can be used in the invention mention may be made of hydrocarbons of mineral or synthetic origin (liquid petroleum jelly, isohexadecane), oils of plant origin (apricot kernel oil, liquid fraction of karite butter, avocado oil, soybean oil), oils of animal origin (lanolin), synthetic oils (perhydrosqualene, pentaerythrityl tetraoctanoate), silicone oils (cylcopentasiloxane and cyclohexasiloxane) and fluoro oils (perfluoro-polyethers).
  • hydrocarbons of mineral or synthetic origin liquid petroleum jelly, isohexadecane
  • oils of plant origin apricot kernel oil, liquid fraction of karite butter, avocado oil, soybean oil
  • oils of animal origin lanolin
  • synthetic oils perhydrosqualene, pentaerythrityl tetraoctanoate
  • silicone oils cylcopentasiloxane and cyclohexasilox
  • fatty alcohols cetyl alcohol or stearyl alcohol
  • fatty acids stearic acid
  • waxes carboxymethylcellulose, stearate
  • emulsifiers and co-emulsifiers that can be used in the invention, mention may be made, for example, of fatty acid esters of polyethylene glycol, such as PEG-100 stearate and PEG-20 stearate, and fatty acid esters of glycerol, such as glyceryl stearate.
  • hydrophilic gelling agents mention in particular may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.
  • carboxyvinyl polymers carboxyvinyl polymers
  • acrylic copolymers such as acrylate/alkyl acrylate copolymers
  • polyacrylamides polysaccharides
  • lipophilic gelling agents mention may be made of modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.
  • esters of para-hydroxybenzoic acid octane-l,2-diol, iodo-3- propynyl-2-butyl carbamate
  • fillers mention may be made, for example, of particles of polyamide (Nylon); microspheres of poly(methyl methacrylate); powders of ethylene-acrylate copolymer; expanded powders such as hollow microspheres, and in particular the microspheres made of a terpolymer of vinylidene chloride, of acrylonitrile and of methacrylate and sold under the name Expancel by the company Kemanord Plast; powders of natural organic materials such as starch powders, in particular powders of corn starch, of wheat starch or of rice starch, which may or may not be crosslinked, such as the powders of starch crosslinked with octenyl succinate anhydride; silicone resin microbeads such as those sold under the name Tospearl by the company Toshiba Silicone; silica; metal oxides such as titanium dioxide or zinc oxide; mica; and mixtures thereof.
  • polyamide Nylon
  • powders of ethylene-acrylate copolymer
  • solvents mention may be made of hydrophilic organic solvents, lipophilic organic solvents, amphiphilic solvents or mixtures thereof.
  • hydrophilic organic solvents mention may be made, for example, of linear or branched lower monoalcohols having from 1 to 8 carbon atoms, such as ethanol, propanol, butanol, isopropanol or isobutanol, optionally oxyethylenated polyethylene glycols, polyols such as propylene glycol, isoprene glycol, butylene glycol, glycerol, sorbitol and its derivatives, glycol ethers and propylene glycol ethers.
  • compositions comprising JAK inhibitors for use according to the invention can also be applied via transdermal delivery systems, which slowly release the active compound for percutaneous absorption.
  • Permeation enhancers can be used to facilitate transdermal penetration of the active factors in the conditioned media. Transdermal patches are described in, for example and without limitation, US Patent No. 5,948,433; US Patent No. 5,407,713; US Patent No. 5,352,456; US Patent No. 5,336,168; US Patent No. 5,290,561.
  • subcutaneous administration can refer to administration just beneath the skin (i.e. beneath the dermis).
  • the subcutaneous tissue is a layer of fat and connective tissue that houses larger blood vessels and nerves. The size of this layer varies throughout the body and from person to person.
  • the interface between the subcutaneous and muscle layers can be encompassed by subcutaneous administration. This mode of administration can be feasible where the subcutaneous layer is sufficiently thin so that the factors present in the compositions can migrate or diffuse from the locus of administration and contact the epidermal cells.
  • the compositions comprising a JAK inhibitor for use according to the invention may additionally comprise one or more other active agent.
  • moisturizers As “hydrophilic or lipophilic active agents” mention may be made of moisturizers, calmatives, depigmenting agents, anti-glycation agents, NO-synthase inhibitors, agents for stimulating the synthesis of dermal or epidermal macromolecules and/or for preventing their degradation, agents for stimulating fibroblast and/or keratinocyte proliferation or for stimulating keratinocyte differentiation, dermo-decontracting agents, tensioning agents, anti-pollution agents and/or free-radical scavengers, photoprotective agents, repairing and/or cicatrizing agents, antidandruff agents, and mixtures thereof.
  • a method for activating epidermal stem cell populations and/or epidermal progenitor cells comprising contacting epidermal tissue or cells with an effective amount of a JAK inhibitor, in particular a JAK inhibitor that inhibits JAK3.
  • a method for stimulating hair growth and/or treating a hair-loss disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a JAK inhibitor, in particular a JAK inhibitor that inhibits JAK3, formulated in a physiological acceptable medium.
  • a JAK inhibitor in particular a JAK inhibitor that inhibits JAK3, formulated in a physiological acceptable medium.
  • a variety of subjects are treatable according to the methods of the invention.
  • Such subjects are mammals or mammalian, where these terms are used broadly to describe organisms which are within the class Mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys).
  • the subjects will be humans.
  • a method for skin regeneration or for wound healing comprising applying to a site in need thereof an effective amount of a JAK inhibitor, in particular a JAK inhibitor that inhibits JAK3, formulated in a physiological acceptable medium.
  • a site in need thereof refers to the site of injury or the site for intended repair or regeneration of skin.
  • Example 1 The hair follicle stem cell population increases during aging
  • Keratin-15 (Krt-15) positive hair follicle cells are one of the best-characterized stem cell populations in the skin. Specifically, studies using Krt-15-promoter reporter mouse models have demonstrated that these cells possess stem cell properties, as they are label retaining cells with multipotent capacity, contributing to hair follicle cycling, sebaceous gland function and wound repair (Morris et al. 2004; Ito et al. 2005; Petersson et al. 2011). In agreement with published work, whole-mount immunostaining for GFP in the tails of young Krt-15-GFP reporter mice confirmed these cells as a subset of the Krt-15 protein-expressing fraction, with the GFP reporter identifying the most primitive compartment (Morris et al.
  • Example 2 The functional capacity of the hair follicle stem cell population declines with aging
  • Example 3 Comparative expression analysis of hair follicle stem cell population during aging.
  • Example 5 JAK inhibitors restore stem cell functioning and hair follicle status in vivo
  • Chemical activators/inhibitors were used as follows: pyridone-6 (Calbiochem, 50-500nM), DAPT (Sigma, 1-lOuM), BIO (Cayman Chemical, 500nM-luM), IWR-1 endo and exo (Cayman Chemical, l-5uM), Cyclopamine (Calbiochem, l-5uM), Tofacitinib (Selleck Chemicals, 80-400nM), Ruxolitinib (Selleck Chemicals, 80-400nM). To visualize clonogenic keratinocyte expansion, co-cultures were fixed in 10% formalin, stained with a crystal violet/methanol, and imaged using conventional scanning and imaging tools.
  • Back skin and/or tail skin was fixed in 10% NBF (Sigma-Aldrich) overnight, washed in PBS, then embedded in paraffin. Deparaffinized sections were boiled for 10 min in 0.01 M citric acid for antigen retrieval. Primary antibodies were incubated overnight at 4 °C, and secondary antibodies were incubated for 2h at room temperature in 0.25% gelatin/PBS. Nuclei were stained with DAPI (1:10000, Roche), and the slides were mounted in Vectashield (Vector labs).
  • Anti-keratin 15 MS-1068-P1, NeoMarkers, 1:200
  • anti-Ki67 abl5580, Abeam, 1:200
  • anti-GFP A11122, Invitrogen 1:200
  • anti-CD34 560233, BD Biosciences, 1:50
  • anti-ICAM-1 4915, Cell Signaling, 1:50
  • anti-Stat3 9132, Cell Signaling, 1:50
  • anti-p-Stat3 Teyr705
  • Epidermal cells from back skin of Keratin-15-GFP or wild type C57BI6/J mice were isolated as described above. Cell suspensions were incubated for 30min on ice with the following antibodies at the given dilutions: APC-conjugated anti-CD34 (1:200, clone RAM34, BD Pharmingen), and FITC-conjugated anti- a6-integrin (1:200, CD49f clone NKI-GoH3, Serotec). Keratinocytes were sorted on the basis of single cellularity, viability (DAPI), GFP positivity (Keratin-15+) and/or CD34/CD49f status.
  • FACS purification of was performed on a FACS Aria system equipped with FACS DiVa software (BD Bioscience). Sorted cells were collected in keratinocyte medium supplemented to 50% FBS, and either plated for clonogenic assays or pelleted and stored at -80C for RNA isolation. FACS analysis was performed using LSRII FACS Analysers (BD Biosciences) and analysed using Flowjo software. RNA-seq and analysis
  • RNA from cultured or FACS-sorted cells was purified using the RNeasy Micro or Mini Kit (Qiagen). Equal amounts of RNA were reverse-transcribed using random hexamer priming and Superscript III (Invitrogen). RT-qPCR was performed with SYBR Green Master Mix (Roche) and gene-specific primers (sequences provided in Table 1) using a Light Cycler 480 Instrument (Roche). Relative levels of expression were determined using the AAQ method relative to the housekeeping gene actin.
  • Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell 9(1): 121-131.

Abstract

La présente invention concerne des procédés d'activation de cellules souches épidermiques et/ou de cellules progénitrices par interférence avec la voie de signalisation JAK/STAT. La présente invention concerne plus spécifiquement des inhibiteurs de JAK pour leur utilisation dans l'activation des cellules souches épidermiques et des applications cosmétiques ou pharmaceutiques en étant dérivées, par exemple la promotion de la croissance capillaire, le traitement des troubles de perte des cheveux, la réparation et la régénération de la peau.
PCT/EP2013/065177 2012-07-18 2013-07-18 Inhibiteurs de jak pour l'activation de populations de cellules souches épidermiques WO2014013014A1 (fr)

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WO2017112990A1 (fr) * 2015-12-28 2017-07-06 Natura Cosméticos S.A. Composition de lipides de plante pour stimuler la croissance des cheveux, procédé de stimulation de la croissance des cheveux et utilisations desdits lipides de plante
WO2017155325A1 (fr) * 2016-03-09 2017-09-14 울산대학교 산학협력단 Composition destinée à la prolifération, à la promotion de la différenciation, ou à l'inhibition de la sénescence de cellules souches, contenant l'inhibiteur jak1 comme ingrédient actif
CN107847428A (zh) * 2015-05-07 2018-03-27 纽约市哥伦比亚大学理事会 用于促进毛发生长的方法和组合物
US20190231782A1 (en) * 2018-01-31 2019-08-01 Twi Pharmaceuticals, Inc. Topical formulations comprising tofacitinib
CN110423719A (zh) * 2018-05-01 2019-11-08 云南济慈再生医学研究院有限公司 调控Jak-Stat通路使细胞分化、去分化、年轻化的技术及其应用
CN110423721A (zh) * 2018-05-01 2019-11-08 云南济慈再生医学研究院有限公司 一种年轻化的修复型成纤维细胞的制备方法及其应用

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