An activator of PIK3ca for stimulating hair follicle formation and cycling

Abstract

Inventors observed that local application of minoxidil was able to modestly increase the growth of the hair following shaving compared to controls. However, UCL-TRO-1938 application was associated with a significant acceleration of hair growth as assessed by the surface covered by hair following shaving compared to vehicle and minoxidil. They also observed that UCL-TRO-1938 application was associated with a significantly higher number of hair follicles per mm2 and a higher proliferation rate Consistently, immunofluorescence experiments showed an increased phosphorylation rate for AKT on the residue Ser 473 in the UCL-TRO-1938 treatment group compared to others, as well as an increased proliferation assessed with BRDU and finally more expression of hair follicle cells as assessed with CD34, SOX9 and SOX2. The invention relates to a method for stimulating hair follicle formation and cycling in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of an activator of PIK3CA.

Description

[0001] METHODS AND COMPOSITIONS FOR STIMULATING HAIR FOLLICLE FORMATION AND CYCLING

[0002] FIELD OF THE INVENTION:

[0003] The invention is in the field of hair growth. More particularly, the invention relates to methods and compositions for stimulating hair follicle formation and cycling.

[0004] BACKGROUND OF THE INVENTION:

[0005] Alopecia is a general term for hair loss, and the most common form of this condition is alopecia areata, an autoimmune disease leading to hair loss in patches whom exact trigger remains unknownl. The causes of alopecia are multiples including genetic factors with a male predisposition (called androgenetic alopecia)1. A family history of alopecia increases the likelihood of developing the condition, particularly alopecia areata. Hormonal fluctuations influence hair growth particularly during pregnancy, childbirth, menopause, or thyroid issues. It is also well known that various health conditions can trigger alopecia, including thyroid diseases, autoimmune disorders (e.g., lupus, vitiligo), nutritional deficiencies (e.g., vitamin D, iron) but also significant physical or emotional stress. Finally, skin diseases and certain medications, especially those for cancer, arthritis, depression, and heart conditions, can lead to hair loss as a side effect1.

[0006] Indeed, alopecia can stem from a complex interplay of genetic predisposition, autoimmune responses, hormonal changes, medical conditions, stress factors, medications, and physical damage to the hair. Understanding these causes is crucial for effective management and treatment strategies for those affected by alopecia.

[0007] Alopecia treatment is challenging and mainly relies on the treatment of the underlying cause but treatment efficacy is very limitedl. In addition to the original cause of the disease, topical treatment using minoxidil or systemic drug administration such as cystine are frequently usedl. Identification of new treatments are needed.

[0008] SUMMARY OF THE INVENTION:

[0009] The invention relates to a method for stimulating hair follicle formation and cycling in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of an activator of PIK3CA.

[0010] In particular, the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION:

[0011] Inventors observed that the PIK3CA mutation in stem cells during hair regeneration was able to activate the PIK3CA in cells from the hair follicle leading to an excessive growth of the hair. Inventors decided to test the efficacy of the UCL-TRO-1938 as a topical formulation to improve hair growth in mice.

[0012] They observed that local application of minoxidil was able to modestly increase the growth of the hair following shaving compared to controls. However, UCL-TRO-1938 application was associated with a significant acceleration of hair growth as assessed by the surface covered by hair following shaving compared to vehicle and minoxidil. The efficacy was dose dependent with a statistically significant increase after 7 days in the concentration 50 pM group. They also observed that UCL-TRO-1938 application was associated with a significantly higher number of hair follicles per mm2 and a higher proliferation rate Consistently, immunofluorescence experiments showed an increased phosphorylation rate for AKT on the residue Ser 473 in the UCL-TRO-1938 treatment group compared to others, as well as an increased proliferation assessed with BRDU and finally more expression of hair follicle cells as assessed with CD34, SOX9 and SOX2.

[0013] All together these data demonstrate that activating PIK3CA topically with a small molecule favor hair growth and thus can be a new therapeutic strategy to improve alopecia.

[0014] Method for stimulating hair follicle formation and cycling

[0015] Accordingly, the present invention relates to a method for stimulating hair follicle formation and cycling in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of an activator of PIK3CA.

[0016] In a particular embodiment, the invention relates to a method for treating hair and follicle loss in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of an activator of PIK3CA.

[0017] As used herein, the term “stimulating” refers to up regulating or activating the growth of hair and follicle.

[0018] As used herein, the terms “treating” or “treatment” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). In some embodiments, the activator of PIK3CA is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23 or 24 times a day. In some embodiments, the activator of PIK3CA is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days. In some embodiments, the activator of PIK3CA is administered once every 1, 2, 3, 4, 5 or 6 weeks. In some embodiments, the activator of PIK3CA is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.

[0019] In a particular embodiment the method according to the invention is suitable to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of hair follicle formation and cycling alteration. As used herein, the term “subject” refers to any mammals, such as a rodent, a feline, a canine, and a primate. Particularly, in the present invention, the subject is a human afflicted with or susceptible to be afflicted with at least one of health condition selected from the group consisting of but not limited to: aging and hormonal changes, poor nutrition, physical and emotional stress, diseases with hair and follicle loss (alopecia aerate, psoriasis, seborrheic dermatitis, and microbial infections etc), medications such as chemotherapy or targeted therapies such as PIK3CA inhibitors.

[0020] In a particular embodiment, the subject is a human afflicted with or susceptible to be afflicted with alopecia.

[0021] As used herein, “alopecia” refers to abnormal or excessive hair loss. There are complex causes of the pathological alopecia, and the pathological alopecia includes, for example, androgenetic alopecia, neuropathic alopecia, endocrine alopecia, nutritional alopecia, and congenital alopecia.

[0022] As used herein, the term “hair” refers to specialized keratinized structures derived or protruding from invaginations of the epidermal epithelium that are observed on animals, including mammals, and includes fur.

[0023] Hair loss (i.e., baldness or hair thinning) from areas where hair is normally present. Hair loss also includes but not limited to: hair thinning, baldness, male and female pattern baldness, thinned eye lashes, and thinned eye brows. The term encompasses full or partial hair loss, shedding or any decrease in the number of follicles or follicles in the anagen phase at any body site where hair is normally present. In some embodiments, the alopecia-affected skin is part or all of the scalp of the subject.

[0024] The invention relates also to a method of stimulating hair growth or regrowth including the step of contacting a target region of skin of the subject with an effective amount of the hair regrowth composition. In some embodiments, the target region of skin is alopecia- affected skin.

[0025] In a particular embodiment, the subject is a human has been treated or susceptible to have chemotherapy.

[0026] As used herein, the term “chemotherapy” refers to use of chemotherapeutic agents to treat a subject. As used herein, the term "chemotherapeutic agent" refers to chemical compounds that are effective in inhibiting tumor growth.

[0027] Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimus tine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Inti. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idanrbicin, marcellomycin, mitomycins, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomgrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophospharnide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defo famine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pento statin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogennanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridinA and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobromtol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisp latin and carbop latin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are antihormonal agents that act to regulate or inhibit honnone action on tumors such as antiestrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti -androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0028] In a particular embodiment, the subject is a human has been treated or susceptible to have radiation therapy.

[0029] As used herein, the term “radiation therapy” or “radiotherapy” have their general meaning in the art and refers the treatment of cancer with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated (the target tissue) by damaging their genetic material, making it impossible for these cells to continue to grow. One type of radiation therapy commonly used involves photons, e.g. X-rays. Depending on the amount of energy they possess, the rays can be used to destroy cancer cells on the surface of or deeper in the body. The higher the energy of the x-ray beam, the deeper the x-rays can go into the target tissue. Linear accelerators and betatrons produce x-rays of increasingly greater energy. The use of machines to focus radiation (such as x-rays) on a cancer site is called external beam radiation therapy. Gamma rays are another form of photons used in radiation therapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, and cobalt 60) release radiation as they decompose, or decay. In some embodiments, the radiation therapy is external radiation therapy. Examples of external radiation therapy include, but are not limited to, conventional external beam radiation therapy; three-dimensional conformal radiation therapy (3D-CRT), which delivers shaped beams to closely fit the shape of a tumor from different directions; intensity modulated radiation therapy (IMRT), e.g., helical tomotherapy, which shapes the radiation beams to closely fit the shape of a tumor and also alters the radiation dose according to the shape of the tumor; conformal proton beam radiation therapy; image-guided radiation therapy (IGRT), which combines scanning and radiation technologies to provide real time images of a tumor to guide the radiation treatment; intraoperative radiation therapy (IORT), which delivers radiation directly to a tumor during surgery; stereotactic radiosurgery, which delivers a large, precise radiation dose to a small tumor area in a single session; hyperfractionated radiation therapy, e.g., continuous hyperfractionated accelerated radiation therapy (CHART), in which more than one treatment (fraction) of radiation therapy are given to a subject per day; and hypofractionated radiation therapy, in which larger doses of radiation therapy per fraction is given but fewer fractions.

[0030] In a particular embodiment, the subject is a human afflicted with or susceptible to be afflicted with microbial infection.

[0031] As used herein, the term “PI3K” refers to phosphoinositide 3-kinases also called phophatidylinositide 3-kinases. PI3K belongs to a family of enzymes which phosphorylate the 3 ’hydroxyl group of the onositol ring of the phosphatidylinositol (Ptdins). The PI3K signalling pathway can be activated, resulting in the synthesis of PIP3 from PIP2. PIK3CA is mainly recruited through tyrosine kinase receptors. PIK3CA encodes the 110-kDa catalytic alpha subunit of PI3K (pl 10a), which converts, at the plasma membrane, phosphatidylinositol 4, 5 -bisphosphate (PtdIns(4,5)P2) to phosphatidylinositol 3, 4, 5 -trisphosphate (PtdIns(3,4,5)P3; or PIP3) with subsequent recruitment of PDK1, which in turn phosphorylates AKT on the Thr308 residue to initiate downstream cellular effects. PIK3CA also regulates many other pathways, including the Rho / Racl signaling cascade.

[0032] As used herein, the term “PI3K activator” refers to a natural or synthetic compound that has a biological effect to activate the activity or the expression of PI3K. More particularly, such compound is capable of activating the kinase activity of at least one member of PI3K family, for example, at least a member of Class I PI3K. In particular embodiment, said PI3K activator may be a pan-inhibitor of Class I PI3K (known as pl 10) or isoform specific of Class I PI3K isoforms (among the four types of isoforms, pl 10a, pl 100, pl lOy or pl 106).

[0033] In a particular embodiment, the PI3K activator is a peptide, peptidomimetic, small organic molecule. The term “peptidomimetic” refers to a small protein-like chain designed to mimic a peptide. In a particular embodiment, the inhibitor of PI3K is an aptamer. Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.

[0034] In a particular embodiment, the PI3K activator is a small organic molecule. The term “small organic molecule” refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e.g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.

[0035] In a particular embodiment, the PI3K activator is UCL-TRO 1938 or its pharmaceutically acceptable salts. As used herein, the term “UCL-TRO 1938” also called 2919575-27-0 or l-[7-[[2-[[4-(4-ethylpiperazin-l-yl)phenyl]amino]pyridin-4-yl]amino]-2,3- dihydroindol-l-yl]ethenone. It is a small-molecule activator of the PI3Ka isoform (described in Bart Vanhaesebroeck et al 2023, Nature 2023 Jun;618(7963): 159-168; doi: 10.1038 / s41586-023-05972-2. Epub 2023 May 24.). This molecule has the following formula and structure in the art C27H32N6O:

[0036] Combined preparation

[0037] In another aspect, the invention relates to the PI3K activator for use according to the invention, and a classical treatment as a combined preparation for simultaneous, separate or sequential use in the stimulating hair follicle formation and cycling in a subject in need thereof

[0038] In another embodiment, the invention relates to the PI3K activator for use according to the invention, and a classical treatment as a combined preparation for simultaneous, separate or sequential use in the treatment of hair and follicle loss in a subject in need thereof As used herein, the terms “combined treatment”, “combined therapy” or “therapy combination” refer to a treatment that uses more than one medication. The combined therapy may be dual therapy or bi-therapy.

[0039] As used herein, the term “classical treatment” refers to treatments well known in the art and used to treat hair follicle formation and cycling (Status of research on the development and regeneration of hair follicles, Dan Liu et al 2024, doi: 10.7150 / ijms.88508).

[0040] In a particular embodiment, the classical treatment is selected from the group consisting of but not limited to: Corticosteroids(Glucocorticoids, Mineralocorticoids etc), minoxidil, finasteride, cystine B6, Dutasteride, Bepanthen, Scalp microneedle therapy, also known as micro needling or derma rolling for the scalp, Hair transplantation, Fractional radiofrequency (FRF) therapy, Light therapy (photo biomodulation therapy, cold laser therapy, or red light therapy), cold caps, scalp cooling, Excimer lamp, CO2 laser, Regenerative medicine -based therapy (PRP therapy, Stem cell therapy), Dietary supplementation with natural plant extracts, hair anti-loss shampoo or controlled shampoo use.

[0041] In a particular embodiment, the classical treatment is performed by oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration,

[0042] As used herein the terms "administering" or "administration" refer to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an activator of PI3K) into the subject, such as by mucosal, topical, intradermal, intravenous, subcutaneous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art. When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof.

[0043] In a particular embodiment, the administration of the activator of PI3K is performed topically.

[0044] As used herein, the terms “Topical administration” or “topically administered” refer to the administration of a substance, such as an active ingredient, to the skin or a localized region of the body of a subject. Topical administration can be used for delivering the substance to external body tissues and / or for transdermal administration of the substance.

[0045] As used herein, the terms “Topical formulation” or “topical composition” refer to a composition that may be applied to the skin of a subject. Topical formulations can be used for both topical and transdermal administration of a substance, such as an active ingredient. Preferably, topical formulations are pharmaceutically acceptable.

[0046] As used herein, the term “Transdermal administration” refers to the administration of a substance, such as an active ingredient, through the skin of a subject. In the invention, transdermal administration is preferably used for delivering the substance to tissues underlying the skin with minimal systemic absorption, however transdermal administration may also generally be used for systemic delivery of the active ingredient.

[0047] In the context of the invention, topical administration is formulated for use as transdermal devices, linimens, aerosols, creams, ointments, lotions, gels, foam, solutions, suspensions, emulsions, pastes, aerosolized mixtures or powders and the like.

[0048] In a particular embodiment, the topical administration is formulated for use as a cream.

[0049] In a particular embodiment, the topical administration further comprises the step of facilitating penetration of the skin of the target region using a skin penetration enhancer. Skin penetration enhancers include both physical and chemical skin penetration enhancers. For example, physical skin penetration enhancers can be selected from needles (e.g., a manifold of needles), abrasive materials, or the application of high pressure to the skin.

[0050] Alternately, a chemical skin penetration enhancer can be used. Examples of chemical skin penetration enhancers include glyceryl oleate (glycerol monooleate); isopropyl myristate; methyl laurate; N-lauroyl sarcosine; oleic acid (octadecenoic acid); sodium lauryl sulfoacetate; and sodium octyl sulfate, dimethyl sulfoxide (DMSO).

[0051] As used herein, the term “administration simultaneously” refers to administration of at least 2 or 3 active ingredients by the same route and at the same time or at substantially the same time. The term “administration separately” refers to an administration of at least 2 or 3 active ingredients at the same time or at substantially the same time by different routes. The term “administration sequentially” refers to an administration of at least 2 or 3 active ingredients at different times, the administration route being identical or different.

[0052] A “therapeutically effective amount” is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg / kg to about 20 mg / kg of body weight per day, especially from about 0.001 mg / kg to 7 mg / kg of body weight per day.

[0053] In a particular embodiment, the therapeutically effective amount (activator of

[0054] PI3KCA) is 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,

[0055] 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,

[0056] 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,

[0057] 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134,

[0058] 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153,

[0059] 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172,

[0060] 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,

[0061] 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229,

[0062] 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248,

[0063] 249 or 250 mg / kg of body weight per day.

[0064] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy.

[0065] In a particular embodiment the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.001 to 20% by weight of the total weight of the composition.

[0066] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.001 to about 20%, preferably from about 0.002 to about 16%, more preferably from about 0.003 to about 12%, furthermore preferably from about 0.004 to about 8%, furthermore preferably from about 0.005 to about 4%, by weight of the total weight of the composition.

[0067] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.01 to 10% by weight of the total weight of the composition.

[0068] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.01 to about 10%, preferably from about 0.02 to about 8%, more preferably from about 0.03 to about 6%, furthermore preferably from about 0.04 to about 4%, furthermore preferably from about 0.05 to about 2%, by weight of the total weight of the composition.

[0069] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.1 to 5% by weight of the total weight of the composition.

[0070] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.1 to about 5%, preferably from about 0.2 to about 4%, more preferably from about 0.3 to about 3%, furthermore preferably from about 0.4 to about 2%, furthermore preferably from about 0.5 to about 1%, by weight of the total weight of the composition.

[0071] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.1 to 4.5%, from 0.25 to 4%, from 0.5 to 3%, from 0.75 to 3.5%, from 1 to 3%, from 1.25 to 2.5% or from 1.5 to 2%, by weight of the total weight of the composition.

[0072] In a particular embodiment, the therapeutically effective amount comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.1 to about 4.5%, from about 0.25 to about 4%, from about 0.5 to about 3%, from about 0.75 to about 3.5%, from about 1 to about 3%, from about 1.25 to about 2.5% or from about 1.5 to about 2%, by weight of the total weight of the composition.

[0073] All ranges recited in this paragraph by weight of the total weight of the composition (w / w) are herein further recited (i) by weight of the total volume of the composition (w / v) or (ii) by volume of the total volume of the composition (v / v).

[0074] In a particular embodiment, the therapeutically effective amount (activator of PI3KCA) for the topical treatment is an appropriate dosage level will generally be 0.1 to 10 mg of composition per square centimeter (cm2) of skin of the subject administrated from one to five times per day.

[0075] In a particular embodiment, the dosage level is about 0.1 to about 10 mg, preferably about 0.05 to about 5 mg, more preferably about 0.1 to about 2.5 mg, of composition per cm2f skin of the subject administrated from one to three times per day.

[0076] In a particular embodiment, the dosage level is 0.5 to 5 mg of composition per cm2of skin of the subject administrated from one to three times per day.

[0077] In a particular embodiment, the dosage level is about 0.5 to about 5 mg, preferably about 0.75 to about 2.5 mg, more preferably about 1.25 to about 1.75 mg, of composition per cm2of skin of the subject administrated from one to three times per day.

[0078] In a particular embodiment, the dosage level is 1 to 3 mg of composition per cm2of skin of the subj ect administrated from one or two times per day.

[0079] In a particular embodiment, the dosage level is about 1 to about 3 mg, preferably about 1.5 to about 2.5 mg, more preferably about 1.5 to about 2 mg, of composition per cm2of skin of the subject administrated from one to three times per day.

[0080] In another aspect, the invention relates to a cosmetic composition comprising an activator of PIK3CA for stimulating hair follicle formation and cycling in a subject in need thereof.

[0081] As used herein, the term “cosmetic” refers to a substance, a process, a procedure, or a device that is intended to improve the appearance of an individual or biological entity.

[0082] In the context of the invention, the activator of PIK3CA is used in a cosmetically acceptable formulation.

[0083] In a particular embodiment, the cosmetic composition according to the invention, wherein the activator of PIK3CA is UCL-TRO-1938. As used herein, the term “cosmetically acceptable” means that activator of PIK3CA or its derivatives is not harmful for the user, in particular a human, and that in the framework of a cosmetic composition it is compatible with the other components.

[0084] Pharmaceutical composition

[0085] The PIK3CA activator alone or combined with a classical treatment, as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.

[0086] Accordingly, the invention relates to a pharmaceutical composition comprising a PIK3CA activator for use in the stimulating hair follicle formation and cycling in a subject in need thereof.

[0087] In a particular embodiment, the invention relates to a pharmaceutical composition comprising a PIK3CA activator for use in the treatment of hair and follicle loss in a subject in need thereof.

[0088] In a further embodiment, the invention relates to a pharmaceutical composition comprising i) an activator of PIK3CA and ii) a classical treatment as described above as combined preparation to treat hair and follicle loss in a subject in need thereof.

[0089] In a further embodiment, the invention relates to a pharmaceutical composition comprising i) an activator of PIK3CA and ii) a classical treatment as described above as combined preparation for stimulating hair follicle formation and cycling in a subject in need thereof.

[0090] "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, 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, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

[0091] In a particular embodiment, the pharmaceutical composition as described above is formulated for use in transdermal devices, aerosols, creams, ointments, lotions, dusting powders, gels, and the like.

[0092] In a particular embodiment, the pharmaceutical composition as described above is formulated for use in a cream.

[0093] A wide variety of pharmaceutically acceptable carriers are described herein. In some embodiments, the pharmaceutically acceptable carrier comprises a hydrogel. The hydrogel can include a hydrogel formed from a variety of different polymers. In the medical field, many proprietary hydrogel formulations are known. In certain embodiments, hydrogel sheets of cross-linked polymer gels are used. It is contemplated that hydrogels from various sources will find use with the present methods and compositions, including, but not limited to commercially available hydrogels.

[0094] In some embodiments, the hydrogel comprises a thermosensitive hydrogel.

[0095] Thermosensitive hydrogels are aqueous polymer solutions that are transformed into gels by changes in environmental temperature, thus resulting in in situ hydrogel formation.

[0096] Examples of thermosensitive hydrogels include chitosan and related derivatives, poly(Nisopropylacrylamide)-based (PNIPAAM) copolymers, poly(ethylene oxide) / poly(propylene oxide) (PEO / PPO) copolymers and its derivatives, and poly(ethylene glycol) / biodegradable polyester copolymers. Gong et al., Curr Med Chem20(l):79-94 (2013). In some embodiments, the thermosensitive hydrogel is pluronic-F127, also known as poloxamer 407, which is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG).

[0097] In some embodiments, the pharmaceutical composition as described above further comprises the step of facilitating penetration of the skin of the target region using a skin penetration enhancer. Skin penetration enhancers include both physical and chemical skin penetration enhancers. For example, physical skin penetration enhancers can be selected from needles (e.g., a manifold of needles), abrasive materials, or the application of high pressure to the skin.

[0098] Alternately, a chemical skin penetration enhancer can be used. Examples of chemical skin penetration enhancers include glyceryl oleate (glycerol monooleate); isopropyl myristate; methyl laurate; N-lauroyl sarcosine; oleic acid (octadecenoic acid); sodium lauryl sulfoacetate; and sodium octyl sulfate.

[0099] In a particular embodiment, the pharmaceutical composition as described above is suitable for use in a cosmetic composition.

[0100] In the context of the invention, the pharmaceutical composition comprises an activator of PIK3CA in a cosmetically acceptable formulation.

[0101] As used herein, the term “cosmetically acceptable” means that activator of PIK3CA or its derivatives is not harmful for the user, in particular a human, and that in the framework of a cosmetic composition it is compatible with the other components.

[0102] In a particular embodiment, the pharmaceutical composition comprises UCL-TRO- 1938 in a cosmetically acceptable formulation. In some embodiments, the pharmaceutical solution comprises dimethyl sulfoxy de (DMSO), polyethylene glycerol; ethanol and Excipial formula lipolotion.

[0103] As used herein, the term “dimethylsulfoxyde” (DMSO) has its general meaning in the art and refers to a highly polar organic reagent with the formula (CH 2SO that has exceptional solvent properties for organic and inorganic chemicals. It is routinely used as solvent or in molecular biology, especially in the polymerase chain reaction (PCR), in transformation and transfection, for cell lysis, and in cytofluorimetric assessment.

[0104] As used herein, the term “polyethylene glycol” (PEG), also known as “polyethylene oxide” or “polyoxyethylene”, has its general meaning in the art and refers to a polyether compound with the formula C2nH4n+2On+i. Polyethylene glycol shows characteristics of organic solvents. Polyethylene glycol includes but is not limited to PEG-300, PEG-400 or PEG-900.

[0105] As used herein, the term “Excipial formula lipolotion” refers to a cream comprising Aqua, Paraffinum Liquidum, Caprylic / Capric Triglyceride, Myristyl Lactate, Dimethicone, Methoxy PEG-22 / Dodecyl Glycol Copolymer, Sodium Lactate, PEG-7 Hydrogenated Castor Oil, Phenoxyethanol, Sorbitan Isostearate, PEG-2 Hydrogenated Castor Oil, Ozokerite, Hydrogenated Castor Oil, Lactic Acid.

[0106] In a particular embodiment, the pharmaceutical composition according to the invention comprises: UCL-TRO-1938 dissolved in DMSO, cream (Excipial formula lipolotion) and ethanol.

[0107] In a particular embodiment, the pharmaceutical composition according to the invention comprises at least lOpM of UCL-TRO-1938 dissolved in DMSO.

[0108] In a particular embodiment, the pharmaceutical composition according to the invention comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249 or 250 pM of UCL- TRO-1938 dissolved in DMSO.

[0109] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy.

[0110] In a particular embodiment, the pharmaceutical composition comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.001 to 20% by weight of the total weight of the composition.

[0111] In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.001 to about 20%, preferably from about 0.002 to about 16%, more preferably from about 0.003 to about 12%, furthermore preferably from about 0.004 to about 8%, furthermore preferably from about 0.005 to about 4%, by weight of the total weight of the composition.

[0112] In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.01 to 10% by weight of the total weight of the composition.

[0113] In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.01 to about 10%, preferably from about 0.02 to about 8%, more preferably from about 0.03 to about 6%, furthermore preferably from about 0.04 to about 4%, furthermore preferably from about 0.05 to about 2%, by weight of the total weight of the composition.

[0114] In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.1 to 5% by weight of the total weight of the composition.

[0115] In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.1 to about 5%, preferably from about 0.2 to about 4%, more preferably from about 0.3 to about 3%, furthermore preferably from about 0.4 to about 2%, furthermore preferably from about 0.5 to about 1%, by weight of the total weight of the composition. In a particular embodiment, the pharmaceutical composition comprises comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from 0.1 to 4.5%, from 0.25 to 4%, from 0.5 to 3%, from 0.75 to 3.5%, from 1 to 3%, from 1.25 to 2.5% or from 1.5 to 2%, by weight of the total weight of the composition.

[0116] In a particular embodiment, the pharmaceutical composition comprises an activator of PI3KCA (e.g.UCL-TRO 1938) in an amount ranging from about 0.1 to about 4.5%, from about 0.25 to about 4%, from about 0.5 to about 3%, from about 0.75 to about 3.5%, from about 1 to about 3%, from about 1.25 to about 2.5% or from about 1.5 to about 2%, by weight of the total weight of the composition.

[0117] All ranges recited in this paragraph by weight of the total weight of the composition (w / w) are herein further recited (i) by weight of the total volume of the composition (w / v) or (ii) by volume of the total volume of the composition (v / v).

[0118] In a particular embodiment, the pharmaceutical composition comprises (activator of PI3KCA such as UCL-TRO-1938) for the topical treatment is an appropriate dosage level will generally be 0.1 to 10 mg of composition per square centimeter (cm2) of skin of the subject administrated from one to five times per day.

[0119] In a particular embodiment, the dosage level is about 0.1 to about 10 mg, preferably about 0.05 to about 5 mg, more preferably about 0.1 to about 2.5 mg, of composition per cm2f skin of the subject administrated from one to three times per day.

[0120] In a particular embodiment, the dosage level is 0.5 to 5 mg of composition per cm2of skin of the subject administrated from one to three times per day.

[0121] In a particular embodiment, the dosage level is about 0.5 to about 5 mg, preferably about 0.75 to about 2.5 mg, more preferably about 1.25 to about 1.75 mg, of composition per cm2of skin of the subject administrated from one to three times per day.

[0122] In a particular embodiment, the dosage level is 1 to 3 mg of composition per cm2of skin of the subject administrated from one or two times per day.

[0123] In a particular embodiment, the dosage level is about 1 to about 3 mg, preferably about 1.5 to about 2.5 mg, more preferably about 1.5 to about 2 mg, of composition per cm2of skin of the subject administrated from one to three times per day.

[0124] Typically, in the context of the invention, the pharmaceutical composition comprises 10 pM: cream (Excipial formula lipolotion) + 20% ethanol + 10 pM UCL-TRO-1938 (dissolved in DMSO). Typically, in the context of the invention, the pharmaceutical composition comprises cream(Excipial formula lipolotion) + 20% ethanol + 50 pM UCL-TRO-1938 (dissolved in DMSO).

[0125] In some embodiments, the pharmaceutical composition is a sterile composition.

[0126] As used herein, the term “sterile composition” refers to any form of administration which is substantially free, or even devoid of viable or revivable germs, potentially infectious, microbial known to those skilled in the art.

[0127] As used herein, the term “substantially free”, when used in relation to a given component of a solution (e.g. “a pharmaceutical solution substantially free of germs”), refers to a solution to which essentially none of said component has been added. When a solution is “substantially free” of a given component, said solution suitably comprises no more than 0.001 wt % of said component, suitably no more than 0.0001 wt % of said component, suitably no more than 0.00001 wt %, more suitably no more than 0.000001 wt.

[0128] Kits

[0129] In another aspect, the invention relates to a kit comprising the activator of PIK3CA.

[0130] In a particular embodiment, the invention relates to a kit the activator of PIK3CA and instructions for use in a topical administration.

[0131] In a further embodiment, the invention relates to a container comprising the pharmaceutical composition of the present invention. Hence, the invention further relates to a container comprising a pharmaceutical solution, comprising: i) an activator of PIK3CA or any one of its pharmaceutically acceptable derivatives; ii) UCL-TRO-1938 dissolved in DMSO, iii) cream (Excipial formula lipolotion) and iv) ethanol.

[0132] In some embodiment, the pharmaceutical solution is preservative free.

[0133] As used herein, the term “container” refers to any primary or secondary packaging material which is compatible with the storage of the pharmaceutical composition. In a non- exhaustive manner, such container may include single-dose containers, multi -dose containers, well-closed containers, airtight containers, light-resistant containers. Such containers may be formed, completely or in-part, in glass, plastics, rubbers, paper / card boards and metals. For example, glass containers may include or consist of Type-I glass, Type-II glass, Type-III glass or any other non-parental usage glass. Plastic containers may include or consist of Urea formaldehyde (UF), Phenol formaldehyde, Melamine formaldehyde (MF), Epoxy resins (epoxides), Polyurethanes (PURs), Polyethylene, Polyvinylchloride, Polyethylene terephthalate (PET), Polyvinylidene chloride (PVdC), Polycarbonate Acrylonitrile butadiene styrene (ABS) or preservative-free low-density polyethylene (LDPE).

[0134] In some embodiment, the container is a bottle.

[0135] In some embodiment, the container is a spray.

[0136] In some embodiment, the container is an aerosol.

[0137] In some embodiment, the container is a preservative-free low-density polyethylene (LDPE) bottle.

[0138] Method of screening

[0139] A further object of the present invention relates to a method of screening a drug suitable for the treatment of proliferative glomerulonephritis comprising i) providing a test compound and ii) determining the ability of said test compound to activate the activity of PI3K.

[0140] Any biological assay well known in the art could be suitable for determining the ability of the test compound to activate the activity of PI3K. In some embodiments, the assay first comprises determining the ability of the test compound to bind to PI3K. In some embodiments, a population of cells is then contacted and activated so as to determine the ability of the test compound to activate the activity of PI3K. In particular, the effect triggered by the test compound is determined relative to that of a population of immune cells incubated in parallel in the absence of the test compound or in the presence of a control agent either of which is analogous to a negative control condition. The term "control substance", "control agent", or "control compound" as used herein refers a molecule that is inert or has no activity relating to an ability to modulate a biological activity or expression. It is to be understood that test compounds capable of inhibiting the activity of PI3K, as determined using in vitro methods described herein, are likely to exhibit similar modulatory capacity in applications in vivo. Typically, the test compound is selected from the group consisting of peptides, peptidomimetics, small organic molecules, aptamers or nucleic acids. For example the test compound according to the invention may be selected from a library of compounds previously synthesised, or a library of compounds for which the structure is determined in a database, or from a library of compounds that have been synthesised de novo. In some embodiments, the test compound may be selected form small organic molecules.

[0141] The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

[0142] FIGURES:

[0143] Figure 1: UCL-TRO-1938 molecule increases hair growth. A. Experimental plan. B. Representative pictures of mice treated with different drugs and quantification (C).

[0144] Figure 2: UCL-TRO-1938 molecule increase hair follicle. Quantification of number of hair follicles / mm2.

[0145] EXAMPLE :

[0146] A set of 40 wild type aged of 8 weeks, a mix of male and female, were shaved on the back using a hair removal cream. The shaved surface was measured for each mouse. Male and female were then equally distributed to the different treatment group (Figure 1A).

[0147] • Mice in Group 1 (n= 10) were daily treated topically with the vehicle (cream) during 14 consecutive days (one application per day).

[0148] • Mice in Group 2 (n= 10) were daily treated topically with minoxidil 2% during 14 consecutive days (one application per day).

[0149] • Mice in Group 3 (n= 10) were daily treated topically with UCL-TRO-1938 (concentration 10 pM) during 14 consecutive days (one application per day).

[0150] • Mice in Group 4 (n= 10) were daily treated topically with UCL-TRO-1938 (concentration 50 pM) during 14 consecutive days (one application per day).

[0151] We observed that local application of minoxidil was able to modestly increase the growth of the hair following shaving compared to controls (Figure IB). However, UCL- TRO-1938 application was associated with a significant acceleration of hair growth as assessed by the surface covered by hair following shaving compared to vehicle and minoxidil (Figure IB). The efficacy was dose dependent with a statistically significant increase after 7 days in the concentration 50 pM group (Figure IB).

[0152] We then sacrificed the mice on day 14 after shaving and explored the skin histology. Interestingly, we observed that UCL-TRO-1938 application was associated with a significantly higher number of hair follicles per mm2 and a higher proliferation rate (Figure 2). Consistently, immunofluorescence experiments showed an increased phosphorylation rate for AKT on the residue Ser 473 in the UCL-TRO-1938 treatment group compared to others, as well as an increased proliferation assessed with BRDU and finally more expression of hair follicle cells as assessed with CD34, SOX9 and SOX2 (data now shown).

[0153] All together these data demonstrate that activating PIK3CA topically with a small molecule favor hair growth and can be a new therapeutic strategy to improve alopecia.

[0154] REFERENCES:

[0155] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

[0156] 1 Pratt, C. H., King, L. E., Jr., Messenger, A. G., Christiano, A. M. & Sundberg,

[0157] J. P. Alopecia areata. Nat Rev Dis Primers 3, 17011 (2017). https: / / doi.org: 10.1038 / nrdp.2017.11

[0158] 2 Morin, G. M. et al. PIK3CA-Related Disorders: From Disease Mechanism to Evidence-Based Treatments. Annu Rev Genomics Hum Genet (2024). http s : / / doi . org : 10.1146 / annurev-genom -121222-114518

[0159] 3 Gentile, P. et al. Evaluation of Not- Activated and Activated PRP in Hair Loss Treatment: Role of Growth Factor and Cytokine Concentrations Obtained by Different Collection Systems. Int J Mol Sci 18 (2017). https: / / doi.org: 10.3390 / ijmsl8020408

[0160] 4 Gong, G. Q. et al. A small-molecule PI3Kalpha activator for cardioprotection and neuroregeneration. Nature 618, 159-168 (2023). https: / / doi.org: 10.1038 / s41586-023-

[0161] 05972-2

Claims

- 25 -CLAIMS:

1. A method for stimulating hair follicle formation and cycling in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of an activator of PIK3CA.

2. The method according to claims 1, wherein the PIK3CA activator is UCL-TRO- 1938 or its pharmaceutically acceptable salts.

3. The method according to claim 1, wherein the subject is afflicted with or susceptible to be afflicted with at least one of health condition selected from the group consisting of but not limited to: aging and hormonal changes, poor nutrition, physical and emotional stress, diseases such as, medications such as chemotherapy.

4. The method according to claims 1 to 3, wherein the subject is afflicted with or susceptible to be afflicted with alopecia.

5. The method according to claims 1 to 3, wherein the subject is afflicted with or susceptible to be afflicted with chemotherapy.

6. The method according to claims 1 to 2, wherein the activator of PIK3CA is administered topically.

7. The method according to claims 1 to 2, wherein the activator of PIK3CA is formulated as a cream.

8. A PIK3CA activator and ii) a classical treatment as a combined preparation for simultaneous, separate or sequential use in a method for stimulating hair follicle formation and cycling in a subject in need thereof.

9. The combined preparation according to claim 8, wherein the classical treatment is selected from the group consisting of but not limited to: minoxidil, finasteride, Dutasteride, Scalp microneedle therapy, also known as micro needling or derma rolling for the scalp, Hair transplantation, Fractional radiofrequency (FRF) therapy, Light therapy (photo biomodulation therapy, cold laser therapy, or red light therapy), Excimer lamp, CO2 laser, Regenerative medicine -based therapy(PRP therapy, Stem cell therapy), Dietary supplementation with natural plant extracts, or controlled shampoo use.

10. A cosmetic composition comprising an activator of PIK3CA for stimulating hair follicle formation and cycling in a subject in need thereof.

11. The cosmetic composition according to claim 10, wherein the activator of PIK3CA is UCL-TRO-1938.

12. A pharmaceutical composition comprising a PIK3CA activator for stimulating hair follicle formation and cycling in a subject in need thereof.

13. The pharmaceutical composition according to claim 12, wherein the subject is afflicted with or susceptible to be afflicted with alopecia.

14. A pharmaceutical composition comprising a PIK3CA activator and a classical treatment as a combined preparation for simultaneous, separate or sequential use for stimulating hair follicle formation and cycling in a subject in need thereof.

15. The pharmaceutical composition according to claims 12 to 14 comprises: UCL- TRO-1938 dissolved in DMSO, cream (Excipial formula lipolotion) and ethanol.

Images