Active agents for regulating hair growth

Abstract

In order to provide a novel agent for the active control of hair growth in a subject, the present invention proposes an active agent for regulating hair growth, especially for treating hair growth (stimulation or inhibition), wherein the active agent activates, enhances, inactivates, blocks or attenuates the cellular response of the olfactory receptor OR10J1 or interferes with the expression of the receptor. Furthermore, the present invention relates to a composition for treating hair growth as a cosmetic or pharmaceutical or dietary supplement, which comprises at least one of the above-mentioned active agents and at least one auxiliary agent. Furthermore, a non-therapeutic method for regulating hair growth is disclosed, wherein an effective amount of at least one of the above-mentioned active agents is administered to a subject.

Description

[0001] This invention relates to an active agent for regulating hair growth, particularly for treating hair growth, wherein the active agent modulates the activity of olfactory receptors, including but not limited to activating, enhancing, inactivating, blocking, or weakening the cellular response of olfactory receptors, or interfering with the expression of said receptors. Furthermore, this invention relates to a composition comprising at least one of the above-described active agents, and a non-therapeutic method for regulating hair growth, wherein an effective amount of at least one of the above-described active agents is administered to a subject.

[0002] Hair follicles form only once in the lifetime of a healthy mammal, and the number of follicles is determined in the womb. Follicle morphogenesis refers to the formation of the complete structure of the hair follicle from the epidermis and mesoderm. After birth, hair follicles undergo lifelong cyclical changes, successively experiencing a rapid growth phase (anagen phase), a regression phase (catagen phase), and a relatively quiescent phase (telogen phase). These phases can be classified according to morphological indicators and molecular markers.

[0003] Many common and rare conditions are associated with hair follicles and their growth cycle, such as non-scarring alopecia, scarring alopecia, chronic hair shedding, acute hair shedding, hypertrichosis, or hirsutism. In addition, many other conditions require controlling unwanted hair on the body or promoting hair growth in certain areas, such as drug-induced hair loss (e.g., chemotherapy), radiation-induced hair loss (e.g., radiotherapy), and unwanted hair growth caused by drugs such as cyclosporine A or diazoxide.

[0004] To treat hair loss disorders, existing technologies offer treatments such as corticosteroids, hormone modulators, and immunosuppressants, but these are all associated with significant undesirable side effects. Piperidine-pyrimidine derivatives like minoxidil and anthracene derivatives like dithranol, which have been reported to promote hair growth, also present similar problems.

[0005] EP 3766545 B1 discloses promising active agents for the active control of hair growth in subjects, wherein the active agents activate, enhance, inactivate, block or attenuate the cellular response of the taste receptor TAS2R4, or interfere with the expression of the receptor.

[0006] In the process of continuously exploring active agents that can actively control and regulate hair growth in subjects, the inventors of this invention discovered that the olfactory receptor OR10J1 is involved in the regulation and control of hair growth.

[0007] In particular, the inventors of this application have discovered that OR10J1 agonists can promote the growth phase of hair follicles and increase their elongation. Furthermore, the inventors' findings reveal that OR10J1 expression is increased in the basal CD34+ region in the presence of an OR10J1 receptor agonist.

[0008] In summary, the inventors of this application have discovered that applying activators that activate, enhance, inactivate, block, or weaken the cellular response of OR10J1 receptors or interfere with the expression of olfactory receptor OR10J1 can effectively regulate hair growth.

[0009] "Olive receptors" are chemoreceptors, typically expressed on the cell membrane of olfactory receptor neurons, and responsible for detecting odor molecules. Olfactory receptors form a multi-gene family, consisting of approximately 400 genes in humans. The reason for the existence of so many different olfactory receptors is to provide a system for distinguishing as many different odor molecules as possible, enabling the characterization of even "unknown" molecules.

[0010] "OR10J1" is the official gene symbol for "member J of the olfactory receptor type 10 subfamily". It identifies the protein encoded by the human OR10J1 gene (NCBI gene ID: 26476; HGNC: OR10J1; NCBI mRNA sequence: NC_000001.11; NCBI protein sequence: ALI87856.1).

[0011] According to an alternative of the invention, an active agent that activates, enhances, inactivates, blocks, or weakens the cellular response of the olfactory receptor OR10J1 is used to treat, regulate, or modulate hair growth, wherein the active agent is an agonist or antagonist of the olfactory receptor OR10J1.

[0012] Agents that activate, enhance, inactivate, block, or attenuate cellular responses to receptors are receptor agonists or antagonists / reverse agonists. An "agonist" is a substance that binds to a receptor and activates or enhances the receptor to produce a cellular response. An "antagonist" is a substance that binds to a receptor and blocks or attenuates the cellular response to an agonist, rather than activating or enhancing the receptor like an agonist. A "reverse agonist" is a substance that binds to a receptor and inactivates the cellular response to an agonist, rather than activating or enhancing the receptor like an agonist.

[0013] Therefore, the agonist of the olfactory receptor OR10J1 of the present invention activates or enhances the OR10J1 receptor to generate a cellular response; while the antagonist of the olfactory receptor OR10J1 of the present invention blocks or weakens the response of the OR10J1 receptor to endogenous agonists; and the inverse agonist of the olfactory receptor OR10J1 of the present invention inactivates the response of the OR10J1 receptor to endogenous agonists, thereby generating a cellular response.

[0014] In those embodiments where the active agent is an agonist of the olfactory receptor OR10J1, the active agent is used to treat unwanted hair growth. In those embodiments where the active agent is an antagonist / reverse agonist of the olfactory receptor OR10J1, the active agent is used to treat unwanted hair loss.

[0015] In a specific embodiment of the present invention, the olfactory receptor agonist / antagonist / reverse agonist used is 2,6-dimethylhept-2-ol, a natural odor molecule with a citrus aroma, which has been shown to increase intracellular calcium concentration in Hana3A cells transfected with the OR10J1 receptor, and is therefore classified as an OR10J1 agonist.

[0016] In other specific embodiments of the invention, the olfactory receptor agonist / antagonist / reverse agonist used is an OR10J1 agonist selected from: trimethylcyclopentan-3-enylbutane-1-ol compounds, wherein the butane-1-ol residues are saturated or monounsaturated and substituted by one or more methyl residues, such as 2-methyl-4-(2,2,3-trimethylcyclopentan-3-enyl)butane-1-ol, 2-ethyl-4-(2,2,3-trimethylcyclopentan-3-enyl)butane-2-en-1-ol, 3-methyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentane-4-en-2-ol and 3,3-dimethyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentane-4-en-2-ol (e.g., DE 10 2005 026). (as disclosed in 801), or selected from trimethylcyclopent-3-enyl-cyclohexenyl compounds, such as 1-[4-(2,2,3-trimethylcyclopent-3-enyl)-cyclohex-3-enyl]-ethanol, 1-[3-(2,2,3-trimethylcyclopent-3-enyl)-cyclohex-3-enyl]-ethanol, [4-(2,2,3-trimethylcyclopent-3-enyl)-cyclohex-3-enyl]-methanol and [3-(2,2,3-trimethylcyclopent-3-enyl)-cyclohex-3-enyl]-methanol (as disclosed in US 5,189,013).

[0017] Alternatively, an OR10J1 agonist is an aptamer that binds to the OR10J1 receptor and activates or enhances the receptor to produce a cellular response.

[0018] As used in this article, "aptamer" refers to a DNA, RNA, or XNA oligonucleotide or peptide molecule that binds to a specific target molecule, such as a receptor molecule.

[0019] In other embodiments of the invention, the olfactory receptor agonist / antagonist / reverse agonist used is a low molecular weight OR10J1 antagonist / reverse agonist. Alternatively, the OR10J1 antagonist / reverse agonist is an aptamer that binds to and inactivates, blocks, or attenuates the OR10J1 receptor to produce a cellular response.

[0020] Even if the inventor is unaware of such circumstances, it cannot be ruled out that there exist prior art compositions for treating hair growth containing one of the specific active agents of the present invention as an ingredient, without specifying any effect of said ingredient on OR10J1. In such cases, the previously disclosed active agent can be excluded from the scope of the present invention by a corresponding waiver declaration. Apart from excluding the specific previously disclosed active agent, the waiver declaration should not further affect the scope of the claims.

[0021] Non-limiting examples of previously disclosed surfactants in the prior art include: - The corresponding existing technology does not impart any medical, pharmacological, or biologically active chemical substances; - Compared to the specific active agents disclosed herein, the corresponding prior art imparts another medically, pharmacologically, or biologically active chemical substance; and / or -Compared to the specific active agent of this invention disclosed herein, the corresponding prior art confers the same medical, pharmacological or biological activity, but is a chemical substance that does not involve OR10J1 but involves other targets (e.g., receptors, enzymes, hormones, metabolites).

[0022] According to an alternative embodiment of the invention, an active agent that interferes with the expression of the olfactory receptor OR10J1 is used to regulate hair growth. The active agent that interferes with the expression of the olfactory receptor OR10J1 is a miRNA, siRNA, or ribozyme that targets the OR10J1 gene or the mRNA corresponding to the OR10J1 gene.

[0023] The term "miRNA" refers to microRNAs, small non-coding RNA molecules containing 18 to 25 nucleotides that function in RNA knockdown and post-transcriptional regulation of gene expression. miRNAs function by pairing with complementary base sequences within the mRNA molecule. Therefore, these mRNA molecules can be knocked down due to mRNA cleavage, instability, and / or reduced translation efficiency.

[0024] The term "siRNA" refers to small interfering RNA, which is a small non-coding RNA molecule with a length of 18 to 25 base pairs. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA post-transcriptionally, thereby preventing translation.

[0025] According to the present invention, the gene is "targeted" by miRNA, siRNA, or ribozyme when miRNA, siRNA, or ribozyme molecules selectively reduce or inhibit the expression of OR10J1. The phrase "selectively reduce or inhibit" as used herein refers to miRNA, siRNA, or ribozyme that affects the expression of OR10J1.

[0026] In a specific embodiment of the invention, miRNA or siRNA interferes with the gene expression of the olfactory receptor OR10J1 by hybridizing with the gene transcript (i.e., OR10J1 mRNA) under stringent conditions. Hybridization under stringent conditions means annealing with the target mRNA region under standard conditions (e.g., high temperature (e.g., <60°C for 2 hours) and / or low salt concentration (e.g., 0.1 × SSC)), conditions that are generally unfavorable for hybridization.

[0027] According to the present invention, one of the above-described active agents is used to treat hair growth. In specific embodiments of the invention, the treatment is performed locally, i.e., within the skin area to be treated, on the surface of the skin area, or at the skin area. In some embodiments of the invention, the treatment is performed locally, wherein the term "local" refers to drug treatment applied to a specific location on the skin and / or its appendages (e.g., hair). In specific embodiments, local application is epidermal administration, meaning the agonist or antagonist is applied directly to the skin. In other embodiments of the invention, the treatment is transdermal, wherein the term "transdermal" refers to the application of drug treatment through the stratum corneum to deeper layers of the skin, for example, via standard needles or microneedles. In other embodiments of the invention, the treatment is performed via skin appendages, wherein the term "via skin appendages" means the application of the formulation through skin appendage structures (e.g., hair follicles, sebaceous glands, and sweat glands) to deeper layers of the skin. In yet another embodiment of the invention, the treatment is performed orally, in the form of, for example, capsules or tablets, or as a dietary supplement beverage.

[0028] As used herein, the term "treatment" refers to any action that alters a person's physical condition. Specifically, "treatment of hair growth" refers to any change to an initial hair growth condition, such as excessive or insufficient hair growth, slow or rapid hair growth, chemotherapy-induced hair loss, drug-related hair loss, and radiation-related hair loss. In other words, this invention relates to any type of regulation of hair growth.

[0029] In a specific embodiment of the present invention, the above-mentioned active agent is used as a cosmetic for treating hair growth. Specifically, its use as a cosmetic is not for therapeutic purposes, but to achieve a change in the initial hair growth condition, such as excessive hair, insufficient hair, or hair growth that is too slow / too fast, wherein the initial condition is not caused by disease or disorder.

[0030] In those embodiments, when the above-described active agent is used in cosmetics, the active agent used should be cosmetically acceptable, wherein "cosmetically acceptable" means that the active agent should not have toxicity, harmfulness or any other harmful side effects when applied to hair and / or skin.

[0031] In some specific embodiments of the present invention, the above-mentioned active agent is used as a dietary supplement to regulate hair growth.

[0032] In other specific embodiments of the invention, the above-described active agent is used as a medicament for the topical treatment of hair growth disorders, wherein the term "disorder" refers to any functional abnormality or disorder of normal health, and the term "medicament" refers to a substance that can be used to cure, treat, or prevent the disorder.

[0033] In some embodiments, the above-described active agent is used as a medicament for the topical treatment of hair growth disorders selected from the group consisting of: non-scarring alopecia, such as alopecia areata, telogen effluvium, androgenetic alopecia, and anagen effluvium; scarring alopecia, such as cutaneous lichenplanopilaris, discoid lupus erythematosus, dissecting cellulitis, and folliculitis decalvans; hirsutism and female hirsutism.

[0034] In those embodiments, when the above-described active agent is used as a drug, the active agent used should be pharmaceutically acceptable, wherein "pharmaceutically acceptable" means that the active agent should not have toxicity, harmfulness or any other harmful side effects when applied to hair and / or skin.

[0035] In some embodiments, at least one of the active agents of the present invention is used as an ingredient in a composition used as a cosmetic, dietary supplement, or medicine for treating hair growth, the composition further comprising at least one adjuvant selected from the group consisting of a carrier, a recipient, an adjuvant, a diluent, a penetration enhancer, and a disintegrant.

[0036] In specific embodiments of such compositions, the adjuvant is selected from the group consisting of liposomes, nanoparticles, carboxymethyl cellulose, hydroxyethyl cellulose, mineral oil, petrolatum, glycerin, polysorbate 80, hydroxyethyl starch, dextran, and polyethylene glycol.

[0037] In the compositions of the present invention, the concentration of the surfactant is typically in the range of 10 to 10,000 µM. In some embodiments, the lower limit of the surfactant concentration is 30 µM or even 100 µM. In some embodiments, the upper limit is 3,000 µM or 1,000 µM. Preferred ranges are thus derived, such as 30 to 10,000 µM, 30 to 3,000 µM, 10 to 3,000 µM, 100 to 3,000 µM, etc.

[0038] With respect to the total weight of the composition of the present invention, the concentration of the active agent may vary in the range of 0.001 to 30 wt.% in specific embodiments. In some embodiments, the lower limit is 0.01 wt.%, 0.1 wt.%, or even 1 wt.%. In some embodiments, the upper limit is 20 wt.%, 10 wt.%, or even 5 wt.%. Preferred ranges are thus derived, such as 0.001 to 10 wt.%, 0.01 to 5 wt.%, 0.01 to 20 wt.%, 1 to 30 wt.%, etc.

[0039] In a specific embodiment, such a composition also includes at least one other commonly used active agent that is effective in treating hair growth.

[0040] In such embodiments, other active agents may be selected from hair growth inhibitors, such as active agents that activate, enhance, inactivate, block or weaken the cellular response to the taste receptor TAS2R4 or interfere with the expression of the receptor, as disclosed in the aforementioned EP3 766 545 B1.

[0041] In other embodiments, other active agents may be selected from ornithine decarboxylase inhibitors (including difluoromethylornithine (DFMO)), anti-androgen compounds, 5α-reductase inhibitors, androgen receptor inhibitors, S-adenosylmethionine decarboxylase inhibitors, gamma-glutamyl transpeptidase inhibitors, adenosylsuccinate synthase inhibitors, aspartate transcarbamoylase inhibitors, transglutaminase inhibitors, L-asparagine synthase inhibitors, pantothenic acid and its analogues, thiol-reactive compounds, lipoxygenase inhibitors, cyclooxygenase inhibitors, nitric oxide synthase inhibitors, ornithine aminotransferase inhibitors, and cysteine ​​synthesis pathways. Inhibitors of phosphatase, protein kinase C inhibitors, catechin compounds, green tea polyphenols, nonsteroidal angiogenesis inhibitors, arginase inhibitors, inhibitors of the glucose-to-acetyl-CoA metabolic pathway, compounds that inhibit the formation of glycoproteins, proteoglycans and glycosaminoglycans, matrix metalloproteinase inhibitors, cholesterol synthesis pathway inhibitors, DNA topoisomerase inhibitors, aminoacyl-tRNA synthetase inhibitors, hydroxybutyric acid (HbA1c) biosynthesis pathway inhibitors, compounds that activate androgen binding, alkaline phosphatase inhibitors, protein tyrosine kinase inhibitors, and compounds that increase cellular ceramide levels. Specific examples include: cyproterone acetate, progesterone, azithromycin, anthglutinin, L-aranoxin, guanidinosuccinic acid, ethacrynic acid, D-pantothenic acid, panthenol, gabaculin, canaline, isoniazid, verapamil, phentolamine, pentosan sulfate, nafoxidin, tropine, octapine, phloretin, argaric acid, simvastatin, atorvastatin, lovastatin, fluvastatin, mevastatin, N... G -Methyl-L-arginine, NG-nitro-L-arginine, benzoyl-L-arginine, L-arginine, quercetin, apigenin, nordihydroguaiac acid (NDGA), ketoprofen, naproxen, tometetin, diclofenac, diflunisal, sulinic acid, thiosalicylic acid, cysteine, diethyldithiocarbamate, D-penicillamine, N-acetyl-L-cysteine, copper sulfate, enalapril, tamoxifen, cimetidine, mycophenolic acid, tetracycline, doxycycline, minocycline, thioridazine, trifluoperazine, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, glycyrrhetinic acid, epigallocatechin gallate, epicatechin gallate, epigallocatechin, epicatechin, fusidic acid, and nitrosacetylpenicillamine.

[0042] In other embodiments, another active agent may be selected from drugs for preventing chemotherapy- or radiotherapy-induced alopecia or hair loss, such as 4-((cyanoimino((1,2,2-trimethylpropyl)amino)methyl)amino)benzonitrile, epidermal growth factor, fibroblast growth factor (including but not limited to keratinocyte growth factor (FGF7)), prostaglandins, cyclin-dependent kinases, p53 inhibitors, cysteine ​​aspartate protease-3 inhibitors, N-acetylcysteine, parathyroid hormone antagonists, α-tocopherol, cyclosporine, angiotensin receptor blockers, and minoxidil.

[0043] Generally, the compositions of this invention can be used in any formulation suitable for treating hair growth. In specific embodiments of the invention, the compositions are formulated as ointments, lotions, creams, shampoos, emulsions, gels, sprays, suspensions, capsules, tablets, plasters, or sustained-release plasters. In other specific embodiments of the invention, the compositions are formulated as solutions. The solutions can be applied via microneedle devices, or before ultrasound treatment, electrical stimulation, etc. Alternatively, the solutions can be administered orally, for example, in the form of capsules, tablets, or dietary supplement drinks. Another route of administration is intraocular administration.

[0044] As described above, the uses of the above-mentioned active agent in this invention can also occur in a non-therapeutic manner, wherein non-therapeutic means treatment that is not intended to cure, treat or prevent a certain disorder (see above).

[0045] Therefore, the present invention also relates to a non-therapeutic method for regulating hair growth, wherein an effective amount of at least one of the above-mentioned active agents is administered to a subject.

[0046] The non-therapeutic method also includes the following embodiments: applying the above-described active agent, along with at least one other active agent for treating hair growth, simultaneously, sequentially, or separately to the subject to be treated (see above).

[0047] The following examples illustrate some features of specific embodiments of the present invention. However, those skilled in the art should understand that these embodiments are merely examples and do not limit the inventive concept to the features or combinations thereof of these examples.

[0048] The example is described with reference to the following figures, in which... Figure 1 The experimental data showed that, in the group treated with the OR10J1 agonist 2,6-dimethylhept-2-ol, the number of HFs in the growth phase increased significantly, while the number of HFs in the regression phase decreased.

[0049] Figure 2Experimental data are shown, according to which the hair shafts in the group treated with the OR10J1 agonist 2,6-dimethylhept-2-ol showed significant elongation.

[0050] Figure 3 The experimental data showed that, in the group treated with the OR10J1 agonist 2,6-dimethylhept-2-ol, the number of Ki67-positive cells in the HF matrix increased significantly after 6 days.

[0051] Figure 4 The experimental data showed that, in the group treated with the OR10J1 agonist 2,6-dimethylhept-2-ol, the expression of CD34 protein and the number of CD34+ cells in the HF basal outer root sheath increased significantly after 6 days.

[0052] Figure 5 The experimental data showed that, in the group treated with the OR10J1 agonist 2,6-dimethylhept-2-ol, the growth factor IGF-1 during the growth phase was significantly increased, while the regression inducing factor was significantly decreased.

[0053] Figure 6 The experimental data showed that, after 6 days of incubation with 2,6-dimethylhept-2-ol, the expression of OR10J1 protein in the outer root sheath region of basal CD34 was significantly increased.

[0054] Figure 7 The experimental data shown indicate that OR10J1 protein expression is correlated with cell proliferation markers and growth factors.

[0055] Figure 8 Micrographs of hair follicles after MF and Ki67 staining are shown.

[0056] Figure 9 The experimental data shown indicates that 2,6-dimethylhept-2-ol loses its ability to induce growth after incubation with siOR10J1.

[0057] Figure 10 The experimental data shown indicates that 2,6-dimethylhept-2-ol loses its ability to produce hair shaft elongation effect after incubation with siOR10J1.

[0058] Example Effects of 1,2,6-Dimethylhept-2-ol on hair follicle (HF) biology To investigate the effects of 2,6-dimethylhept-2-ol on hair follicle (HF) biology, HFOC (Follicle Organ Culture) was used. HFOC is a whole-organ culture technique that allows HF to remain active in vitro.

[0059] Experimental plan: • 3 experimental groups: - Vector group, cell culture medium only (WEM, 1% P / S, 0.1% Insulin, 0.02% HC, 0.2% DMSO) - Group 250DT, cell culture medium containing 250 μM 2,6-dimethylhept-2-ol - 500DT group, cell culture medium containing 500 μM 2,6-dimethylhept-2-ol • Three patients donated HF (high-frequency hair transplant) during hair transplantation: - 25-30 HF transducers for the vector group (10 transducers per patient), 250DT group: 25-30 HF transducers, 500DT group: 25-30 HF transducers - 7-10 HFs per patient per group: 80-90 HFs in total.

[0060] Immunofluorescence: Quantitative (immunomorphometry) methods were used to assess the staining intensity of well-defined hair growth reference regions in the hair matrix and / or outer root sheath using a panel of antibodies including Ki67, cleaved cysteine ​​aspartate protease-3, TGFβ2, CD34, OR10J1, and IGF-1.

[0061] Samples were fixed for 10 minutes under different conditions (PFA, acetone, or methanol), followed by serum blocking or not. Afterwards, samples were incubated with primary antibody overnight, and then with secondary antibody for 45 minutes at room temperature the following day.

[0062] Statistical analysis: All charts were analyzed using Student's t-test, where: 0.001 0.01 and 0.05 result: a) 2,6-Dimethylhept-2-ol in vitro promotes the hair growth cycle phase and increases HF elongation. Six days after culture, MF and Ki67 staining was performed to evaluate hair cycle phase. We found that the number of HFs in the anagen phase was significantly increased in both treatment groups, while the number of HFs in the catagen phase was decreased. Compared with the 500DT group, the 250DT group induced a greater number of HFs in the anagen phase. See the attached document for more details. Figure 1 Data and Figure 8 HF micrographs.

[0063] To assess whether the stimulation during the growth phase translated into a physiological response, we measured hair shaft formation. Comparing the percentage hair shaft elongation on day 1 (treatment start) and day 6, we observed a significant increase in hair shaft formation in both the 250DT and 500DT groups compared to the control group. See the attached document for more details. Figure 2 The data in the middle.

[0064] b) 2,6-Dimethylhept-2-ol increases the number of Ki67 proliferating cells in the keratinocytes of the hair follicle matrix and the number of outer root sheath cells. The number of CD34 stem cells To assess whether the macroscopic changes in HF phase and elongation induced by 2,6-dimethylhepta-2-ol also translate into changes at the molecular level, we performed qIHM analysis on the HF hair matrix (HM) and outer root sheath (ORS), well-defined and studied regions where the production of mediators for hair growth (cell proliferation / apoptosis) occurs. Therefore, we employed antibodies targeting proliferation and apoptosis markers, as well as key nutrients involved in the anagen / catagen phase transition.

[0065] - After 6 days of culture, the number of Ki67-positive cells in the HM cells of the treated HF was significantly increased compared to the control group (vector group). Although the number of apoptotic cysteine ​​aspartate protease-3-positive cells was reduced, this difference was not significant. See the attached document for more details. Figure 3 The data in the middle.

[0066] Next, to assess the proliferation level of hair follicle ORS, we quantitatively analyzed the expression level of CD34 protein. CD34 is a stem cell marker present in subcarinal ORS and is associated with the etiology of androgenetic alopecia. Interestingly, in both the 250Dt and 500DT groups, treatment with 2,6-dimethylhept-2-ol for 6 days significantly increased the expression level of CD34 protein in subcarinal ORS, along with an increase in the number of CD34+ cells. For more details, please see the attached... Figure 4 The data in the middle.

[0067] c) 2,6-Dimethylhepta-2-ol regulates the expression levels of TGF-β-2 and IGF-1 proteins. To determine whether the increase in long-term HF (high-frequency hemorrhagic foci) in graduate students is related to an increase in growth phase maintenance-related growth factor (IGF-1) and a decrease in regression-induced growth factor (TGF-β-2), we used antibodies targeting these specific growth factors.

[0068] We observed that both groups incubated with DIMETOL (250 DT and 500 DT) showed a significant increase in growth factor IGF-1 during the growth phase and a significant decrease in regression-inducing factor TGFβ-2, with differences of approximately 2-fold under each condition. Please see the attached document for more details. Figure 5 The data in the middle.

[0069] d) 2,6-Dimethylhept-2-ol increases the protein expression of OR10J1. To investigate whether 2,6-dimethylhepta-2-ol enhances the expression of its receptor OR10J1, we used a validated anti-OR10J1 antibody to quantify the difference in protein expression between the 2,6-dimethylhepta-2-ol incubation group and the vector incubation group. Compared with the vector group, after 6 days of incubation with 2,6-dimethylhepta-2-ol, OR10J1 protein expression was significantly increased, approximately 2-fold, in the subprotruding CD34+ ORS region. See the attached document for more details. Figure 6 The data in the middle.

[0070] e) OR10J1 protein expression was correlated with cell proliferation markers and growth factors. After performing Pearson correlation coefficient analysis, we found a significant correlation between CD34 and OR10J1 protein expression in the 250DT group, with a correlation coefficient of 0.68. Figure 7 A). Parallel correlation analysis using our proliferation marker Ki67 confirmed a non-significant positive correlation between the Ki67-500DT group and the OR10J1-250DT group, with a correlation coefficient of 0.30 (A). Figure 7 B).

[0071] Next, we evaluated the correlation between CD34 and Ki67 biomarkers using IGF-1 and TGFβ2. We observed that the growth factor IGF-1 during the growth phase was positively correlated with both CD34 and Ki67. Figure 7 Conversely, the regression-inducing factor TGFβ2 was negatively correlated with the expression of OR10J1 and CD34 stem cell markers (CD). Figure 7 ,EF).

[0072] 2. Function of OR10J1-siRNA The following experiment was conducted on patients with HF using siRNA targeting the OR10J1 receptor.

[0073] Experimental plan: • 4 experimental groups: -NTO (control RNA) -NTO+250µM 2,6-Dimethylhepta-2-ol (250DT) -siOR10J1 (OR10J1 blocks RNA) -siOR10J1+250µM 2,6-Dimethylhepta-2-ol (250DT) Experimental steps: Day 0: Separation, Taking Photos Day 1: Take photos + change culture medium / add NTO or siRNA - Day 2: Let stand Day 3: Take photos + change culture medium / add 2,6-dimethylhept-2-ol - Day 4: Let stand Day 5: Take photos + change culture medium / add 2,6-dimethylhept-2-ol Day 6: Taking photos + embedding in OCT. result: Experiments showed that 2,6-dimethylhept-2-ol promoted the growth phase through the OR10J1 receptor. Figure 9 ) and hair shaft elongation ( Figure 10 However, when 2,6-dimethylhept-2-ol was incubated with siOR10J1, it lost the ability to induce growth phase and produce hair shaft elongation effect observed in the control group.

Claims

1. An active agent for treating hair growth, wherein the active agent activates, enhances, inactivates, blocks or weakens the cellular response of the olfactory receptor OR10J1, or interferes with the expression of the receptor.

2. The active agent for treating hair growth according to claim 1, wherein the active agent is an agonist of the olfactory receptor OR10J1 for treating unwanted hair loss.

3. The active agent for treating hair growth according to claim 1, wherein the active agent is an antagonist / reverse agonist of the olfactory receptor OR10J1 for treating unwanted hair growth.

4. The active agent for treating hair growth according to any one of claims 1 to 3, wherein the active agent is: a) OR10J1-activating agonist 2,6-dimethylhepta-2-ol or aptamers that bind to the OR10J1 receptor and activate or enhance the receptor to produce a cellular response, or b) OR10J1 inactivating antagonists / reverse agonists, or aptamers that bind to and inactivate, block, or attenuate the OR10J1 receptor to produce a cellular response, or c) Agents that act on the co-receptor of OR10J1 to stimulate or promote the expression of the receptor OR10J1.

5. The active agent for treating hair growth according to claim 1, wherein the active agent is a miRNA, siRNA or ribozyme targeting OR10J1, or a miRNA, siRNA or ribozyme targeting the mRNA corresponding to the OR10J1 gene.

6. The active agent according to any one of claims 1 to 5, used as a cosmetic for treating hair growth.

7. The active agent according to any one of claims 1 to 5, which is used as a medicine or dietary supplement to treat hair growth disorders.

8. The active agent as a medicine or dietary supplement according to claim 7, wherein the hair growth disorder to be treated is alopecia, non-scarring alopecia, scarring alopecia, hirsutism, or female hirsutism.

9. A composition for use as a cosmetic, pharmaceutical or dietary supplement to treat hair growth, said composition comprising at least one active agent according to any one of claims 1 to 8 and at least one adjuvant selected from the group consisting of a carrier, excipients, auxiliaries, diluents, penetration enhancers and disintegrants.

10. The composition according to claim 9 for treating hair growth as a cosmetic, pharmaceutical or dietary supplement, wherein the adjuvant is selected from the group consisting of liposomes, nanoparticles, carboxymethyl cellulose, hydroxyethyl cellulose, mineral oil, petrolatum, glycerin, polysorbate 80, hydroxyethyl starch, dextran and polyethylene glycol.

11. The composition for treating hair growth as a cosmetic, pharmaceutical, or dietary supplement according to claim 9 or 10, further comprising at least one other active agent that is effective in treating hair growth.

12. The composition for treating hair growth as a cosmetic, pharmaceutical or dietary supplement according to any one of claims 9 to 11, wherein the composition is formulated as an ointment, lotion, cream, shampoo, gel, solution, emulsion, spray, suspension, capsule, tablet, plaster or sustained-release plaster.

13. A non-therapeutic method for regulating hair growth, wherein an effective amount of at least one active agent is administered to a subject, said active agent activating, enhancing, inactivating, blocking or weakening the cellular response of the olfactory receptor OR10J1, or interfering with the expression of said receptor.

14. The non-therapeutic method for regulating hair growth according to claim 13, wherein the active agent is a) OR10J1-activating agonist 2,6-dimethylhepta-2-ol or aptamers that bind to the OR10J1 receptor and activate or enhance the receptor to produce a cellular response, or b) OR10J1 inactivating antagonists / reverse agonists, or aptamers that bind to and inactivate, block, or attenuate the OR10J1 receptor to produce a cellular response, or c) Agents that act on the co-receptor of OR10J1 to stimulate or promote the expression of the receptor OR10J1.

15. The non-therapeutic method for regulating hair growth according to any one of claims 13 and 14, wherein the active agent is a miRNA, siRNA, or ribozyme targeting the OR10J1 gene, or a miRNA, siRNA, or ribozyme targeting the mRNA corresponding to the OR10J1 gene.

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