Treatment for skin disorders

Abstract

The present disclosure provides methods and related compositions for treating skin disorders such as inflammatory skin diseases and skin wounds. The methods comprise administering Lion's Mane (Hericium erinaceus) extracts and / or erinacine compounds to subjects in need thereof.

Description

TREATMENT FOR SKIN DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 601,460, filed November 21, 2023, which is incorporated by reference herein in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to the use of an extract, or one or more components therefrom, from Lion’s Mane mushroom in the treatment, remedying, or prevention of skin disorders, such as inflammatory skin disease and / or wounds of the skin.BACKGROUND OF THE DISCLOSURE

[0003] Psoriasis is a chronic inflammatory skin disease that afflicts about 2 percent of the population. The disease is associated with the rapid turnover of skin cells (hyperproliferation) accompanied by a loss of differentiation so that silvery white scales form on the surface of the skin. Additionally, the capillaries become tortuous and dilated and an inflammatory reaction occurs, so that the skin reddens. The elevated silvery white scales on a contrasting red background produce the unsightly lesions characteristic of psoriasis. Psoriasis most commonly appears on the scalp, knees, elbows, hands and feet, but can affect any part of the skin. The cause of the disease is unknown, though it is believed to have a genetic component, and it has been suggested to be a T-cell mediated autoimmune skin disorder. There have been many attempts to treat the disease, and several topical and systemic treatments for psoriasis which inhibit cell division have been tried, with limited success in clearing the skin for short periods of time. Yet, the reason why these treatments work is not yet clearly understood. Treatments which have been suggested in the art appear to be symptomatic and palliative. Lesions may disappear spontaneously or as a result of the therapy, but recurrences are likely.

[0004] Atopic dermatitis (“AD”), also known as atopic eczema, is a long-term type of inflammatory skin disease. AD is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditions. AD results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which can thicken over time. Atopic dermatitis affects about 20% of people at some point in their lives. It is more common in younger children. Females are affected slightly more often than males. Many people outgrow the condition.

[0005] Another phenomenon that involves inflammation of the skin is the wound-healing process. The wound-healing process consists of four highly integrated and overlapping phases: hemostasis, inflammation, proliferation, and tissue remodeling or resolution (Gosain and DiPietro (2004) Factors Affecting Wound Healing, World J Surg, 3, 321-6). These phases and their biophysiological functions must occur in the proper sequence, at a specific time, and continue for a specific duration at an optimal intensity (Mathieu et al. (2006) Non-healing wounds. In: Handbook on hyperbaric medicine, Mathieu DE, editor. Netherlands: Springer, pp. 401-427). There are many factors that can affect wound healing which interfere with one or more phases in this process, thus causing improper or impaired tissue repair. Wounds that exhibit impaired healing, including delayed acute wounds and chronic wounds, generally have failed to progress through the normal stages of healing. Such wounds frequently enter a state of pathologic inflammation due to a postponed, incomplete, or uncoordinated healing process.SUMMARY OF THE DISCLOSURE

[0006] A need remains for new inflammatory skin disease and wound healing treatments, particularly from natural sources such as from fungal species. The disclosure herein meets these and other needs by providing fungal-derived extracts, compounds, and compositions, as well as methods of using such extracts, compounds and compositions in the treatment of skin disorders, such as e.g. inflammatory skin diseases and / or wounds of the skin.

[0007] In one aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of Lion’s Mane (Hericium erinaceus) extract to a subject in need thereof. In another aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Lion’s Mane extract and a pharmaceutically acceptable carrier to a subject in need thereof. In specific embodiments, the skin disorder is an inflammatory skin disease such as e.g., psoriasis or atopic dermatitis. In other specific embodiments, the skin disorder is a wound.

[0008] In yet another aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of an erinacine compound to a subject in need thereof. In a further aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an erinacine compound and a pharmaceutically acceptable carrier to asubject in need thereof. In specific embodiments, the skin disorder is an inflammatory skin disease such as e.g., psoriasis or atopic dermatitis. In other specific embodiments, the skin disorder is a wound.

[0009] In some embodiments, the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof. In a particular embodiment, the erinacine compound is erinacine C. In one embodiment, the erinacine compound is a synthetic compound.

[0010] In some embodiments, the methods further comprise administration of at least one additional therapeutic agent selected from the group consisting of an antimicrobial agent, an analgesic agent, and a combination thereof. In some embodiments, the methods include administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

[0011] In some embodiments, the methods include administration of at least one additional therapeutic agent selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma-lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof.

[0012] In some embodiments, the administration is topical administration. In one embodiment, the extract or pharmaceutical composition is applied twice daily. In one embodiment, the extract or pharmaceutical composition is administered at a pre-psoriatic rim on the skin of the subject. In an embodiment, the composition is administered topically.

[0013] In some embodiments, the expression of genes shown in FIG. 11 is decreased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein. In some embodiments, the expression of genes shown in FIG. 12 is increased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0014] In some embodiments, the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein. In some embodiments, theexpression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0015] In some embodiments, the expression of genes shown in FIG. 14 is decreased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein. In some embodiments, the expression of genes shown in FIG. 15 is increased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0016] In some embodiments, the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBI3, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein. In some embodiments, the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0017] In some embodiments, the Lion’s Mane extract, erinacine compound or pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, fdm, transdermal patch and any combination thereof.

[0018] In one embodiment, the pharmaceutically acceptable carrier comprises compositions selected from the group consisting of glyceryl stearate, PEG- 100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, P-caryophyllene, cannabis oil, stearic acid, and combinations thereof.

[0019] In one embodiment, the administration of at least one additional therapeutic agent is in combination with a topically administered Lion’s Mane extract, erinacine compound or pharmaceutical composition, as provided herein, so as to provide a synergistic effect with respect to treating the skin disorder relative to the effect provided by the therapeutic agent administered separately. In one embodiment, the synergistic effect provided is with respect to at least one of: (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnoverrate. In one embodiment, the synergistic effect provided is with respect to inhibition of inflammation.

[0020] In one embodiment, a topically administered Lion’s Mane extract, erinacine compound or pharmaceutical composition provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone. In one embodiment, a topically administered Lion’s Mane extract, erinacine compound or pharmaceutical composition provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

[0021] In some embodiments, the antimicrobial agent is selected from the group consisting of loracarbef, cephalexin, cefadroxil, cefixime, ceftibuten, cefprozil, cefpodoxime, cephradine, cefuroxime, cefaclor, neomycin, dicloxacillin, nitrofurantoin, nitrofurantoin macrocrystal, nitrofurantoin / nitrofuran mac, dirithromycin, gemifloxacin, ampicillin, gatifloxacin, ciprofloxacin, enoxacin, amoxicillin, clarithromycin, levofloxacin, moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin, trovafloxacin, lomefloxacin, erythromycin, norfloxacin, clindamycin, quinupristin, doxycycline, amikacin sulfate, vancomycin, kanamycin, netilmicin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetracycline, framycetin, minocycline, nalidixic acid, demeclocycline, trimethoprim, miconazole, colistimethate, paromomycin, sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate, metronidazole, oxacillin sodium, nafcillin sodium, vancomycin hydrochloride, clindamycin, cefotaxime sodium, co-trimoxazole, ticarcillin disodium, piperacillin sodium, ticarcillin disodium / clavulanate potassium, neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, penicillin, ceftriaxone sodium, ceftazidime, imipenem, aztreonam, cinoxacin, cefotetan disodium, cefoperazone sodium, cefamandole nafate, gentamicin, tobramycin, lincomycin, al atr ofloxacin, linezolid, tetracycline, mupirocin, fosfomycin, pentamidine isethionate, imipenem / cilastatin, troleandomycin, gatifloxacin, chloramphenicol, cycloserine, meropenem, cephalosporins, fluconazole, cefepime, sulfamethoxazole, chloroquine phosphate, silver sulfadiazine, and combinations thereof.

[0022] In some embodiments, the analgesic agent is selected from the group consisting of acetaminophen, anileridine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, codeine, rofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride,levorphanol, alfentanil hydrochloride, meperidine, meperidine hydrochloride, methadone, morphine, nalbuphine, opium, levomethadyl, hyaluronate sodium, sufentanil citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, propoxyphene, benzocaine, lidocaine, dezocine, clonidine, butalbital, phenobarbital, tetracaine, phenazopyridine, sulfamethoxazole / phenazopyridine, sulfisoxazole / phenazopyridine, and combinations thereof.

[0023] Other aspects and embodiments of the disclosure will be apparent on review of the figures, detailed description and non-limiting examples herein.

[0024] Terms used herein will be understood to take on their ordinary meaning in the relevant art unless specified otherwise. Several terms used herein and their meanings are set forth below.

[0025] Unless otherwise specified, "a," "an," "the," and "at least one" are used interchangeably and mean one or more than one.

[0026] As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise. The term "and / or" means one or all of the listed elements or a combination of any two or more of the listed elements. The use of "and / or" in some instances does not imply that the use of "or" in other instances may not mean "and / or."

[0027] As used herein, "have," "has," "having," "include," "includes," "including," "comprise," "comprises," "comprising" or the like are used in their open ended inclusive sense, and generally mean "include, but not limited to," "includes, but not limited to," or "including, but not limited to."

[0028] Throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.BRIEF DESCRIPTION OF THE FIGURES

[0029] FIG. 1 shows glioblastoma-derived T98G cells treated with a range of lion’s mane (LM) extract concentrations compared to vehicle alone (70% EtOH).

[0030] FIG. 2 shows nerve growth factor (NGF) gene expression levels in T98G cells treated with LM extract (squares) or vehicle alone with either 70% EtOH (triangles) or PBS (diamonds) for 24 hours. Transcript levels for NGF were 3.4-fold higher (p= 9 x 10'4, ttest) in the LM extract treated cells versus vehicle alone.

[0031] FIG. 3 shows human primary fibroblasts (hFB’s) treated with LM extract (top) or vehicle alone (bottom) for 48 and 72 hours.

[0032] FIG. 4 shows NGF gene expression levels in hFB’s treated with LM my celia (My) extract (diamonds), vehicle alone (squares) or media alone (triangles) for 24 hours. Transcript levels for NGF were 9.8-fold higher (p=1.4 x 10‘8, ttest) in the LM extract (LM-My) treated cells versus vehicle alone.

[0033] FIG. 5 shows mass spectrometry automated isolation of candidates for bioactivity screening. LM extracts were divided into 95 fractions containing 1-4 constituents each. Candidates in each fraction were matched or distinguished from peaks associated with known compounds and / or noise. Fractions containing majority erinacine A, erinacine C and cyathin T compounds were lyophilized and resuspended in 70% EtOH at a concentration of 2% of cell media for treatment on hFB cells.

[0034] FIG. 6 shows Principle Component Analysis (PCA) plot of hFB gene expression response to LM Mycelia (My) extract and isolated components of the extract: erinacine A, erinacine C and cyathin T. Two natural occurring antioxidants (beta carotene and ergothionene) not found in LM extract are also included as controls.

[0035] FIG. 7 shows comparison of genes that change with erinacine C (Bsl) and whole LM extract (Bs2). Genes were considered responsive to treatment based on an absolute fold change > 1.2 and p- value < 0.01 compared to vehicle alone.

[0036] FIG. 8 shows NGF gene expression levels in hFB’s treated with LM mycelia (My) extract, along with isolated bioactives from the extract, other natural bioactives not present in the extract and vehicle alone. Transcript levels for NGF were 9.8-fold higher (p=1.4 x 10'8, ttest) in the LM extract treated cells versus vehicle alone.

[0037] FIG. 9 shows a Venn diagram of genes differentially expressed (|Fold Change|>l .2; p< 0.05) due to Psoriasis (based on 50 studies), 2% Erinacine C and 0.25% lion’s mane (LM) total extract in human primary fibroblasts. Of the 2242 common genes, there were 1,131 genes that demonstrated the opposite effect between gene changes produced by psoriasis compared to changes due to erinacine C and LM total extract. There were 807 genes that increased due to psoriasis that were decreased by erinacine C and LM total extract and 324 genes that decreased due to psoriasis that were increased by erinacine C and LM total extract.

[0038] FIG. 10 shows the 1,131 genes that were differentially expressed due to psoriasis where the LM extract and erinacine C had the opposite effect on expression of the listed genes. "Psoriasis” is the fold change in gene expression due to the disease compared to matched normal controls; "Erinacine C" is the fold change in gene expression due to erinacine C (2% in cell media) vs. vehicle controls in human primary fibroblasts (hFB); "LM extract" is the fold change in gene expression due to total LM extract (0.25% in cell media) vs. vehicle controls in hFB. FIG. 10 also shows the effect two monoclonal antibody therapies for psoriasis ("Brodalumab FC vs Ctrl" and "Ustekinumab FC vs Ctrl") had on the same genes compared to untreated human psoriasis tissue. The probability of obtaining these results by random chance for the two monoclonal antibodies brodalumab and ustekinumab were p= 2.3 x 10'150and p= 1.7 x 10’155, respectively.

[0039] FIG. 11 shows the genes from FIG. 10 that showed increased expression due to psoriasis and that showed a decrease in expression due to LM extract and erinacine C. "Psoriasis” is the fold change in gene expression due to the disease compared to matched normal controls; "Erinacine C" is the fold change in gene expression due to erinacine C (2% in cell media) vs. vehicle controls in human primary fibroblasts (hFB); "LM extract" is the fold change in gene expression due to total LM extract (0.25% in cell media) vs. vehicle controls in hFB. FIG. 11 also includes the effect two monoclonal antibody therapies for psoriasis ("Brodalumab FC vs Ctrl" and "Ustekinumab FC vs Ctrl") had on the same genes compared to untreated human psoriasis tissue. The probability of obtaining these results by random chance for the two monoclonal antibodies brodalumab and ustekinumab were p= 2.3 x IO’130and p= 1.7 x 10'153, respectively.

[0040] FIG. 12 shows the genes from FIG. 10 that showed decreased expression due to psoriasis and that showed an increase in expression due to LM extract and erinacine C. "Psoriasis” is the fold change in gene expression due to the disease compared to matched normal controls; "Erinacine C"is the fold change in gene expression due to erinacine C (2% in cell media) vs. vehicle controls in human primary fibroblasts (hFB); "LM extract" is the fold change in gene expression due to total LM extract (0.25% in cell media) vs. vehicle controls in hFB. FIG. 12 also includes the effect two monoclonal antibody therapies for psoriasis ("Brodalumab FC vs Ctrl" and "Ustekinumab FC vs Ctrl") had on the same genes compared to untreated human psoriasis tissue. The probability of obtaining these results by random chance for the two monoclonal antibodies brodalumab and ustekinumab were p= 2.3 x IO’150and p= 1.7 x 10'155, respectively.

[0041] FIG. 13 shows a Venn diagram of genes differentially expressed (|Fold Change|>1.2; p< 0.05) due to acute dermatitis (“AD”) (based on 15 studies), 2% Erinacine C and 0.25% lion’s mane (LM) total extract in human primary fibroblasts. Of the 1998 common genes, there were 1,063 genes that demonstrated the opposite effect between gene changes produced by AD compared to changes due to erinacine C and LM total extract. There were 784 genes that increased due to AD that were decreased by erinacine C and LM total extract and 279 genes that decreased due to AD that were increased by erinacine C and LM total extract.

[0042] FIG. 14 shows the genes that showed increased expression due to AD and that showed a decrease in expression due to LM extract and erinacine C. "Atopic Dermatitis” is the fold change in gene expression due to the disease compared to matched normal controls; "Erinacine C" is the fold change in gene expression due to erinacine C (2% in cell media) vs. vehicle controls in human primary fibroblasts (hFB); "LM extract" is the fold change in gene expression due to total LM extract (0.25% in cell media) vs. vehicle controls in hFB.

[0043] FIG. 15 shows the genes that showed decreased expression due to AD and that showed an increase in expression due to LM extract and erinacine C. "Atopic Dermatitis” is the fold change in gene expression due to the disease compared to matched normal controls; "Erinacine C" is the fold change in gene expression due to erinacine C (2% in cell media) vs. vehicle controls in human primary fibroblasts (hFB); "LM extract" is the fold change in gene expression due to total LM extract (0.25% in cell media) vs. vehicle controls in hFB.

[0044] FIG. 16 shows a list of genes differentially expressed after treatment with LM total extract, erinacine C fraction and four current therapies for AD. Only genes differentially expressed in all treatments are shown. Values given for each gene reflect the fold change in gene expression of the indicated treatment compared to either placebo or vector-alone controls. Dosages used for eachtreatment are as follows: 0.25% lion’s mane extract for 24 hrs., 2% erinacine C fraction for 24 hrs., 200mg / day dupilumab for 4 weeks, 80mg gusacitinib for 24 hrs., 2% crisaborole for 8 days, and 5mg / kg / day cyclosporine A for 2 weeks.DETAILED DESCRIPTION

[0045] The present disclosure relates to compositions and methods for treating skin disorders such as inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, eczema, eruption, dermatosis, autoimmune skin disease and wounds. In particular, this disclosure relates to pharmaceutical compositions comprising active ingredients derived from fungal sources, and methods of using the same, for treating skin disorders such as inflammatory skin diseases, e.g., psoriasis, atopic dermatitis and / or wounds. This disclosure provides experimental support showing that extracts from Lion’s Mane or powdered mycelial biomass, as well as compounds found within the extracts, e.g., erinacines, provide therapeutic effects for various skin disorders such as inflammatory skin conditions.

[0046] Several aspects of the disclosure are described below, with reference to examples for illustrative purposes only. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the disclosure. One having ordinary skill in the relevant art, however, will readily recognize that the inventive concepts can be practiced without one or more of the specific details or practiced with other methods, protocols, reagents, and animals. The present disclosure is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and / or concurrently with other acts or events. Furthermore, not all illustrated acts, steps or events are required to implement a methodology in accordance with the present disclosure. Many of the techniques and procedures described, or referenced herein, are well understood and commonly employed using conventional methodology by those skilled in the art.

[0047] Inflammatory Skin Disease

[0048] The skin is a large and vital organ that functions as mechanical, biochemical, and immunological barrier to protect the organism from damage (Perera, G. K., et al., Amu. Rev. Pathol. 7:385-422 (2012)). Human skin consists of several layers including the outer epidermis and the dermis below that separates it from the subcutaneous tissue. The epidermis mainly consists of epithelial cells, termed keratinocytes, that give rise to the cornified layer on top. Langerhans cells,the epidermal APCs, are located in the basal layer close to the basement membrane (Fujita, H. et al. Proc. Natl. Acad. Sci. U S. A 106, 21795-21800 (2009)). The dermis consists of connective tissue containing blood vessels, dermal dendritic cells (DCs), and T cells. Human skin contains 1-2 million T lymphocytes per cm2in the steady-state, and thus, the skin is a large immunological organ (Clark, R. A. et al. J. Immunol. 176, 4431-4439 (2006)).

[0049] Various skin conditions are associated with increased T cell activation and abnormal antigen presentation in the dermis and epidermis (Cooper, Curr. Probl. Dermatol, eds. van Vloten et al., 19, pp. 69-80 at pp. 73, 74, 76 (1990)). For example, in contact allergic dermatitis, activation of intracutaneous T-cells is observed. It is known that skin from patients exhibiting atopic dermatitis contains an increased number of Langerhans cells (Cooper, supra). In psoriatic skin, there is an increased number of antigen presenting cells, composed of both Langerhans cells and nonLangerhans cell Class II MHC -bearing antigen presenting cells (Cooper, supra).

[0050] Dysregulation of skin homeostasis can lead to inflammation such as in psoriasis and atopic dermatitis (Perera, G. K., et al. Annu. Rev. Pathol. 7:385-422 (2012)). Psoriasis is known as T cell- mediated chronic relapsing skin inflammation that represents an important public health problem with a prevalence of ~5% in the U.S. It macroscopically presents with classical skin lesions, including elevation, erythema, and scaling. Histologically, psoriatic skin is characterized by thickening of the epidermis (acanthosis), epidermal extensions into the dermis (papillomatosis), and a differentiation defect of keratinocytes leading to a nucleated cornified layer (parakeratosis) (Perera, G. K., et al., supra). Cellular infiltrate in psoriatic skin consists of CD8 T cells in the epidermis and mainly CD4 T cells in the dermis. Seminal work by Nestle and colleagues demonstrated that pre-psoriatic (healthy) skin from psoriasis patients transplanted onto immunodeficient mice spontaneously developed psoriasis (Boyman, O. et al. J. Exp. Med. 199, 731- 736 (2004)). In this context, skin-resident passenger T cells were responsible for generating inflammatory disease (Boyman, O. et al. J. Exp. Med. 199, 731-736 (2004)).

[0051] The methods and compositions described herein are useful to treat mammalian (e.g., human) skin conditions characterized by increased T cell activation and abnormal antigen presentation in the dermis and epidermis, by administering Lion’s Mane extracts or erinacine compounds. The methods and compositions described herein are contemplated for both therapeutic treatment of inflammatory skin disease and for prophylaxis of inflammatory skin disease.

[0052] As used herein, the term “inflammatory skin disease” refers to a skin condition accompanied by inflammation that is mediated, in part, by T-cells. Non-limiting examples of inflammatory skin diseases related to the present disclosure include psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea due to systemic lupus erythematosus, rosacea due to urticaria, rosacea due to herpetic pain, Sweet's disease, neutrophilic hydrodenitis, sterile pustule, drug rash, seborrheic dermatitis, pityriasis rosea, Kikuchi's disease of the skin, pruritic urticarial papules and plaques of pregnancy, Stevens- Johnson syndrome and toxic epidermal necrolysis, tattoo reaction, Wells syndrome (eosinophilic cellulitis), reactive arthritis (Reiter syndrome), bowel-associated dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatosis, neutrophilic eccrine hi dradenitis, neutrophilic skin disease of dorsum of hand, balanitis circumscripta plasmacellularis, balanoposthitis, Behcet's disease, erythema annulare centrifugum, erythema dyschromicum perstans, erythema multiforme, granuloma annulare, dermatitis of hand, lichen nitidus, lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subkeratinous pustular dermatosis, urticaria, transient acantholytic dermatosis, urushiol-induced contact dermatitis, and the like.

[0053] In one embodiment, the inflammatory skin disease is psoriasis.

[0054] Psoriasis is an inflammatory skin condition characterized by frequent episodes of redness, itching, and thick, dry, silvery scales on the skin. Psoriasis comprises lesions that can involve primary and secondary alterations in epidermal proliferation, inflammatory responses of the skin, and an expression of regulatory molecules such as lymphokines and inflammatory factors. Psoriatic skin is morphologically characterized by an increased turnover of epidermal cells, thickened epidermis, abnormal keratinization, inflammatory cell infiltrates into the epidermis and polymorphonuclear leukocyte and lymphocyte infiltration into the epidermis layer. Psoriasis can also involve fingernails or toenails, which frequently exhibit pitting, separation of the nail, thickening, and discoloration. Psoriasis is often associated with other inflammatory disorders, for example, arthritis, including rheumatoid arthritis, inflammatory bowel disease (IBD), and Crohn's disease.

[0055] Evidence of psoriasis is most commonly seen on the trunk, elbows, knees, scalp, skin folds, or fingernails, but it may affect any or all parts of the skin. Normally, it takes about a month for new skin cells to move up from the lower layers to the surface. In psoriasis, this process takes only a few days, resulting in a build-up of dead skin cells and formation of thick scales. Symptoms of psoriasis include: skin patches, that are dry or red, covered with silvery scales, raised patches of skin, accompanied by red borders, that can crack and become painful, and that are usually located on the elbows, knees, trunk, scalp, and hands; skin lesions, including pustules, cracking of the skin, and skin redness; joint pain or aching which can be associated with of arthritis, e.g., psoriatic arthritis.

[0056] A diagnosis of psoriasis is usually based on the appearance of the skin. Additionally, a skin biopsy, or scraping and culture of skin patches may be needed to rule out other skin disorders. An x- ray can be used to check for psoriatic arthritis if joint pain is present and persistent.

[0057] Severity of psoriasis can be determined according to standard clinical definitions. For example, the Psoriasis Area and Severity Index (PASI) is used by dermatologists to assess psoriasis disease intensity. This index is based on the quantitative assessment of three typical signs of psoriatic lesions: erythema, infiltration, and desquamation, combined with the skin surface area involvement. Since its development in 1978, this index has been used throughout the world by clinical investigators (Fredriksson T, Petersson U: Severe psoriasis — oral therapy with a new retinoid. Dermatologica 1978; 157: 238-41). PASI is indicated as PASI 50 (a 50 percent improvement in PASI from baseline), PASI 75 (a 75 percent improvement in PASI from baseline), PASI 90 (a 90 percent improvement in PASI from baseline), and PASI 100 (a 100 percent improvement in PASI from baseline).

[0058] The Physicians Global Assessment (PGA) is used to assess psoriasis activity and follow clinical response to treatment. It is a six-point score that summarizes the overall quality (erythema, scaling and thickness) and extent of plaques relative to the baseline assessment. A patient's response is rated as worse, poor (0-24%), fair (25-49%), good (50-74%), excellent (75-99%), or cleared (100%) (van der Kerkhof P. The psoriasis area and severity index and alternative approaches for the assessment of severity: persisting areas of confusion. Br J Dermatol 1997; 137:661-662).

[0059] Another measure of improvement in the disease state of a subject having psoriasis includes clinical responses, such as the Dermatology Life Quality Index (DLQI) or the Minimum Clinically Important Difference (MCID).

[0060] In one embodiment, the inflammatory skin disease is atopic dermatitis. Atopic Dermatitis (AD) is another chronic inflammatory skin disease with a prevalence of 5-20% in children and ~11% in the total population of the US. The cardinal symptoms include pruritus (itch) and xerosis (dry skin). In addition, patients show erythema and development of vesicles. In the chronic phase, epidermal thickening leads to lichenification mainly of flexural sites. The etiology of AD is unknown, and historically pathogenesis was explained by atopy (hence the name), which is characterized by IgE and Th2 cell-mediated allergic inflammation. However, most cases of AD are not associated with the atopic complex, including allergic rhinitis and asthma. Current opinion rather explains the generation of AD by an underlying defect in epidermal barrier function that leads to exposure to skin irritants inducing subsequent inflammation. In the acute phase, a predominant Th2 cell infiltrate influences inflammation. However, in the chronic phase of AD, Thl cells as well as IL-17-producing cells are involved in the inflammatory response. Additionally, IL-22 facilitates keratinocyte proliferation and promotes epidermal thickening. Treatment of AD is largely symptomatic and is based on emollients against xerosis and corticosteroids to suppress inflammation. Biologies for therapy of AD are currently not available.

[0061] Wound Healing

[0062] The primary goal in the treatment of wounds is to achieve wound closure. Open cutaneous wounds represent one major category of wounds and include burn wounds, wounds resulting from chemical (especially alkali) burns, wounds from physical trauma, neuropathic ulcers, pressure sores, venous stasis ulcers, and diabetic ulcers. Open cutaneous wounds routinely heal by a process which comprises six major components: i) inflammation, ii) fibroblast proliferation, iii) blood vessel proliferation, iv) connective tissue synthesis, v) epithelialization, and vi) wound contraction. Wound healing is impaired when these components, either individually or as a whole, do not function properly. Numerous factors can affect wound healing, including but not limited to malnutrition, systemic debility due to a variety of causes, wound infection, local lack of progenitor cells, local and / or systemic pharmacological agents (e.g., numerous chemotherapeutic agents, actinomycin and steroids), repeated local trauma, diabetes and other endocrine / metabolic diseases (e g., Cushing's disease), and advanced age (Hunt and Goodson, 1988, Current Surgical Diagnosis & Treatment, Appleton & Lange, pp. 86-98). Additionally, wounds that are extensive in size, regardless of the initiating cause, present special challenges due to the large surface area that must be re- epithelialized to re-establish surface integrity.

[0063] Normal wound healing is an enormously complex process involving the coordinated interplay between fibroblasts, vascular cells, extracellular matrix and epithelial cells to result in a seamless progression through an inflammatory reaction, wound repair, contracture and coverage by an epithelial barrier. However, in many patients, due to either the local wound environment or systemic disease or other factors, the wound healing processes can become asynchronous (i.e., loss of connectivity with triggering mechanisms associated with prior cellular events) and are unable to progress to closure, resulting in a chronic ulcer.

[0064] The methods and compositions described herein are useful to treat mammalian (e.g., human) wounds of the skin by administering Lion’s Mane extracts or erinacine compounds to the wound and surrounding skin.

[0065] Lion’s Mane (LM) Mushrooms

[0066] Hericium erinaceus (also called lion's mane mushroom, mountain-priest mushroom, bearded tooth fungus, and bearded hedgehog) is an edible mushroom belonging to the tooth fungus group. Native to North America, Europe, and Asia, it can be identified by its long spines, its occurrence on hardwoods, and its tendency to grow a single clump of dangling spines. The fruit bodies can be harvested for culinary use.

[0067] LM mushrooms contain many beneficial plant compounds. The mushroom contains diverse mycochemicals, including polysaccharides, such as -glucan, as well as hericenones and erinacines. In particular, erinacines are mainly found in the mycelia of the LM mushroom. Research suggests these compounds may stimulate the growth of new brain cells, improve depression and anxiety, and support gut, heart, and immune health. The present disclosure shows that LM mushroom extracts or powders derived from the mycelia and components thereof, e.g., erinacines, provide therapeutic effectiveness for skin disorders such as various inflammatory skin diseases and for the process of wound repair.

[0068] The present disclosure includes extracts of LM mushrooms, compositions including an extract of LM mushrooms, and methods for making an extract of LM mushrooms. The present disclosure also includes LM mycelial powders, compositions including LM mycelial powders, and methods for making LM mycelial powders. In one non-limiting example, an extract / powder of LM mushrooms can be produced by growing mycelia under appropriate conditions for replication and production of biomass, harvesting and washing the biomass, and reducing the biomass to powder after freezing. The powdered biomass can be exposed to a water-miscible solvent or an organicsolvent. Examples of suitable water-miscible solvents include alcohols such as ethanol. In one embodiment, a solution of ethanol and water is used to extract soluble components from powdered mycelial biomass. In one embodiment, the solution can be at least about 55%, at least about 60%, or at least about 65% ethanol. In one embodiment, the solution can be no greater than about 85%, no greater than about 80%, or no greater than about 75% ethanol. Ranges of extraction solution include at least about 55% to no greater than about 85%, at least about 60% to no greater than about 80%, or at least about 65% to no greater than about 75%. In one embodiment, the extraction solution is 70% ethanol. The amount of biomass added to 10 ml extraction solution can be at least about 0.01 gram or at least about 0.1 gram added to about 10 mis of solution, and no greater than about 100 grams or no greater than about 10 grams added. Ranges of biomass added to 10 mis extraction solution can be at least about 0.01 gram to no grearter than about 100 grams, or at least about 0.1 gram to no grearter than about 10 grams. In one embodiment, 1 gram of biomass is added to 10 mis extraction solution. The mixture of powder and solvent is typically incubated together to allow the extraction to occur. The incubation can be for at least about 10 hours, at least about 14 hours, at least about 18 hours, or at least about 24 hours; and / or no greater than about 28 hours, no greater than about 24 hours, no greater than about 18 hours, or no greater than about 14 hours. The incubation can be at a temperature of at least about 30° C, at least about 40° C, or at least about 50° C; and / or no greater than about 60° C, no greater than about 50° C, no greater than about 40° C. In one embodiment the incubation can be for 24 hours at 50° C. After separation, the supernatant is collected and optionally concentrated using standard methods including, but not limited to, filtration and centrifugation. Other methods for extraction of compounds can be found in Zhang et al. (Chin Med, 2018, 13:20).

[0069] In another non-limiting example, an extract of LM mushrooms can be produced by growing my celia under appropriate conditions for replication and production of biomass, harvesting and washing the biomass, and reducing the biomass to powder. In the embodiments provided herein, the powder generated from the biomass can be utilized instead of the LM extract.

[0070] Methods of Treatment

[0071] In one aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of Lion’s Mane Hericium erinaceus) extract to a subject in need thereof. In yet another aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of an erinacinecompound to a subject in need thereof. In one embodiment, the skin disorder is a wound of the skin. In specific embodiments, the skin disorder is an inflammatory skin disease. In one embodiment, the inflammatory skin disease is psoriasis. In one embodiment, the inflammatory skin disease is atopic dermatitis. In one embodiment, the inflammatory skin disease is eczema. In one embodiment, the inflammatory skin disease is eruption. In one embodiment, the inflammatory skin disease is dermatosis. In one embodiment, the inflammatory skin disease is autoimmune skin disease. In embodiments, the erinacine compound is an erinacine C compound.

[0072] In yet another aspect, the present disclosure provides methods of treating a skin disorder comprising administering a therapeutically effective amount of Lion’s Mane (Hericium erinaceus) powder generated from Lion’s Mane mycelial biomass to a subject in need thereof.

[0073] In some embodiments, the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof. In one embodiment, the erinacine compound is obtained from LM mushrooms. In one embodiment, the erinacine compound is a synthetic compound. Erinacine C is commercially available (e.g., BenchChem, Pasadena, CA, Cat. No. Bl 249065).

[0074] In some embodiments, the methods disclosed also include administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, carnosic acid, vitamin D and derivatives thereof, and any combination thereof. In some embodiments, the at least one additional therapeutic agent is selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma-lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof. In other embodiments, the at least one additional therapeutic agent is selected from an antimicrobial agent, an analgesic agent and a combination thereof. In embodiments, the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the skin disorder relative to the effect provided by the therapeutic agent administered separately. For instance, the synergistic effect provided is with respect to at least one of: (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate. In some embodiments, the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation,reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

[0075] In some embodiments, the antimicrobial agent is selected from the group consisting of loracarbef, cephalexin, cefadroxil, cefixime, ceftibuten, cefprozil, cefpodoxime, cephradine, cefuroxime, cefaclor, neomycin, dicloxacillin, nitrofurantoin, nitrofurantoin macrocrystal, nitrofurantoin / nitrofuran mac, dirithromycin, gemifloxacin, ampicillin, gatifloxacin, ciprofloxacin, enoxacin, amoxicillin, clarithromycin, levofloxacin, moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin, trovafloxacin, lomefloxacin, erythromycin, norfloxacin, clindamycin, quinupristin, doxycycline, amikacin sulfate, vancomycin, kanamycin, netilmicin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetracycline, framycetin, minocycline, nalidixic acid, demeclocycline, trimethoprim, miconazole, colistimethate, paromomycin, sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate, metronidazole, oxacillin sodium, nafcillin sodium, vancomycin hydrochloride, clindamycin, cefotaxime sodium, co-trimoxazole, ticarcillin disodium, piperacillin sodium, ticarcillin disodium / clavulanate potassium, neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, penicillin, ceftriaxone sodium, ceftazidime, imipenem, aztreonam, cinoxacin, cefotetan disodium, cefoperazone sodium, cefamandole nafate, gentamicin, tobramycin, lincomycin, alatrofloxacin, linezolid, tetracycline, mupirocin, fosfomycin, pentamidine isethionate, imipenem / cilastatin, troleandomycin, gatifloxacin, chloramphenicol, cycloserine, meropenem, cephalosporins, fluconazole, cefepime, sulfamethoxazole, chloroquine phosphate, silver sulfadiazine, and combinations thereof.

[0076] In some embodiments, the analgesic agent is selected from the group consisting of acetaminophen, anileridine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, codeine, rofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride, levorphanol, alfentanil hydrochloride, meperidine, meperidine hydrochloride, methadone, morphine, nalbuphine, opium, levomethadyl, hyaluronate sodium, sufentanil citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, propoxyphene, benzocaine, lidocaine, dezocine, clonidine, butalbital, phenobarbital, tetracaine, phenazopyridine, sulfamethoxazole / phenazopyridine, sulfisoxazole / phenazopyridine, and combinations thereof.

[0077] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with, a disease or disorder. The terms“treat,” “treatment,” “treating,” or “amelioration” includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a skin disorder, including an inflammatory skin disease or wound. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disease or disorder is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers but can also include a cessation or at least slowing of progress or worsening of symptoms that would be expected in absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s) of an inflammatory skin disease, diminishment of extent of the inflammatory skin disease, stabilized (i.e., not worsening) state of the inflammatory skin disease, delay or slowing of progression of the disease, amelioration or palliation of the inflammatory skin disease state, and remission (whether partial or total), whether detectable or undetectable. The term “treatment” of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment). With regard to wound repair, the “treatment” is effective if the repair / closing of the wound progresses faster than in an absence of the treatment. Beneficial or desired clinical results for wound repair include, but are not limited to, alleviation of the inflammatory reaction, repair of the wound (fibroblast proliferation, blood vessel proliferation, and connective tissue synthesis), coverage by an epithelial barrier and wound contraction.

[0078] As used herein, the term “therapeutically effective amount” means that amount necessary, at least partly, to attain the desired effect (e.g., wound repair), or to delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the particular disease or disorder being treated (e.g., an inflammatory skin disease). Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters, including age, physical condition, size, weight and concurrent treatment. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. In some embodiments, a maximum dose of a therapeutic agent is used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a lower dose or tolerable dose can be administered for medical reasons, psychological reasons or for virtually any other reason.

[0079] In some embodiments, therapeutically effective amounts of an extract, a Lion’s Mane powder generated from mycelial biomass, a pharmaceutical formulation, or a composition described herein(e.g., a composition that includes an erinacine) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds which exhibit high therapeutic indices are preferred.

[0080] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For a compound used in the methods of the disclosure, a therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of disease or condition) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

[0081] In one embodiment, a therapeutically effective amount of an extract, a pharmaceutical formulation, a Lion’s Mane powder generated from mycelial biomass, or a composition described herein (e.g., a composition that includes an erinacine) for a method of treating an inflammatory skin disease, is an amount sufficient to reduce the level of at least one symptom of the inflammatory skin disease (e.g., pain, inflammation, itchiness, redness, pus, cytokine production, etc.) as compared to the level in the absence of the extract, the pharmaceutical formulation, or the composition. As described herein, the extract, the pharmaceutical formulation, or the composition can include a compound, or a combination of compounds. In other embodiments, the amount of the composition administered is preferably safe and sufficient to treat, delay the development of an inflammatory skin disease, and / or delay onset of the disease. In some embodiments, the amount can thus cure or result in amelioration of the symptoms of an inflammatory skin disease, slow the course of the disease, slow or inhibit a symptom of the disease, or slow or inhibit the establishment or development of secondary symptoms of the inflammatory skin disease. For example, an effective amount of a compound / composition described herein can inhibit further pain and / or inflammation associated with an inflammatory skin disease, cause a reduction in or even completely inhibit pain and / or inflammation associated with an inflammatory skin disease, even initiate completeregression of the disease, and reduce clinical symptoms associated with the inflammatory skin disease, or a combination thereof. In one embodiment, an effective amount for treating or ameliorating a disorder, disease, or condition is an amount sufficient to result in a reduction or complete removal of the symptoms of the disorder, disease, or condition. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. Thus, it is not possible or prudent to specify an exact “therapeutically effective amount.” However, for any given case, an appropriate “effective amount” can be determined by a skilled artisan according to established methods in the art using only routine experimentation.

[0082] In another embodiment, a therapeutically effective amount of an extract, a pharmaceutical formulation, a Lion’s Mane powder generated from mycelial biomass, or a composition described herein (e.g., a composition that includes an erinacine) for a method of treating a wound (i.e., wound repair), is an amount sufficient to show an increase in healing as compared to the time of healing in the absence of the extract, the pharmaceutical formulation, or the composition. As described herein, the extract, the pharmaceutical formulation, or the composition can include a compound or a combination of compounds.

[0083] The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein,“reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0084] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms“increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10- 100% as compared to a reference level, or at least about a 2-fold, or at least about a 3 -fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, at least about a 20- fold increase, at least about a 50-fold increase, at least about a 100-fold increase, at least about a 1000-fold increase or more as compared to a reference level.

[0085] The term “statistically significant” or “significantly” refers to statistical significance and generally means a two standard deviation (2SD) below normal, or lower. The term refers to statistical evidence that there is a difference. It is defined as the probability of making a decision to reject the null hypothesis when the null hypothesis is actually true. The decision is often made using the p-value.

[0086] In one aspect, the methods described herein provide methods for treating an inflammatory skin disease (e.g., contact dermatitis, atopic dermatitis, psoriasis, among others) in a subject. In another aspect, the methods described herein provide methods for treating a wound (e.g., a burn wound of the skin, a cut, an abrasion or a surgical incision) in a subject. In another aspect, the methods described herein provide methods for altering gene expression of a specific set of genes. In another aspect, the methods described herein provide methods for modulating an immune response. In one embodiment, the subject can be a mammal. In another embodiment, the mammal can be a human, although the approach is effective with respect to all mammals. The methods comprise administering to the subject an effective amount of an erinacine compound or a pharmaceutical composition comprising an erinacine compound in a pharmaceutically acceptable carrier. In some embodiments, the erinacine compound is erinacine C. In other embodiments, the methods comprise administering to the subject an effective amount of a Lion's Mane extract or a pharmaceutical composition comprising a Lion’s Mane extract or a Lion’s Mane powder generated from mycelial biomass, in a pharmaceutically acceptable carrier.

[0087] The dosage range for the disclosed compositions depends upon the potency, and includes amounts large enough to produce the desired effect, e.g., reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a skin disorder, including an inflammatory skin disease or wound, or altering gene expression. The dosage should not be so largeas to cause unacceptable adverse side effects. The dosage can be determined by one of skill in the art and can also be adjusted by the individual physician in the event of any complication.

[0088] Administration can be repeated for a period of time. In some embodiments, the doses are given once a day, or multiple times a day, for example but not limited to three times a day. In another embodiment, the doses are administered daily for several weeks or months. The duration of treatment depends upon the subject's clinical progress and responsiveness to therapy. Continuous, relatively low maintenance doses are contemplated after an initial higher therapeutic dose.

[0089] The compositions useful in the methods and compositions described herein can be formulated for administration topically, intravenously (by bolus or continuous infusion), orally, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intracavity, and can be delivered by peristaltic means, if desired, or by other means known by those skilled in the art. In one embodiment, the compositions for the methods described herein are formulated to be administered directly to a lesion or wound (e.g., during surgery or by direct injection or application).

[0090] In one particular embodiment, the composition is administered at a pre-psoriatic rim of the skin of the subject. The pre-psoriatic rim is normal looking skin that is substantially adjacent to a psoriatic lesion and characterized by at least one of the following as compared to normal skin: increased blood flow, fewer Langerhans cells, increased dilation of blood vessels, and increased T- cell infiltration.

[0091] Therapeutic compositions containing at least one active ingredient, e.g., an extract, or erinacine C, can be conventionally administered in a unit dose. The term “unit dose” when used in reference to a therapeutic composition refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required physiologically acceptable diluent, i.e., carrier, or vehicle.

[0092] The compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The quantity to be administered and timing depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired.

[0093] Precise amounts of the compounds or compositions required to be administered depend on the judgment of the practitioner and are particular to each individual. However, suitable dosage ranges depend on the route of administration. Suitable regimes for administration are also variable,but are typified by an initial administration followed by repeated doses at one or more intervals by a subsequent injection, topical administration, or other administration. Alternatively, continuous intravenous infusion sufficient to maintain concentrations in the blood in the ranges specified for in vivo therapies are contemplated.

[0094] The methods according to the disclosure include both systemic and / or local treatment. Accordingly, the compositions / compounds / extracts for use according to the disclosure may be administered orally, nasally, rectally, pulmonary, buccally or via subcutaneous, intravenous or intramuscular injection in order to reach the lesions from a distal administration, or by administering the composition locally, such as topically, dermally, intradermally or subcutaneously, or via dermal or subcutaneous infusion such as through microdialysis. However, commonly employed embodiments comprise topical administration. In one embodiment, the method comprises administration to the pre-psoriatic rim of a subject with psoriasis. In one embodiment, a composition such as an erinacine compound is topically administered to the pre-psoriatic rim, the area outside the visible psoriatic lesion. The pre-psoriatic rim is in a normal looking skin outside of the lesion and is confirmed by increased blood flow measured using laser Doppler technology. Laser-Doppler flow measurement is a technique for measuring localized superficial blood flow in the skin. In one embodiment, the method comprises administration to the area in and around a wound of the skin. In one embodiment, a composition such as an erinacine compound is topically administered to the wound and / or area around the wound. In one embodiment, a composition comprising a Lion’s Mane powder generated from mycelial biomass is topically administered to the wound and / or area around the wound.

[0095] In another aspect, the present disclosure provides methods of treating a skin disorder, such as an inflammatory skin disease (e.g., psoriasis and atopic dermatitis) or wound of the skin, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Lion’s Mane extract and a pharmaceutically acceptable carrier to a subject in need thereof. In a further aspect, the present disclosure provides methods of treating a skin disorder, such as an inflammatory skin disease or wound of the skin, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an erinacine compound and pharmaceutically acceptable carrier to a subject in need thereof. In another aspect, the present disclosure provides methods of treating a skin disorder, such as an inflammatory skin disease (e.g., psoriasis and atopic dermatitis) or wound of the skin, comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising Lion’s Mane mycelial powder and a pharmaceutically acceptable carrier to a subject in need thereof. In specific embodiments, the inflammatory skin disease is psoriasis. In one embodiment, the erinacine compound is an erinacine C compound.

[0096] In some embodiments, the expression of certain genes is decreased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein (see FIGs. 11 and 14). As also shown in FIG. 11, the same genes (which are decreased following the treatments described herein) show an increase in expression in psoriasis cells. As also shown in FIG. 14, the same genes (which are decreased following the treatments described herein) show an increase in expression in atopic dermatitis cells. In one embodiment, the administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein to a subject in need thereof (a subject with psoriasis) results in a decrease in gene expression for the genes shown in FIG.11. In one embodiment, the administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein to a subject in need thereof (a subject with atopic dermatitis) results in a decrease in gene expression for the genes shown in FIG.14.

[0097] In some embodiments, the expression of certain genes is increased relative to untreated control following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein (see FIGs. 12 and 15). As also shown in FIG. 12, the same genes (which are increased following the treatments described herein) show a decrease in expression in psoriasis cells. As also shown in FIG. 15, the same genes (which are increased following the treatments described herein) show a decrease in expression in atopic dermatitis cells. In one embodiment, the administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein to a subject in need thereof (a subject with psoriasis) results in an increase in gene expression for the genes shown in FIG.12. In one embodiment, the administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein to a subject in need thereof (a subject with atopic dermatitis) results in an increase in gene expression for the genes shown in FIG.15.

[0098] In some embodiments, the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBB, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS, and combinations thereof is decreased following administration of the Lion’s Mane extract, erinacinecompounds and / or pharmaceutical compositions described herein. In some embodiments, the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0099] In some embodiments, the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBB, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein. In some embodiments, the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration of the Lion’s Mane extract, erinacine compounds and / or pharmaceutical compositions described herein.

[0100] Pharmaceutical Compositions

[0101] The present disclosure includes, but is not limited to, therapeutic compositions useful for practicing the therapeutic methods described herein. In one aspect, the present disclosure provides pharmaceutical compositions for treating a skin disorder, such as an inflammatory skin disease or wound of the skin, comprising a therapeutically effective amount of an erinacine compound (or alternatively, Lion’s Mane extract or mycelial powder) and a pharmaceutically acceptable carrier. In one embodiment, the erinacine compound is an erinacine C compound. In some embodiments, the erinacine compound is a synthetic compound.

[0102] Therapeutic compositions contain a physiologically tolerable carrier together with an active agent as described herein, dissolved or dispersed therein as an active ingredient. In an embodiment, the therapeutic composition is not immunogenic when administered to a mammal or human patient for therapeutic purposes. As used herein, the terms “pharmaceutically acceptable”, “physiologically tolerable” and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like. A pharmaceutically acceptable carrier will not promote the raising of an immune response to an agent with which it is admixed, unless so desired. The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Typically, such compositions are prepared as injectable either as liquid solutions or suspensions,however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified or presented as a liposome composition. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. The therapeutic composition of the present disclosure can include pharmaceutically acceptable salts of any of the components therein. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. Physiologically tolerable carriers are well known in the art. Exemplary liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate- buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, and water-oil emulsions. The amount of an active agent used in the methods described herein that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques.

[0103] The topical formulations according to the disclosure comprise an active ingredient (e.g., an erinacine compound) together with one or more pharmaceutically acceptable carrier and / or excipient compounds and optionally one or more additional therapeutically active ingredient.

[0104] Formulations suitable for topical administration may be formulated into any pharmaceutical form normally employed for such an application, these include liquid or semi-liquid preparations including lotions, creams, pastes, ointments, liposomes, gels, such as for iontopophoresis,suspensions and emulsions, including oil / water (w / o), w / o, o / w / o, w / o / w emulsions or microemulsions. They may suitably be obtained by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a hydrophobic or hydrophilic basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, waxes (e g., beeswax, carnauba wax), metallic soap, a mucilage, an oil of natural origin such as corn, almond, castor, or olive oil, mineral oils, animal oils (perhydroxysqualene); or a fatty acid such as stearic or oleic together with an alcohol such as ethanol, isopropanol, and propylene glycol. The formulation may include any suitable surface-active agent such as an anionic, cationic, or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums; cellulose derivatives or inorganic materials such as silicas may also be included. The formulations may additionally comprise absorption promoters, stabilizers, e.g. protein stabilizing agents, known in the art.

[0105] In another aspect, the present disclosure provides pharmaceutical compositions for treating a skin disorder, such as an inflammatory skin disease or wound of the skin, comprising an erinacine compound at a therapeutically effective concentration; a liquid oil component, wherein the liquid oil component comprises one or more materials that are practically insoluble or insoluble in water and which are liquid at room temperature of 22° C.; and an aqueous component.

[0106] In another aspect, the present disclosure provides pharmaceutical compositions for treating a skin disorder, such as an inflammatory skin disease or wound of the skin, comprising a Lion’s Mane powder generated from mycelial biomass at a therapeutically effective concentration; a liquid oil component, wherein the liquid oil component comprises one or more materials that are practically insoluble or insoluble in water and which are liquid at room temperature of 22° C.; and an aqueous component.

[0107] In one embodiment, the pharmaceutical composition is formulated as a lotion.

[0108] In one embodiment, the erinacine compound is erinacine C. In a specific embodiment, the erinacine compound is dissolved in the liquid oil component at room temperature.

[0109] In one embodiment, the liquid oil component comprises a dicarboxylic acid ester, a monocarboxylic ester, or a combination thereof. In a specific embodiment, the liquid oil component comprises a dicarboxylic acid ester. In a specific embodiment, the liquid oil component comprises a monocarboxylic acid ester.

[0110] In one embodiment, the liquid oil component further comprises mineral oil or light mineral oil.

[0111] In another embodiment, the composition further comprises one or more humectants, preservatives, chelating agents, emulsifying agents, pH adjusting agent, and / or thickening agents.

[0112] In one embodiment, the composition is capable of providing a synergistic efficacy when the composition is used to treat psoriasis.

[0113] In one embodiment, the composition is capable of providing a synergistic reduction in at least one adverse event when the composition is used to treat psoriasis, wherein the adverse event is selected from the group consisting of itching, burning, stinging, and combinations thereof.

[0114] In one embodiment, the composition is capable of providing a synergistic efficacy when the composition is used to treat / repair a wound.

[0115] In one embodiment, the composition is capable of providing a synergistic reduction in at least one adverse event when the composition is used to treat / repair a wound, wherein the adverse event is selected from the group consisting of itching, burning, stinging, and combinations thereof.

[0116] In some embodiments, a topical composition of the disclosure further comprises at least one ingredient selected from the group consisting of: Glyceryl Stearate & PEG-100 Stearate, Cetyl Alcohol, Allantoin, Butyrospermum Parkii, Petrolatum, Steareth-21, Tocopheryl Acetate, Lavandula Angustifolia oil, Xanthan Gum, Dipotassium Glycyrrhizate, Aloe Barbadensis Leaf Juice, Triethanolamine, Bisabolol, Disodium EDTA, vitamin B3, keratolytic agent, anti-irritation agent, anti-oxidant, terpene, cannabis terpene, anti-skin redness agent, anti-adherent, binder, coating, disintegrant, flavor, color, lubricant, glidant, sorbent, preservative, filler, emulsifier, humectant, thickener, skin nourishing agent, skin moistening agent, occlusive agent, emollient agent, calming agent, natural smell agent, suspending agent, soothing agent, pH adjustment agent, complexant, purified water, Shea Butter, cannabis oil, Lavender Oil, stearic acid (or derivatives thereof) and any combination thereof.

[0117] In some embodiments, a topical composition of the disclosure further comprises at least one antimicrobial agent / ingredient selected from the group consisting of loracarbef, cephalexin, cefadroxil, cefixime, ceftibuten, cefprozil, cefpodoxime, cephradine, cefuroxime, cefaclor, neomycin, dicloxacillin, nitrofurantoin, nitrofurantoin macrocrystal, nitrofurantoin / nitrofuran mac, dirithromycin, gemifloxacin, ampicillin, gatifloxacin, ciprofloxacin, enoxacin, amoxicillin, clarithromycin, levofloxacin, moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin,trovafl oxaci n, lomefloxacin, erythromycin, norfloxacin, clindamycin, quinupristin, doxycycline, amikacin sulfate, vancomycin, kanamycin, netilmicin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetracycline, framycetin, minocycline, nalidixic acid, demeclocycline, trimethoprim, miconazole, colistimethate, paromomycin, sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate, metronidazole, oxacillin sodium, nafcillin sodium, vancomycin hydrochloride, clindamycin, cefotaxime sodium, co-trimoxazole, ticarcillin disodium, piperacillin sodium, ticarcillin disodium / clavulanate potassium, neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, penicillin, ceftriaxone sodium, ceftazidime, imipenem, aztreonam, cinoxacin, cefotetan disodium, cefoperazone sodium, cefamandole nafate, gentamicin, tobramycin, lincomycin, alatrofloxacin, linezolid, tetracycline, mupirocin, fosfomycin, pentamidine isethionate, imipenem / cilastatin, troleandomycin, gatifloxacin, chloramphenicol, cycloserine, meropenem, cephalosporins, fluconazole, cefepime, sulfamethoxazole, chloroquine phosphate, and silver sulfadiazine.

[0118] In some embodiments, a topical composition of the disclosure further comprises at least one analgesic agent selected from the group consisting of acetaminophen, anileridine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, codeine, rofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride, levorphanol, alfentanil hydrochloride, meperidine, meperidine hydrochloride, methadone, morphine, nalbuphine, opium, levomethadyl, hyaluronate sodium, sufentanil citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, propoxyphene, benzocaine, lidocaine, dezocine, clonidine, butalbital, phenobarbital, tetracaine, phenazopyridine, sulfamethoxazole / phenazopyridine, and sulfi soxazol e / phenazopy ri dine .

[0119] In another embodiment, the composition for topical application may be dissolved in a lipophilic solvent or suspension carrier selected from a group consisting of medium-chain triglyceride, short-chain triglyceride, medium-chain partial glyceride, polyoxyethylated fatty alcohol, polyoxyethylated fatty acid, polyoxyethylated fatty acid triglyceride or partial glyceride, ester of fatty acids with low molecular weight alcohols, a partial ester of sorbitan with fatty acids, a polyoxyethylated partial ester of sorbitan with fatty acids, a partial ester of sugars or oligomeric sugars with fatty acids, a polyethylene glycol, lecithin, vegetable oil, and any combination thereof.

[0120] An example topical pharmaceutical composition of the disclosure comprises:(a) a pharmaceutically acceptable carrier formulation comprising one or more of:Glyceryl Stearate PEG- 100 Stearate Glycerin Niacinamide Cetyl Alcohol Salicylic Acid AllantoinButyrospermum Parkii Petrolatum Steareth-21Tocopheryl AcetateLavandula Angustifolia oil Xanthan GumDipotassium Glycyrrhizate Aloe Barbadensis Leaf Juice Triethanolamine BisabololDi sodium EDTAP-Caryophyllene 0.5% cannabis oil; and(b) erinacine C or Lion’s Mane Extract.

[0121] It is understood that the foregoing description and the following examples are illustrative only and are not to be taken as limitations upon the scope of the disclosure. Various changes and modifications to the disclosed embodiments, which will be apparent to those of skill in the art, may be made without departing from the spirit and scope of the present disclosure. Further, all patents, patent applications, and publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0122] As used herein the term “consisting essentially of’ refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the disclosure.

[0123] The term “consisting of’ refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0124] Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0125] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean±l%.

[0126] It should be understood that embodiments of this disclosure are not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of embodiments of the present disclosure, which is defined solely by the claims.

[0127] The following examples further illustrate embodiments of the disclosure but, of course, should not be construed as in any way limiting its scope.EXAMPLES

[0128] EXAMPLE 1

[0129] Materials and Methods

[0130] Lion ’s mane extract prep

[0131] Mycelia used for extract preparation or compound separation was grown in 1 L baffled flasks, seeded with 15mL blended inoculum in 300 mL media in an incubator- shaker set to 120 rpm at 26 °C. Biomass was harvested 14-20 days after inoculation by pouring mixture through a sterile miracloth and collecting resulting material after three washes with ultra-pure water. Myceliabiomass was then dried for several hours in an industrial oven until all water content was removed and then stored at -70° C.

[0132] To make Lion’s mane extracts, the saved biomass was removed from the freezer and allowed to thaw to room temperature. The sample was centrifuged for 10 minutes @ 8000 rpm, 4° C to remove any residual media. The biomass was then ground into a fine frozen powder using liquid nitrogen and a mortar and pestle and incubated with sterile 70% EtOH (1g biomass: lOmls solvent) for 24hrs on a heat block set at 50° C. After incubation, the samples were centrifuged at 8k rpm / 4° C for 10 minutes and resulting supernatant collected and biomass discarded. The supernatant was then run through a 0.2 uM filter and dried to completion using a rotovap. The final sample was rehydrolyzed to the desired concentration with the appropriate buffer for cell culture treatments.

[0133] Cell Culture and RNA isolation

[0134] Human Fibroblasts (hFBs) (Cat#C0045C) were obtained from Thermofisher (https: / / www.thermofisher.com / us / en / home.html) and cultured in Human Fibroblast Expansion Basal Medium (Cat#M106500) with the Low Serum Growth Supplement (Cat#S00310). hFBs were subcultured at 70% confluency every 2-3 days using 0.05% Trypsin. hFBs were seeded at 3 x 105cells per 60 mm dishes. After 24 h, media was replaced with fresh media containing Lion’s mane extract between 0-0.25% media concentation or vehicle alone. After 24 h, cells were washed once with DPBS and lysed in Quick-RNA MiniPrep Kit lysis buffer (Cat# R1055)(www.zymoresearch.com) and RNA isolated according to the manufacturer’s recommendations.

[0135] Results

[0136] Lion’s Mane (LM) extract has been shown to induce nerve growth factor (NGF) in nerve- associated cells (Mori K, Obara Y, Hirota M, Azumi Y, Kinugasa S, Inatomi S, Nakahata N. Nerve growth factor-inducing activity of Hericium erinaceus in 132 INI human astrocytoma cells. Biol Pharm Bull. 2008 Sep;31(9):1727-32. doi: 10.1248 / bpb.31.1727. PMID: 18758067; Kawagishi H., Ando M., Sakamoto H., et al. Hericenones C, D and E, stimulators of nerve growth factor (NGF)- synthesis, from the mushroom Hericium erinaceum. Tetrahedron Letters. 1991;32(35):4561-4564. doi: 10.1016 / 0040-4039(91)80039-9; Kawagishi H., Shimada A., Shirai R., et al. Erinacines A, B and C, strong stimulators of nerve growth factor (NGF)-synthesis, from the mycelia of Hericium erinaceum. Tetrahedron Letters._1994;35(10):1569-1572. doi: 10.1016 / S0040-4039(00)76760-8; Zhang CC, Yin X, Cao CY, Wei J, Zhang Q, Gao JM. Chemical constituents from Hericium erinaceus and their ability to stimulate NGF -mediated neurite outgrowth on PC12 cells. Bioorg MedChem Lett. 2015 Nov 15;25(22):5078-82. doi: 10.1016 / j.bmcl.2015.10.016. Epub 2015 Oct 16. PMID: 26481911), which provides protective effects in this tissue type. It is also known that the inclusion of NGF as a topical agent in wound repair models accelerates healing in skin tissue (Kawamoto K, Matsuda H. Nerve growth factor and wound healing. Prog Brain Res. 2004; 146:369- 84. doi: 10.1016 / S0079-6123(03)46023-8. PMID: 14699974; Muangman P, Muffley LA, Anthony JP, Spenny ML, Underwood RA, Olerud JE, Gibran NS. Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regen. 2004 Jan-Feb; 12(l):44-52. doi: 10.111 l / j.1067- 1927.2004.012110.x. PMID: 14974964; Lawman MJ, Boyle MD, Gee AP, Young M. Nerve growth factor accelerates the early cellular events associated with wound healing. Exp Mol Pathol. 1985 Oct;43(2):274-81. doi: 10.1016 / 0014-4800(85)90048-6. PMID: 4043347), so a goal of the study was to determine if the LM extract could induce NGF in a skin cell line as a potential treatment for a variety of skin injuries and / or diseases. Most skin conditions have some element of skin barrier dysfunction. Thus, wound healing and the reintegration of the barrier is needed for the resolution of the majority of skin diseases.

[0137] Before testing the LM extract on skin cells, it was determined whether the extracts could replicate known phenotypic changes observed in nerve-associated cells from previous studies (Rascher M, Wittstein K, Winter B, Rupcic Z, Wolf-Asseburg A, Stadler M, Koster RW. Erinacine C Activates Transcription from a Consensus ETS DNA Binding Site in Astrocytic Cells in Addition to NGF Induction. Biomolecules. 2020 Oct 14; 10(10): 1440. doi: 10.3390 / bioml0101440. PMID: 33066380; PMCID: PMC7602259). The glioblastoma derived T98G cell line was plated at a density of 5 x 105cells per well in 6-well dishes in 10% FBS MEM media with ImM sodium pyruvate and non-essential amino acids. After 24 h, media was replaced with fresh media containing several concentrations of Lion’s mane extract (2%, 1% and 0.5%) or vehicle alone (70% EtOH) for 24 hrs (FIG. 1).

[0138] Treatment of the T98G cells with the LM extract produced dose-responsive morphologic changes over controls in this cell type typical of NGF induction (FIG. 1). After 24 hours, the extract-treated cells appeared more differentiated, becoming more elongated than round with the development of cell-to-cell connections (FIG. 1). To confirm the induction of NGF with the LM extract, mRNA was harvested from the 2% extract-treated and vehicle alone cells 24 hrs after treatment. A significant 3.4-fold increase (p= 9 x 10’4, ttest) in NGF gene expression was observed due to the extract over EtOH vehicle control (FIG. 2). Results from the experiments with the T98Gcells confirmed that the LM extracts are bioactive and capable of induction of NGF gene expression in this cell type.

[0139] Confident that the LM extract has bioactivity based on the results using a cell type known to be responsive to it, it was decided to treat human skin cells to see what effect it would have on this cell type. Human primary fibroblasts (hFBs) were purchased from Thermofisher (Cat#C0045C), cultured in Human Fibroblast Expansion Basal Medium (Cat#Ml 06500) with the Low Serum Growth Supplement (Cat#S00310), and plated on 6-well plates (lOOmm / well) at a density of 1.5 x 105cells / well. After 24 hrs. the media was removed and replaced with media plus LM extract (2%) or vehicle alone (70% EtOH @ 2%). Cells were visually inspected microscopically 48 and 72 hrs after treatment. Cells treated with LM extract demonstrated morphological changes over controls that were consistent with induced differentiation (FIG. 3). hFB cells treated with LM extract demonstrated dramatically decreased cell proliferation over controls, indicative of cells becoming more specialized. The formation of complex extra-cellular structures connecting the cells typically associated with cell differentiation was observed (Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Fibroblasts and Their Transformations: The Connective-Tissue Cell Family). The results demonstrate that LM extract is bioactive in a prominent human skin cell type.

[0140] Gene expression profiling was then used to determine the mechanism for the observed morphological changes in this cell type. There was interest in determining whether the LM extract is capable of inducing NGF in the fibroblasts because of its potential in accelerating wound healing. Human primary fibroblasts were plated and treated with LM extract at a concentration of 0.25% media, vehicle alone (EtOH @ 0.25%) or media alone. Total RNA was then extracted, sequenced and quantified for all detectable human gene transcription using RNAseq. Results for NGF expression with these treatments demonstrated a clear induction of NGF over vehicle and media controls with LM extract (FIG. 4).

[0141] Applicants were also interested in what other changes to gene expression were induced with the addition of LM extract in this cell type. 9,026 gene transcripts (out of a total of -55,000) that had altered expression (P< 0.05, ttest) compared to the vehicle alone control were observed. This list was submitted for gene set enrichment analysis (www.gsea-msigdb.or / ) (Subramanian A, Tamayo P, Mootha VK, Mukheijee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach forinterpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43): 15545-50. doi: 10.1073 / pnas.0506580102. Epub 2005 Sep 30. PMID: 16199517; PMCID: PMC1239896; Mootha, V., Lindgren, C., Eriksson, KF. et al. PGC- la-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34, 267-273 (2003). doi.org / 10.1038 / ngl 180), a computational method that determines whether an a priori defined set of genes shows statistically significant, concordant differences between two biological states (e.g., phenotypes). Highlights from this analysis are given in Table 1, but, overall, the changes in gene expression were consistent with upregulation of protective pathways and cellular metabolism and downregulation of mitosis and cytokine signaling, which is consistent with changes observed in skin wound repair.

[0142] Table 1. Cellular pathways affected by LM extract.

[0143] A psoriasis profile of gene expression was created using the average fold change from 50 psoriasis biosets collected from the NCBI Gene Expression Omnibus database (ncbi.nlm.nih.gov / geo / ) comparing disease vs. normal skin samples(ncbi.nlm.nih.gov / gds / ?term=psoriasis) (FIG. 9 and 10). The monoclonal antibody results were obtained from the results of a phase-3 clinical trial (GEO Acc# GSE117468) in skin biopsies of plaque psoriasis patients treated with brodalumab or ustekinumab for 12 weeks versus matchedcontrols (Tomalin et al., J Allergy Clin Immunol. 2020 Mar;145(3):922-932. Epub 2019 Dec 27). These data indicate that the expression of certain genes that correlate with the presence of psoriasis can be selectively modulated in the opposite direction by LM extract and by erinacine C. That is, it is possible to reduce the expression of genes that show increased expression in psoriasis, and it is possible to increase the expression of genes that show reduced expression in psoriasis. Moreover, two monoclonal antibodies are being investigated as psoriasis treatments, and there is striking overlap in the effect LM and erinacine C have on gene expression and the effect two monoclonal antibodies have on gene expression. These data are consistent with the inventors' reasonable expectation that LM extract and erinacine C treatment can reduce psoriasis.

[0144] An atopic dermatitis (AD) profile of gene expression was created using the average normalized fold change from 15 AD biosets collected from the NCBI Gene Expression Omnibus database (ncbi.nlm.nih.gov / geo / ) comparing disease vs. normal skin samples (ncbi.nlm.nih.gov / gds / ?term=psoriasis) (FIGs. 13 and 14 and 15). These data indicate that the expression of certain genes that correlate with the presence of AD can be selectively modulated in the opposite direction by LM extract and by erinacine C. That is, it is possible to reduce the expression of genes that show increased expression in AD, and it is possible to increase the expression of genes that show reduced expression in AD. Moreover, two monoclonal antibodies are being investigated as skin inflammatory disease treatments, and there is striking overlap in the effect LM and erinacine C have on gene expression and the effect four current AD therapies have on gene expression. These data are consistent with the inventors' reasonable expectation that LM extract and erinacine C treatment can reduce the effects from AD.

[0145] Next, it was determined whether the LM extract was capable of reversing the changes in gene expression that occur with many types of skin injury and disease, providing a potential therapy to these conditions. We submitted our list of genes altered with 0.25% LM extract in our human fibroblasts to an expression database that compares gene expression signatures to its extensive collection of human diseases expression signatures. Significant matches are scored based on a 1-100 scale, with 100 being the most significant correlation and those closer to 1 being the least significant. The search was restricted to skin disorders and looked for matches that produced a negative correlation to the LM transcription signature. Results from this analysis produced a wide range of skin conditions where the changes in gene expression show the opposite trends with LMextract (Table 2). It was hypothesized that skin conditions showing the gene expression patterns that are opposite those caused by LM extract could be treated by administration of LM extract.

[0146] Table 2. List of skin disorders with a significant negative correlation to the gene expression signature produced with M treatment in hFBs.

[0147] An attempt was made to identify specific bioactive(s) in the LM extracts responsible for the observed changes in this skin cell type. LM extracts were fractionated into 95 components using automated mass spectrometry (FIG. 5). Fractions were isolated containing the two most abundant erinacines in the extract (erinacines A and C) as well as a related, different class of diterpene (cyathin T) to test on the fibroblast cell line. Purified extracts of other natural bioactives (ergothionene and beta-carotene) not found in the LM extract were also compared to the other signatures. Treatment of hFB cells with cell media or vehicle- alone was used as controls. Overall transcriptional response was summarized using principle component analysis and plotted in 2D (FIG. 6). Results of this analysis demonstrate a clear correlation between the types of gene signatures produced by erinacine C and those produced using the entire LM extract, suggesting that erinacine C is the main extract component driving the majority of bioactivity in this cell type.

[0148] A more direct comparison of the genes that change due to LM extract and erinacine C provide further support for this compound being the main bioactive in the LM extract (FIG. 7). It was found that 77% and 75% of the genes responsive to LM extract and erinacine C respectively arecommon to both groups, with -99% of these common genes showing the same trends with treatment (i.e. increased or decreased expression in response to both treatments). The probability of attaining these results by random chance are below 1 x 10'323(Fisher’s exact test).

[0149] Given how similar the overall gene expression response to erinacine C was to the entire LM extract, we wanted to confirm it was capable of also inducing NGF expression. Again, the addition of NGF in skin wound models accelerates healing (Kawamoto K, Matsuda H. Nerve growth factor and wound healing. Prog Brain Res. 2004;146:369-84. doi: 10.1016 / S0079-6123(03)46023-8.PMID: 14699974., Muangman P, Muffley LA, Anthony JP, Spenny ML, Underwood RA, Olerud JE, Gibran NS. Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regen. 2004 Jan-Feb; 12(l):44-52. doi: 10.1111 / j.l067-1927.2004.012110.x. PMID: 14974964., Lawman MJ, Boyle MD, Gee AP, Young M. Nerve growth factor accelerates the early cellular events associated with wound healing. Exp Mol Pathol. 1985 Oct;43(2):274-81. doi: 10.1016 / 0014- 4800(85)90048-6. PMID: 4043347) and therefore the ability of erinacine C to induce this important growth factor was seen as critical for potential therapeutic uses. Only erinacine C and total LM extract were shown to significantly induce NGF in the hFB cell type (FIG. 8). Moreover, the potential of erinacine C to reverse the changes in gene expression due to a wide range of skin disorders (Table 3) was also demonstrated.

[0150] Tabel 3. Lst of skin disorders with a significant negative correlation to the gene expression signature produced with erinacine C fraction (2% in cell media versus 70% EtOH vehicle) from treatment in hFBs.

[0151] Psoriasis is regarded as a T-cell-mediated disease, whereby Thl and Thl7 T-cell pathways are continuously turned on, driving the pathological hyper-proliferation, amplification and aberrant differentiation of skin cells, resulting in thick, painful plaques in genetically susceptible individuals (Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasisvulgaris lesions contain discrete populations of Thl and Thl 7 T cells. J InvestDermatol. 2008;128:1207-11; Tassiulas I, Duncan SR, CentolaM, Theofilopoulos AN, Boumpas DT. Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis. Hum Immunol. 1999;60:479-91 ; Raychaudhuri SP. Role of IL-17 in psoriasis and psoriatic arthritis. Clin Rev Allergy Immunol. 2013;44: 183-93). We observed a significant number of genes associated with the Gene Ontology (GO) category of T cell activation (p= 1 x 10'4) were induced in psoriasis and demonstrated a decrease in expression due to the erinacine C and lion’s mane (LM) total extract. The 11 genes involved in T-cell activation (BAX, BLM, CASP8, CTPS1, DOCK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22 and THEMIS) had an average normalized fold increase in expression of +1.9 in the psoriasis meta-signature, while the average fold decrease in expression of these genes due to erinacine C and LM total extract were -3.6 for both treatments. (FIG. 10). Among other relevant GO categories associated with an increase in expression due to psoriasis and a decrease with the LM extracts, we found 104 genes associated with cell division (p= 1 x 10’"), 11 genes associated with activation of innate immune response (p= 4 x IO’3) and 20 genes associated with positive regulation of cytokine production (p= 9 x 10‘9) (FIG. 10).

[0152] Among the genes that showed decreased expression due to psoriasis that were induced by our LM extracts, we found many that were indicative of cell growth and repair. The betacellulin gene, a member of the epithelial growth factor family, had the sixth greatest negative change due to disease in our psoriasis meta-signature (-12.4 normalized fold change compared to healthy control). This gene showed a positive fold increase in gene expression of 17.9 and 14.7 due to the erinacine C and LM total extract respectively in treated vs. vehicle alone human primary fibroblast cells. (FIG. 10). We also note that the two monoclonal antibody (mAb) treatments currently in use for moderate to severe psoriasis also stimulated this gene compared to disease control (+9.2 with Brodalumab and +11.5 with ustekinumab), although not to the extent of the lion’s mane extracts. (FIG. 10). Another member of this same class of genes, epidermal growth factor, also showed decreases in gene expression due to psoriasis (-2.6 normalized fold change) that was induced by erinacine C (+9.6 fold), LM total extract (+17.4 fold) and mAb treatment (+1.8 fold with Brodalumab and +1.7 fold with Ustekinumnab) (FIG. 10). Other growth factor-related genes with similar decreases in gene expression due to psoriasis and increases due to the lion’s mane extracts include fibroblast growth factor 13 and the receptor fibroblast growth factor receptor-like 1, platelet-derived growth factor alpha polypeptide and vascular endothelial growth factor B (FIG. 10).

[0153] Atopic dermatitis is the most common form of eczema, and it typically begins during childhood. The disease presents as a recurrent, chronic, non-infectious inflammatory dermatosis characterized by persistent itching of the skin. The pathophysiology of atopic dermatitis is complex and multifactorial, with the most important factors being: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. To examine whether the lion’s mane extract affected genes known to have a genetic link to AD, we compared the genes that were differentially expressed due to the lion’s mane extract to several genome-wide association studies on AD in a variety of populations (Hirota, T., Takahashi, A., Kubo, M. etal. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 44, 1222-1226 (2012); Paternoster, L., Standi, M., Chen, CM. et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet 44, 187-192 (2012); Baurecht H, Hotze M, Brand S, et al. Genomewide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am J Hum Genet. 2015 Jan 8;96(l):104-20). We found significant matches to AD- linked genes in cohorts of Japanese (20 genes; p=0.007), Chinese (7 genes; p=0.0005), European (5 genes; p=0.0025) and mixed (3 genes; p=0.004) ancestry. We also note the over-representation of genes associated with the Gene Ontology (GO) categories of regulation of establishment of endothelial barrier (7 genes; p=6xl0'5), negative regulation of the immune response (88 genes; p=5xl0'27) and skin epidermis development (25 genes; p=lxl0’9) among others in the genes affected by lion’s mane total extract treatment. (FIG. 14 and 15)

[0154] We also compared the transcription profiles produced from the total lion’s mane extract and erinacine C fraction to those generated with approved therapeutics currently in use for AD (FIG. 16). The monoclonal antibody (mAb) dupilumab, approved by the U.S. Food and Drug Administration for the treatment of AD since 2017, inhibits IL4 and IL13 signaling in type 2-driven inflammation linked to atopic and allergic diseases. In a research study that looked at efficacy, safety, and effects of dupilumab on moderate to severe AD (Emma Guttman- Yassky, Robert Bissonnette, Benjamin Ungar, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2019 Jan;143(l):155-172), we identified 1188 genes differentially expressed after 4 weeks on 200mg dupilumab compared to placebo that were also affected by 0.25% LM total extract treatment for 24 hrs in hFB cells versus media alone (p=5.6xl0‘17). Among these common genes,207 genes had an increase in expression and 523 genes had a decrease in expression with both treatments. The probability of obtaining these results by random chance is 2.9xl0'6and 6.1xl0'34respectively (modified Fisher’s exact test). We also note significant positive correlations of our LM extract transcriptional signature to AD treatments: gusacitinib at 80mg for 24hrs (p=3.0xl0‘27) (Pavel AB, Song T, Kim HJ, et al. Oral Janus kinase / SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2019 Oct; 144(4): 1011-1024), crisaborole at 2% for 8 days (p=l.lxl0‘24) (Bissonnette R, Pavel AB, Diaz A, et al. Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial. J Allergy Clin Immunol. 2019 Nov; 144(5): 1274- 1289), and cyclosporine A at 5mg / kg / day for 2 weeks (p=3.5xl0'17)(Khattri S, Shemer A, Rozenblit M, Dhingra N et al. Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. J Allergy Clin Immunol 2014 Jun; 133(6): 1626-34).

Claims

CLAIMS:

1. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of Lion’s Mane (Herichim erinaceus) extract to a subject in need thereof, wherein the inflammatory skin disease is psoriasis.

2. The method of claim 1, wherein the administration is topical administration.

3. The method of claim 2, wherein the extract is applied twice daily.

4. The method of claim 2, wherein the extract is administered at a pre-psoriatic rim on the skin of the subject.

5. The method of claim 2, wherein the extract is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, fdm, transdermal patch and any combination thereof.

6. The method of claim 2, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

7. The method of claim 6, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered extract so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

8. The method of claim 7, wherein the synergistic effect provided is with respect to at least one of (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

9. The method of claim 1, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBB, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

10. The method of claim 1, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

11. The method of claim 6, wherein the topically administered extract provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

12. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Lion’s Mane (Hericium erinaceus) extract and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the inflammatory skin disease is psoriasis.

13. The method of claim 12, wherein the administration comprises topical administration.

14. The method of claim 12, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21 , tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

15. The method of claim 13, wherein the pharmaceutical composition is applied twice daily.

16. The method of claim 13, wherein the extract is administered at a pre-psoriatic rim on the skin of the subject.

17. The method of claim 13, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

18. The method of claim 13, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine,hydroxy carbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

19. The method of claim 17, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

20. The method of claim 19, wherein the synergistic effect provided is with respect to at least one of: (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

21. The method of claim 12, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

22. The method of claim 12, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

23. The method of claim 13, wherein the topically administered extract provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

24. A method of treating an inflammatory skin disease, comprising topically administering at a pre-psoriatic rim on the skin of the subject a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutical composition comprising Lion’s Mane (Herichim erinaceus) extract and a pharmaceutically acceptable carrier, wherein the pre-psoriatic rim is a normal looking skin that is substantially adjacent to a psoriatic lesion and characterized by at least one of the following as compared to normal skin: increased blood flow, fewer Langerhans cells, increased dilation of blood vessels, and increased T-cell infiltration.

25. The method of claim 24, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

26. The method of claim 24, wherein the pharmaceutical composition is applied twice daily.

27. The method of claim 24, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

28. The method of claim 24, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

29. The method of claim 28, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

30. The method of claim 29, wherein the synergistic effect provided is with respect to at least one of: (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

31. The method of claim 24, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBB, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

32. The method of claim 24, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

33. The method of claim 28, wherein the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

34. The method of claim 28, wherein the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

35. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of an erinacine compound to a subject in need thereof, wherein the inflammatory skin disease is psoriasis.

36. The method of claim 35, wherein the administration is topical administration.

37. The method of claim 35, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

38. The method of claim 35, wherein the erinacine compound is erinacine C.

39. The method of claim 36, wherein the erinacine compound is applied twice daily.

40. The method of claim 36, wherein the erinacine compound is administered at a pre- psoriatic rim of the skin of the subject.

41. The method of claim 36, wherein the erinacine compound is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch, and any combination thereof.

42. The method of claim 36, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

43. The method of claim 42, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered erinacine compound so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

44. The method of claim 43, wherein the synergistic effect provided is with respect to at least one of: (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

45. The method of claim 35, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

46. The method of claim 35, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

47. The method of claim 42, wherein the topically administered erinacine compound provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

48. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an erinacine compound and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the inflammatory skin disease is psoriasis.

49. The method of claim 48, wherein the administration is topical administration.

50. The method of claim 48, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.51 . The method of claim 48, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

52. The method of claim 49, wherein the pharmaceutical composition is applied twice daily.

53. The method of claim 49, wherein the pharmaceutical composition is administered at a pre-psoriatic rim on the skin of the subject.

54. The method of claim 49, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

55. The method of claim 49, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

56. The method of claim 55, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

57. The method of claim 56, wherein the synergistic effect provided is with respect to at least one of (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

58. The method of claim 48, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

59. The method of claim 48, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

60. The method of claim 55, wherein the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

61. A method of treating psoriasis, comprising administering at a pre-psoriatic rim on the skin of the subject a pharmaceutical composition comprising a therapeutically effective amount of an erinacine compound and a pharmaceutically acceptable carrier, wherein the pre-psoriatic rim is a normal looking skin that is substantially adjacent to a psoriatic lesion and characterized by at least one of the following as compared to normal skin: increased blood flow, fewer Langerhans cells, increased dilation of blood vessels, and increased T-cell infiltration.

62. The method of claim 61, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21 , tocopheiyl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

63. The method of claim 61, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

64. The method of claim 61, wherein the pharmaceutical composition is applied twice daily.

65. The method of claim 61, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

66. The method of claim 61, further comprising administration of at least one additional therapeutic agent selected from the group consisting of methotrexate, cyclosporine, hydroxycarbamide, fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives thereof, and any combination thereof.

67. The method of claim 66, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

68. The method of claim 67, wherein the synergistic effect provided is with respect to at least one of (a) inhibition of proliferation; (b) inhibition of inflammation; and (c) inhibition of epidermal turnover rate.

69. The method of claim 61, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBI3, FKBP1A, FKBP1B, PRKDC, PTN22, THEMIS and combinations thereof is decreased following administration.

70. The method of claim 61, wherein the expression of genes selected from the group consisting of BTC, EGF, FGF13, FGFRL1, PDGFA, VEGFB, and combinations thereof is increased following administration.

71. The method of claim 66, wherein the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of hyperproliferation, reduction of skin inflammation, reduction of epidermal turnover rate, and any combination thereof, as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

72. A pharmaceutical composition for treating a skin disorder, comprising a therapeutically effective amount of an erinacine compound and a pharmaceutically acceptable carrier.

73. The composition of claim 72, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

74. The composition of claim 72, wherein the erinacine compound is erinacine C.

75. The composition of claim 72, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

76. The composition of claim 72, wherein the erinacine compound is a synthetic compound.

77. A pharmaceutical composition for treating inflammatory skin disease, the composition comprising: an erinacine compound at a therapeutically effective concentration; a liquid oil component, wherein the liquid oil component comprises one or more materials that are practically insoluble or insoluble in water and which are liquid at room temperature of about 22° C.; and an aqueous component; wherein the pharmaceutical composition is formulated as a lotion, and wherein the inflammatory skin disease is psoriasis.

78. The pharmaceutical composition of claim 77, wherein the erinacine compound is erinacine C and wherein the erinacine compound is dissolved in the liquid oil component at room temperature.

79. The pharmaceutical composition of claim 77, wherein the liquid oil component comprises a dicarboxylic acid ester, a monocarboxylic ester, or a combination thereof.

80. The pharmaceutical composition of claim 77, wherein the liquid oil component comprises a dicarboxylic acid ester.81 . The pharmaceutical composition of claim 77, wherein the liquid oil component comprises a monocarboxylic acid ester.

82. The pharmaceutical composition of claim 77, wherein the liquid oil component further comprises mineral oil or light mineral oil.

83. The pharmaceutical composition of claim 82, wherein the liquid oil component further comprises light mineral oil.

84. The pharmaceutical composition of claim 77, wherein the composition further comprises one or more humectants, preservatives, chelating agents, emulsifying agents, pH adjusting agent, and / or thickening agents.

85. The pharmaceutical composition of claim 84, wherein the composition further comprises an emulsifying agent.

86. The pharmaceutical composition of claim 77, wherein the composition further comprises a pH adjusting agent.

87. The pharmaceutical composition of claim 77, wherein the composition is capable of providing a synergistic efficacy when the composition is used to treat psoriasis.

88. The pharmaceutical composition of claim 77, wherein the composition is capable of providing a synergistic reduction in at least one adverse event when the composition is used to treat psoriasis, wherein the adverse event is selected from the group consisting of itching, burning, stinging, and combinations thereof.

89. A method of treating a wound in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an erinacine compound and a pharmaceutically acceptable carrier to the subject.

90. The method of claim 89, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG- 100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassiumglycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

91. The method of claim 89, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

92. The method of claim 89, wherein the erinacine compound is erinacine C.

93. The method of claim 89, wherein the administration is topical administration.

94. The method of claim 93, wherein the pharmaceutical composition is applied twice daily.

95. The method of claim 90, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, fdm, transdermal patch and any combination thereof.

96. The method of claim 89, further comprising administration of at least one additional therapeutic agent selected from the group consisting of an antimicrobial agent, an analgesic agent, and a combination thereof.

97. The method of claim 96, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the wound relative to the effect provided by the therapeutic agent administered separately.

98. The method of claim 97, wherein the synergistic effect provided is with respect to inhibition of inflammation.

99. The method of claim 96, wherein the antimicrobial agent is selected from the group consisting of loracarbef, cephalexin, cefadroxil, cefixime, ceftibuten, cefprozil, cefpodoxime, cephradine, cefuroxime, cefaclor, neomycin, dicloxacillin, nitrofurantoin, nitrofurantoin macrocrystal, nitrofurantoin / nitrofuran mac, dirithromycin, gemifloxacin, ampicillin, gatifloxacin, ciprofloxacin, enoxacin, amoxicillin, clarithromycin, levofloxacin, moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin, trovafloxacin, lomefloxacin, erythromycin,norfloxacin, clindamycin, quinupristin, doxycycline, amikacin sulfate, vancomycin, kanamycin, netilmicin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetracycline, framycetin, minocycline, nalidixic acid, demeclocycline, trimethoprim, miconazole, colistimethate, paromomycin, sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate, metronidazole, oxacillin sodium, nafcillin sodium, vancomycin hydrochloride, clindamycin, cefotaxime sodium, co-trimoxazole, ticarcillin disodium, piperacillin sodium, ticarcillin disodium / clavulanate potassium, neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, penicillin, ceftriaxone sodium, ceftazidime, imipenem, aztreonam, cinoxacin, cefotetan disodium, cefoperazone sodium, cefamandole nafate, gentamicin, tobramycin, lincomycin, alatrofloxacin, linezolid, tetracycline, mupirocin, fosfomycin, pentamidine isethionate, imipenem / cilastatin, troleandomycin, gatifloxacin, chloramphenicol, cycloserine, meropenem, cephalosporins, fluconazole, cefepime, sulfamethoxazole, chloroquine phosphate, silver sulfadiazine, and combinations thereof.

100. The method of claim 96, wherein the analgesic agent is selected from the group consisting of acetaminophen, anileridine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, codeine, rofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride, levorphanol, alfentanil hydrochloride, meperidine, meperidine hydrochloride, methadone, morphine, nalbuphine, opium, levomethadyl, hyaluronate sodium, sufentanil citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, propoxyphene, benzocaine, lidocaine, dezocine, clonidine, butalbital, phenobarbital, tetracaine, phenazopyridine, sulfamethoxazole / phenazopyridine, sulfisoxazole / phenazopyridine, and combinations thereof.

101. The method of claim 89, wherein the wound of the subject is a chronic wound.

102. The method of claim 89, wherein the wound of the subject is an ulcer.

103. The method of claim 102, wherein the ulcer is selected from the group consisting of a neuropathic ulcer, a diabetic ulcer, a venous stasis ulcer, and a pressure sore.

104. The method of claim 89, wherein the wound of the subject is a bum wound.

105. The method of claim 89, wherein the wound of the subject is selected from the group consisting of a cut, an abrasion, and a surgical incision site.

106. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of Lion’s Mane Hericium erinctceus) extract to a subject in need thereof, wherein the inflammatory skin disease is atopic dermatitis.

107. The method of claim 106, wherein the administration is topical administration.

108. The method of claim 107, wherein the extract is applied twice daily.

109. The method of claim 107, wherein the extract is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

110. The method of claim 107, further comprising administration of at least one additional therapeutic agent selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma-lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof.

111. The method of claim 110, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered extract so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

112. The method of claim 111, wherein the synergistic effect provided is with respect to inhibition of inflammation.

113. The method of claim 106, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, DOCK2, EBI3, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration.

114. The method of claim 106, wherein the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration.

115. The method of claim 107, wherein the topically administered extract provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

116. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Lion’s Mane (Hericium erinaceus) extract and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the inflammatory skin disease is atopic dermatitis.

117. The method of claim 116, wherein the administration comprises topical administration.

118. The method of claim 117, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG- 100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

119. The method of claim 117, wherein the pharmaceutical composition is applied twice daily.

120. The method of claim 117, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

121. The method of claim 116, further comprising administration of at least one additional therapeutic agent selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma-lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof.

122. The method of claim 121, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

123. The method of claim 122, wherein the synergistic effect provided is with respect to inhibition of inflammation.

124. The method of claim 116, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBB, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration.

125. The method of claim 116, wherein the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration.

126. The method of claim 121, wherein the topically administered extract provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

127. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of an erinacine compound to a subject in need thereof, wherein the inflammatory skin disease is atopic dermatitis.

128. The method of claim 127, wherein the administration is topical administration.

129. The method of claim 127, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

130. The method of claim 129, wherein the erinacine compound is erinacine C.

131. The method of claim 130, wherein the erinacine compound is applied twice daily.

132. The method of claim 127, wherein the erinacine compound is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch, and any combination thereof.

133. The method of claim 127, further comprising administration of at least one additional therapeutic agent selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma-lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof.

134. The method of claim 133, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered extract so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

135. The method of claim 134, wherein the synergistic effect provided is with respect to inhibition of inflammation.

136. The method of claim 127, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBB, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration.

137. The method of claim 127, wherein the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration.

138. The method of claim 133, wherein the topically administered erinacine compound provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

139. A method of treating an inflammatory skin disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an erinacine compound and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the inflammatory skin disease is atopic dermatitis.

140. The method of claim 139, wherein the administration is topical administration.

141. The method of claim 139, wherein the erinacine compound is selected from the group consisting of erinacine A, erinacine B, erinacine C, erinacine D, erinacine E, erinacine F, erinacine G, erinacine H, erinacine I, and combinations thereof.

142. The method of claim 139, wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of glyceryl stearate, PEG-100 stearate, glycerin, niacinamide, cetyl alcohol, salicylic acid, allantoin, butyrospermum parkii, petrolatum, steareth-21, tocopheryl acetate, lavandula angustifolia oil, xanthan gum, dipotassium glycyrrhizate, aloe barbadensis leaf juice, triethanolamine, bisabolol, disodium EDTA, 0- caryophyllene, cannabis oil, and combinations thereof.

143. The method of claim 140, wherein the pharmaceutical composition is applied twice daily.

144. The method of claim 140, wherein the pharmaceutical composition is formulated in a dosage form selected from the group consisting of cream, ointment, lotion, foam, film, transdermal patch and any combination thereof.

145. The method of claim 140, further comprising administration of at least one additional therapeutic agent selected from the group consisting of one or more antihistamine, methotrexate, dupilumab, baricitinib, gusacitinib, crisaborole, cyclosporine, interferon gamma- lb, topical corticosteroid, systemic corticosteroid, topical calcineurin inhibitors, diphenhydramine, and combinations thereof.

146. The method of claim 145, wherein the administration of at least one additional therapeutic agent is in combination with the topically administered pharmaceutical composition so as to provide a synergistic effect with respect to treating the inflammatory skin disease relative to the effect provided by the therapeutic agent administered separately.

147. The method of claim 146, wherein the synergistic effect provided is with respect to inhibition of inflammation.

148. The method of claim 139, wherein the expression of genes selected from the group consisting of BAX, BLM, CASP8, CTPS1, D0CK2, EBB, FKBP1A, CDCA8, CDCA2, RRM2, THEMIS and combinations thereof is decreased following administration.

149. The method of claim 139, wherein the expression of genes selected from the group consisting of BTC, FGF2, FGFRL1, EGF, TAC1, ANGPTL1, SPX, and combinations thereof is increased following administration.

150. The method of claim 145, wherein the topically administered pharmaceutical composition provides a synergistic effect with respect to reduction of skin inflammation as compared to the effect provided by administering at least one additional therapeutic agent, each alone.

151. A pharmaceutical composition for treating inflammatory skin disease, the composition comprising: an erinacine compound at a therapeutically effective concentration; a liquid oil component, wherein the liquid oil component comprises one or more materials that are practically insoluble or insoluble in water and which are liquid at room temperature of about 22° C.; and an aqueous component; wherein the pharmaceutical composition is formulated as a lotion, and wherein the inflammatory skin disease is atopic dermatitis.

152. The pharmaceutical composition of claim 151, wherein the erinacine compound is erinacine C and wherein the erinacine compound is dissolved in the liquid oil component at room temperature.

153. The pharmaceutical composition of claim 151, wherein the liquid oil component comprises a dicarboxylic acid ester, a monocarboxylic ester, or a combination thereof.

154. The pharmaceutical composition of claim 151, wherein the liquid oil component comprises a dicarboxylic acid ester.

155. The pharmaceutical composition of claim 151, wherein the liquid oil component comprises a monocarboxylic acid ester.

156. The pharmaceutical composition of claim 151, wherein the liquid oil component further comprises mineral oil or light mineral oil.

157. The pharmaceutical composition of claim 156, wherein the liquid oil component further comprises light mineral oil.

158. The pharmaceutical composition of claim 157, wherein the composition further comprises one or more humectants, preservatives, chelating agents, emulsifying agents, pH adjusting agent, and / or thickening agents.

159. The pharmaceutical composition of claim 151, wherein the composition further comprises an emulsifying agent.

160. The pharmaceutical composition of claim 151, wherein the composition further comprises a pH adjusting agent.

161. The pharmaceutical composition of claim 151, wherein the composition is capable of providing a synergistic efficacy when the composition is used to treat atopic dermatitis.

162. The pharmaceutical composition of claim 151, wherein the composition is capable of providing a synergistic reduction in at least one adverse event when the composition is used to treat atopic dermatitis, wherein the adverse event is selected from the group consisting of itching, burning, stinging, and combinations thereof.

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