WO2012156310A1 - Nouveaux peptides - Google Patents

Nouveaux peptides Download PDF

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Publication number
WO2012156310A1
WO2012156310A1 PCT/EP2012/058770 EP2012058770W WO2012156310A1 WO 2012156310 A1 WO2012156310 A1 WO 2012156310A1 EP 2012058770 W EP2012058770 W EP 2012058770W WO 2012156310 A1 WO2012156310 A1 WO 2012156310A1
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Prior art keywords
peptide
drug
bone
disorders
diseases
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PCT/EP2012/058770
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English (en)
Inventor
Lars Sävendahl
Farasat Zaman
Emma Eriksson
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Saevendahl Lars
Farasat Zaman
Emma Eriksson
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Publication of WO2012156310A1 publication Critical patent/WO2012156310A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein

Definitions

  • the present invention relates to the field of medical therapeutics, and more particularly to novel therapeutic peptides, designated mutant humanin-like peptides (MHLPs) and fragments, analogs, derivatives, and variants thereof, which have beneficial activities on cartilage tissues and/or bone tissues, including prevention of negative effects of disorders/drugs on cartilage tissues and/or bone tissues by treatment with for example, but not limited to, glucocorticoids.
  • MHLPs mutant humanin-like peptides
  • the MHLPs are also useful in the prevention and/or treatment of cancers, autoimmune diseases, fibrotic diseases, inflammatory diseases, obesity, type I and type II diabetes, neurodegenerative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases.
  • the present invention relates to a number of peptides named "mutant humanin-like peptides" with capacity to regulate biological pathways.
  • endochondral bone formation a process where resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization.
  • the balance between proliferation and differentiation is a crucial regulatory step controlled by various growth factors/hormones acting in both endocrine and
  • Glucocorticoids are widely used as a chemotherapy in cancers, antiinflammatory and immunosuppressive drugs both in children and adults with chronic diseases.
  • GCs Glucocorticoids
  • recent studies have revealed that long-term high- dose GC treatment often leads to growth failure in treated children, an effect which has been shown to be mediated through a negative effect on growth plate chondrocytes (Baron, Huang et al. 1992) (Loeb 1976).
  • Dexamethasone (Dexa) is a widely used glucocortcoid used in children and adults to treat different diseases such as, asthma, inflammation and cancer. Beside the positive effects of Dexa on inflammation and cancer, its long-term use has been linked to negative side effects on bone. Previous studies (pre-clinical and clinical) show that long-term use of Dexa can cause bone growth retardation in children and osteoporosis both in children and adults (Demoly 2008). It is well known that Dexa can alter the processes of proliferation and differentiation in chondrocytes and other cells.
  • CT chemotherapy
  • hepatoblastoma hepatoblastoma, head and neck cancers, nasopharyngeal carcinoma, esophageal/gastric junction adenocarcinoma, glaucoma and skin cancer.
  • 5-FU has been reported to suppress bone growth, an effect associated with rapid and significant suppression of cell proliferation in the growth plate and metaphysis and induction of apoptosis in the metaphysis (Xian, Howarth et al. 2004).
  • Other chemotherapeutic drugs such as etoposide and cyclophosphamide, administered alone or in combination, have been reported to damage the growth plate by causing structural and cellular changes in the growth plate cartilage (Xian, Cool et al. 2007).
  • proteasome inhibitors including Bortezomib (Velcade, PS-341 ), belong to another novel and promising group of CT that has past phase I clinical trials (Blaney, Bernstein et al. 2004) and are now under phase II clinical trials in pediatric cancers.
  • phase I clinical trials Blaney, Bernstein et al. 2004
  • secondary effects on normal bystander tissues of primary life saving modalities are so far unknown.
  • Bortezomib target essential cell populations within the growth plate causing permanent growth retardation and chondrocyte cell death, both in vitro and in vivo (Zaman, Menendez-Benito et al. 2007).
  • HN humanin
  • AD Alzheimer's disease
  • Mamiya and Ukai 2001 chemical-induced damage
  • HN is both an intracellular and secreted protein.
  • HN cerebrospinal fluid
  • HN has also been reported as an antagonist of Bax and Bid that induces survival in cancer cells (Guo, Zhai et al. 2003), cell survival by binding to putative cell-surface receptors (Ying, Iribarren et al. 2004) and as an IGFBP-3 partner that antagonizes the apoptotic actions of IGFBP-3 on cancer cells (Ikonen, Liu et al. 2003).
  • IGFBP-3 is one of a number of peptides including insulin, leptin, adiponectin, and resistin that have been shown to act in the central nervous system to regulate glucose metabolism (Muse, Lam et al. 2007) (Obici, Zhang et al. 2002).
  • IGFBP-3 is an HN partner that has pro- diabetogenic hypothalamic actions that are modulated by IGF-I (Muzumdar and Rao 2006).
  • HN has been reported as a wide spectrum survival factor (Nishimoto, Matsuoka et al. 2004), but its exact mechanism of action remains unclear.
  • HNG humanin-Gly14
  • HNG-F6A non-IGFBP-3 binding
  • colivelin hybrid peptide containing partial sequences of HN and ADNF9
  • HN and its analogs and derivatives have shown therapeutic potential for an array of diseases including Alzheimer's disease (AD), diabetes and kidney failure (Matsuoka and Hashimoto 2010) (Matsuoka 2009) (Xu, Chua et al. 2006) (Hoang, Park et al. 2010) (Singh and Mascarenhas 2008).
  • Alzheimer's disease-related neurotoxicity functional potentiation by isomerization and dimerization.” J Neurochem 85(6): 1521 -1538.
  • the present inventors have identified a number of mutant humanin-like peptides (MHLPs) having the capacity to regulate biological pathways, such as inflammation and exert an inhibitory effect on the death of chondrocyte cells.
  • the peptides are named "mutant humanin-like peptides" (MHLPs) and the present invention relates to the peptides themselves and their use in the treatment and/or prevention of bone- or cartilage disorders/diseases, bone fractures, skeletal chondrodysplasias, cancers, autoimmune diseases, fibrotic diseases, inflammatory diseases, obesity, type I and type II diabetes, neurodegenerative diseases, infectious diseases, lung diseases, infertility, muscular disoders, aging, skin diseases, heart and vascular diseases and metabolic diseases.
  • a number of peptides have been designed, synthesized and tested for their capacity to modulate biological pathways in a cell model system. It was identified that chondrocyte cell death (which is the main cause of bone growth disorders under various conditions) is completely blocked by MHLPs, suggesting that the MHLPs according to the invention affect biological pathways. For instance, chondrocytes were treated with high dose glucocorticoids (GCs) and subsequent MHLP treatment completely rescued chondrocytes from undergoing apoptosis.
  • GCs glucocorticoids
  • the present findings show the use of MHLPs alone or in combination with chemotherapy completely prevents the negative effects of chemotherapy, wihout interfering with the primary effects of the drugs is of considerable clinical importance for their broader application.
  • a peptide comprising an amino acid sequence X1APX2X3FSCLLLLTGEIDLPVKRRA (SEQ ID NO:1 ) wherein
  • Xi is selected from M, L, A, S, G, and P; X2 is selected from R, K, A, G, and E; X3 is selected from G, V, Y, and A; and fragments, analogs, derivatives, and variants thereof, provided that peptides wherein Xi is M; X 2 is R and X3 is G simultaneously, are excluded.
  • a peptide comprising an amino acid sequence
  • Xi is selected from M, L, A, S, G, and P; X2 is selected from R, K, A, G, and E; X3 is selected from G, V, Y, and A; provided that peptides wherein Xi is M; X 2 is R and X3 is G simultaneously, are excluded.
  • a peptide comprising an amino acid sequence
  • Xi is selected from L, A, S, G, and P.
  • a peptide comprising an amino acid sequence
  • X 2 is selected from K, A, G, and E.
  • a peptide comprising an amino acid sequence
  • X 3 is selected from V, Y, and A.
  • a peptide comprising:5 to SEQ ID NO:17; LAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO: :5);
  • AAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO: :6);
  • SAPRGFSCLLLLTGEIDLPVKRRA SEQ ID NO: ⁇ n
  • GAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO: :8);
  • PAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO: :9)
  • MAPAGFSCLLLLTGEIDLPVKRRA SEQ ID NO: :1 1 );
  • MAPEGFSCLLLLTGEIDLPVKRRA SEQ ID NO: 12
  • MAPRGVSCLLLLTGEIDLPVKRRA SEQ ID NO: 14
  • MAPRGYSCLLLLTGEIDLPVKRRA SEQ ID NO: 15
  • MAPRGASCLLLLTGEIDLPVKRRA SEQ ID NO: :16
  • MAPRGGSCLLLLTGEIDLPVKRRA SEQ ID NO:17.
  • a peptide said peptide being LAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:5).
  • peptide in another embodiment, there is provided a peptide, said peptide being AAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:6).
  • peptide in another embodiment, there is provided a peptide, said peptide being SAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:7).
  • a peptide said peptide being GAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:8). In another embodiment of this aspect, there is provided a peptide, said peptide being PAPRGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:9).
  • peptide in another embodiment, there is provided a peptide, said peptide being MAPKGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:10).
  • a peptide said peptide being MAPAGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:1 1 ). In another embodiment of this aspect, there is provided a peptide, said peptide being MAPEGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:12).
  • peptide in another embodiment, there is provided a peptide, said peptide being MAPGGFSCLLLLTGEIDLPVKRRA (SEQ ID NO:13).
  • peptide in another embodiment, there is provided a peptide, said peptide being MAPRGVSCLLLLTGEIDLPVKRRA (SEQ ID NO:14).
  • peptide in another embodiment, there is provided a peptide, said peptide being MAPRGYSCLLLLTGEIDLPVKRRA (SEQ ID NO:15).
  • a peptide said peptide being MAPRGASCLLLLTGEIDLPVKRRA (SEQ ID NO:16). In another embodiment of this aspect, there is provided a peptide, said peptide being MAPRGGSCLLLLTGEIDLPVKRRA (SEQ ID NO:17).
  • a peptide of the invention for use in therapy.
  • a pharmaceutical composition comprising a peptide of the invention, together with
  • a peptide of the invention for use in in the prevention and/or treatment of bone- or cartilages disorders/diseases, cancer, autoimmune diseases, fibrotic diseases, inflammatory diseases, obesity, type I and type II diabetes,
  • neurodegenerative diseases bone fractures, skeletal chondrodysplasias, infectious diseases, lung diseases, infertility, muscular disoders, aging, skin diseases, heart and vascular diseases and metabolic diseases.
  • a peptide of the invention for use in the prevention and/or treatment of bone- or cartilage disorders.
  • Said peptide may improve bone growth.
  • the peptide may improve bone growth by itself targeting the Wnt-signalling or beta-catenin pathway or together with growth hormone (GH) or insulin-like growth factor I (IGF-I). Further, said peptide may improve bone healing. Further, said peptide may prevent development of osteoporosis.
  • Said bone- or cartilage disorder may be a either a primary or secondary bone- or cartilage disorder. Further, said peptide may improve skin healing.
  • a peptide of the invention for use in the prevention and/or treatment of bone- or cartilage disorders wherein said disorder is drug-induced.
  • Said drug-induced disorder may have arisen from drugs used in the treatment of rheumatological disorders, respiratory disorders, gastrointestinal disorders, cardiovascular disorders, endocrinological disorders, cancer, neurodegenerative disorders, kidney disorders, liver disorders, dermatologic disorders, allergic disorders, inflammatory disorders, metabolic disorders, undesired immune response, undesired inflammatory response, obesity or diabetes.
  • a peptide of the invention for use in the prevention and/or treatment of bone- or cartilage disorders wherein said disorder is drug-induced bone growth impairment, short stature or osteoporosis.
  • Said drug may be an anti-inflammatory drug, such as a glucocorticoid drug.
  • Said glucocorticoid drug may be selected from hydrocortisone, hydrocortisone buteprate, hydrocortisone butyrate,
  • budesonide ciclesonide, cortisone acetate, deflazacort, medrysone, tixocortol, cloprednol, halcinonide, pregnadiene, rimexolone, flunisolide, triamcinolone, amcinonide, fluocinolone acetonide, fluocinonide,
  • fluorometholone clocortolone, diflucortolone, fluocortin, desoximetasone, prednisone, prednisolone, methylprednisolone, methylprednisolone
  • aceponate prednicarbate, prednylidene, desonide, fluprednisolone, difluprednate, fluperolone, meprednisone, dexamethasone, betamethasone, triamcinolone, beclometasone, clobetasone, diflorasone, halometasone, ulobetasol, fludrocortisone acetate, beclomethasone dipropionate,
  • glucocorticoid drug is dexamethasone.
  • a peptide of the invention for use in the prevention and/or treatment of bone- or cartilage disorders wherein said disorder is drug-induced by an anti-cancer drug.
  • Said anti-cancer drug may be a proteasome inhibitor, such as bortezomib,
  • a peptide of the invention for use in the prevention and/or treatment of bone- or cartilage disorders, wherein said peptide is administered in combination with another drug known to induce a bone- or cartilage disorder.
  • said another drug is selected from an antiinflammatory drug, a selective estrogen receptor modulator drug, an anti- androgen drug, an aromatase inhibitor drug and an anti-cancer drug.
  • said another drug is an anti-inflammatory drug, it may be a
  • glucocorticoid drug such as hydrocortisone, hydrocortisone buteprate, hydrocortisone butyrate, budesonide, ciclesonide, cortisone acetate, deflazacort, medrysone, tixocortol, cloprednol, halcinonide, pregnadiene, rimexolone, flunisolide, triamcinolone, amcinonide, fluocinolone acetonide, fluocinonide, fluorometholone, clocortolone, diflucortolone, fluocortin, desoximetasone, prednisone, prednisolone, methylprednisolone,
  • methylprednisolone aceponate prednicarbate, prednylidene, desonide, fluprednisolone, difluprednate, fluperolone, meprednisone, dexamethasone, betamethasone, triamcinolone, beclometasone, clobetasone, diflorasone, halometasone, ulobetasol, fludrocortisone acetate, beclomethasone
  • alclometasone fluclorolone, flumetasone, fluprednidene, triamcinolone, flunisolide, cortivazol, fluticasone, fluticasone propionate, fluticasone furoate, loteprednol, fludroxycortide, formocortal or mometasone furoate.
  • said glucocorticoid drug is dexamethasone.
  • said another drug is an anti-cancer drug
  • it may be a proteasome inhibitor, such as bortezomib, MLN9708, MLN273, MLN519, NPI-0052, Disulfiram, Ritonavir, Lactacystin, CEP-18770, Carfilzomib, PS-519, MG132, MG 262, ALLN, Fellutamide B, Tyropeptin A, Omuralide, Salinosporamide A, Eponeomycine, Epoxomicin, TMC-95A, Syringolin A, Glidobactin A, TMC-95 analogs, NLVS, ZLVS.
  • said proteasome inhibitor is bortezomib.
  • said another drug may be selected from leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, cetrorelix, ganirelix, abarelix, degarelix, letrozole, anastrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, testolactone, tamoxifen, afimoxifene, 4- hydroxytamoxifen, arzoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene, tamoxifentoremifene, spironolactone, cyproterone acetate, flutamide, nilutamide, bicalutamide, ketoconazole, finasteride, dutasteride, cyclophosp
  • dexamethasone acetate dexamethasone sodium phosphate, dexasone, dexrazoxane, dhad, die, diodex, docetaxel, doxil, doxorubicin, doxorubicin liposomal, droxia, duralone, efudex, eligard, ellence, eloxatin, elspar, emcyt, epirubicin, epoetin alfa, erbitux, erlotinib, erwinia L-asparaginase,
  • a method of preventing and/or treating bone- or cartilage disorders comprising administering a therapeutically effective amount of a peptide of the present invention.
  • Said peptide may improve bone growth. Further, said peptide may improve bone healing. Further, said peptide may prevent development of osteoporosis.
  • Said bone- or cartilage disorder may be a either a primary or secondary bone- or cartilage disorder. Further, said peptide may improve skin healing.
  • a therapeutically effective amount of a peptide of the present invention wherein said disorder is drug-induced.
  • Said drug-induced disorder may have arisen from drugs used in the treatment of rheumatological disorders, respiratory disorders, gastrointestinal disorders, cardiovascular disorders, endocrinological disorders, cancer, neurodegenerative disorders, kidney disorders, liver disorders, dermatologic disorders, allergic disorders, inflammatory disorders, metabolic disorders, undesired immune response, undesired inflammatory response, obesity or diabetes.
  • Said drug may be an anti-inflammatory drug, such as a glucocorticoid drug.
  • Said glucocorticoid drug may be selected from hydrocortisone, hydrocortisone buteprate, hydrocortisone butyrate,
  • budesonide ciclesonide, cortisone acetate, deflazacort, medrysone, tixocortol, cloprednol, halcinonide, pregnadiene, rimexolone, flunisolide, triamcinolone, amcinonide, fluocinolone acetonide, fluocinonide,
  • fluorometholone clocortolone, diflucortolone, fluocortin, desoximetasone, prednisone, prednisolone, methylprednisolone, methylprednisolone
  • aceponate prednicarbate, prednylidene, desonide, fluprednisolone, difluprednate, fluperolone, meprednisone, dexamethasone, betamethasone, triamcinolone, beclometasone, clobetasone, diflorasone, halometasone, ulobetasol, fludrocortisone acetate, beclomethasone dipropionate,
  • glucocorticoid drug is dexamethasone.
  • Said anti-cancer drug may be a proteasome inhibitor, such as bortezomib, MLN9708, MLN273, MLN519, NPI-0052, Disulfiram, Ritonavir, Lactacystin, CEP-18770, Carfilzomib, PS-519, MG132, MG 262, ALLN, Fellutamide B, Tyropeptin A, Omuralide, Salinosporamide A, Eponeomycine, Epoxomicin, TMC-95A, Syringolin A, Glidobactin A, TMC-95 analogs, NLVS and ZLVS.
  • said proteasome inhibitor is bortezomib.
  • a method of preventing and/or treating bone- or cartilage disorders comprising administering a therapeutically effective amount of a peptide of the present invention, wherein said peptide is administered in combination with another drug known to induce a bone- or cartilage disorder.
  • said another drug is selected from an anti- inflammatory drug, a selective estrogen receptor modulator drug, an anti- androgen drug, an aromatase inhibitor drug and an anti-cancer drug.
  • said another drug is an anti-inflammatory drug, it may be a
  • glucocorticoid drug such as hydrocortisone, hydrocortisone buteprate, hydrocortisone butyrate, budesonide, ciclesonide, cortisone acetate, deflazacort, medrysone, tixocortol, cloprednol, halcinonide, pregnadiene, rimexolone, flunisolide, triamcinolone, amcinonide, fluocinolone acetonide, fluocinonide, fluorometholone, clocortolone, diflucortolone, fluocortin, desoximetasone, prednisone, prednisolone, methylprednisolone,
  • methylprednisolone aceponate prednicarbate, prednylidene, desonide, fluprednisolone, difluprednate, fluperolone, meprednisone, dexamethasone, betamethasone, triamcinolone, beclometasone, clobetasone, diflorasone, halometasone, ulobetasol, fludrocortisone acetate, beclomethasone dipropionate, beclomethasone monopropionate, paramethasone,
  • alclometasone fluclorolone, flumetasone, fluprednidene, triamcinolone, flunisolide, cortivazol, fluticasone, fluticasone propionate, fluticasone furoate, loteprednol, fludroxycortide, formocortal or mometasone furoate.
  • said glucocorticoid drug is dexamethasone.
  • said another drug is an anti-cancer drug
  • it may be a proteasome inhibitor, such as bortezomib, MLN9708, MLN273, MLN519, NPI-0052,
  • said proteasome inhibitor is bortezomib.
  • said another drug may be selected from leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, cetrorelix, ganirelix, abarelix, degarelix, letrozole, anastrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, testolactone, tamoxifen, afimoxifene, 4- hydroxytamoxifen, arzoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene, tamoxifentoremifene, spironolactone, cyproterone acetate, flutamide, nilutamide, bicalutamide, ketoconazole, finasteride, dutasteride, cyclophosp
  • dexamethasone acetate dexamethasone sodium phosphate, dexasone, dexrazoxane, dhad, die, diodex, docetaxel, doxil, doxorubicin, doxorubicin liposomal, droxia, duralone, efudex, eligard, ellence, eloxatin, elspar, emcyt, epirubicin, epoetin alfa, erbitux, erlotinib, erwinia L-asparaginase,
  • osteoarthritis or osteoarthrosis Another such a condition is delayed fracture healing which if untreated can lead to severe consequences including pseudoarthrosis.
  • a primary bone or cartilage disorder growth impairment, short stature, arthritis, osteoarthritis, rheumatoid arthritis, psoriasis arthritis, ankylosing spondylitis, osteoarthrosis, osteomyelitis fibrous dysplasia, fibrodysplasia ossificans, craniosynostosis, metabolic bone disease, osteitis deformans, osteogenesis imperfecta, scoliosis, leg length difference, bone dysplasia, osteopetrosis, osteomalacia, osteopenia, osteoporosis, osteitis fibrosa cystic, osteochondritis, osteonecrosis, osteosarcoma, bone tumor, osteochondroma, osteochondropathy, chondropathy, chondrodysplasia, achondrodysplasia, hypochondrodysplasia, chondrodystrophy,
  • a secondary bone or cartilage disorder is meant a disorder which is a consequence of another disorder not primarily involving bone or cartilage tissues.
  • Another disorder includes Cushing ' s syndrome which is caused by increased Cortisol production.
  • undesired immune response or undesired inflammatory response is meant responses which have undesired effects on bone or cartilage tissues.
  • Rheumatological disorders include, but are not limited to, reumatoid arhtritis, systemic lupus erythematosus, vasculitis, periarhteritis nodosa and
  • Respiratory disorders include, but are not limited to, asthma bronchiale, chronic obstructive lung disease and bronchiolitis obliterans.
  • Gastrointestinal disorders include, but are not limited to, colitis ulcerosa, Crohn ' s disease and pancreatitis.
  • Cardiovascular disorders include, but are not limited to, myocarditis, ischemia, hemolytic anemia and granulocytopenia.
  • Endocrinological disorders include, but are not limited to, adrenal disorder, glucocorticoid deficiency, congenital adrenal hyperplasia,
  • Cancer includes, but is not limited to, acute myeloid leukemia, multiple myeloma and lymphoma.
  • Neurodegenerative disorders include, but are not limited to, multiple sclerosis and encephalitis.
  • Kidney disorders include, but are not limited to,
  • Liver disorders include, but are not limited to, hepatitis and cholangitis.
  • Dermatologic disorders include, but are not limited to, psoriasis, exzema, myositis, dermatomyositis and dermatitis.
  • the disorder is drug-induced from a GnRH agonist drug, such as leuprolide, buserelin, nafarelin, histrelin, goserelin and deslorelin.
  • the disorder is drug-induced from a GnRH antagonist drug, such as cetrorelix, ganirelix, abarelix and degarelix.
  • the disorder is drug-induced from a selective estrogen receptor modulator drug, such as tamoxifen, afimoxifene, 4-hydroxytamoxifen, arzoxifene, avalycation, gammoxifene, femarelle, lasofoxifene, ormeloxifene, raloxifene and tamoxifentoremifene.
  • a selective estrogen receptor modulator drug such as tamoxifen, afimoxifene, 4-hydroxytamoxifen, arzoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene and tamoxifentoremifene.
  • the disorder is drug-induced from an anti- androgen drug, such as spironolactone, cyproterone acetate, flutamide, nilutamide, bicalutamide, ketoconazole, finasteride and dutasteride.
  • an anti- androgen drug such as spironolactone, cyproterone acetate, flutamide, nilutamide, bicalutamide, ketoconazole, finasteride and dutasteride.
  • the disorder is drug-induced from an aromatase inhibitor drug, such as letrozole, anastrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide and testolactone.
  • an aromatase inhibitor drug such as letrozole, anastrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide and testolactone.
  • Figure 1 Provides micrographs and data of potential protective effects of HNG and MHLPs of the invention on skin atrophy in mice (see Example 5 for further explanation).
  • compositions of the invention may be administered by means which include but are not limited to intravenous, oral, subcutaneous, intra-arterial, intramuscular, intracardial, intraspinal, intrathoracic, intraperitoneal, intraventricular, sublingual, transdermal, intranasal, and inhalation.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs as amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as naturally occurring amino acids that are later modified.
  • Amino acid analogs are compounds that have the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that differs from the general chemical structure of an amino acid, but that functions similar to a naturally occurring amino acid.
  • Endogenous refers to a protein, nucleic acid, lipid or other biomolecule produced or originating within the body or within cells, organs, tissues of the body of a subject.
  • Exogenous refers to a protein, nucleic acid, lipid, or other biomolecule originating outside the body of a subject.
  • Cartilage tissues refers to all tissues in the body where cartilage cells (chondrocytes) are the major cellular components. This includes but is not limited to joint cartilage, growth plate cartilage and intervertebral disc cartilage. “Bone tissues” refers to all tissues in the body where bone cells (osteocytes, osteoblasts and osteoclasts) are important cellular components. This includes but is not limited to long bones and vertebrae
  • Bone growth refers to a series of co-ordinated actions which take place at the epiphyseal growth plate of long bones by balanced cycle of cartilage growth, formation of matrix, calcification of cartilage that acts as a scaffold for bone formation and modelling (where bone is being continuously resorbed and replaced by new bone). Bone modelling is highly active in
  • Bone growth disorders occur when there is disruption of the normal cellular activity of chondrocytes (growth plate/articular) and/or bone cells.
  • “Bone metabolism” refers to a process involving bone modeling and bone remodeling where cells produce the substances and energy needed for their survival.
  • bone remodeling bone resorption by osteoclasts is followed by bone formation by osteoblasts.
  • Bone remodeling does not result in changes of bone shape but helps in repairing of microdamage.
  • modeling is the formation of new bone by osteoblasts at locations different from the sites of bone resorption by osteoclasts and results in bone growth.
  • Longitudinal bone growth refers endochondral bone formation that occurs in the growth plates (a thin layer of cartilage located on each end of long boneswhere in a series of co-ordinated steps where resting zone/stem-like chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization resulting in increased bone length.
  • Drug-induced longitudinal bone growth impairement refers to a condition when drugs given to the patient/subject (mammal, children, adolescents, adults, animal) to treat different diseases but as a side effect they also alter/inhibit the normal process of bone elongation causing longitudinal bone growth impairment/retardation.
  • “Drug-induced” refers to an effect which is primarily due to drug(s) given to patient/subject under different disease conditions. “Fragment” refers to a small part synthesised/produced/broken off/or detached from its original place.
  • Derivative refers to a substance derived/produced/obtained either directly or by modification or partial substitution.
  • Catch-up growth refers to acceleration of the growth rate in infants or young children above the limits of normal for age after a transient period of growth inhibition/impairment; it can be complete or incomplete.
  • peptide refers to any of various natural or synthetic compounds containing at least two or more amino acids linked by the carboxyl group of one amino acid to the amino group of another.
  • Polypeptide refers to chains of amino acids, and “proteins” are made up of one or more polypeptide molecules.
  • Polynucleotide refers to a polymeric form of nucleotides af at least 10 bases or base pairs in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, including single and double stranded forms of DNA.
  • polypeptide refers to a polymer (large molecules composed of repeating structural units typically connected by covalent chemical bonds) formed from the linking, in a defined order, of a- amino acids.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • endogenous expression of humanin in cartilage tissues and/or bone tissues refers to the local production and/or secretion of humanin within cartilage tissues and/or bone tissues.
  • agent that affects the local production and/or expression of humanin or another peptide expressed by the humanin gene refers to an agent that for example, but not limited to, triggers endogenous production of humanin or humanin like peptides/derivatives/analogs in cartilage tissues and/or bone tissues by the use of siRNA, miRNA, shRNA (plasmid and lentiviral).
  • MicroRNA refers to a class of small RNA molecules, about 21 nucleotides in length that regulate gene expression in a variety of ways.
  • RNA interference refers to a biological mechanism by which double- stranded RNA (dsRNA) induces gene silencing by targeting complementary mRNA for degradation.
  • siRNA small interfering RNA
  • RNAi RNA interference
  • short hairpin RNA refers to a sequence of RNA that makes a tight hairpin turn that can be used to silence gene expression via RNA
  • “Disorder that affects the endogenous expression of humanin in cartilage tissues and/or bone tissues negatively influencing cartilage tissues and/or bone tissues” refers to the presence, absence, increased or decreased level of humanin in cartilage tissues and/or bone tissues with or without treatment causing cartilage tissue and/or bone tissue disorders. For example, a patient suffering from increased or decreased and/or insufficient levels of locally produced humanin in cartilage tissues and/or bone tissues resulted from with/without treatment of any disease.
  • mutant-humanin-like peptides and derivates, analogs and variants thereof is at least about 30%, preferably 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 95% or 98% identical to amino acid sequence of SEQ ID NO: 5-17.
  • mutant-humanin-like peptides (MHLPs) and dehvates, analogs and variants thereof has an amino acid sequence which is
  • sequence of the corresponding human humanin in that the sequence is at least about 30%-98% or more identical to the sequence of a reference sequence, such as the corresponding
  • amino acid(s) substitution is one in which one or more amino acid reidue(s) is replaced with an amino acid residue.
  • Families of amino acid residues have been defined in the art and include amino acids with basic side chains (e.g lysine, arginine, histidine), acidic side chains (e.g. aspartic acid, glutamic acid), uncharged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g.
  • HLPs humanin and humanin-like peptides
  • dehvates, analogs and variants thereof can typically be replaced with another amino acid residue, preferably from the same side chain family.
  • non-essential amino acid residue is a residue that can be altered from the original sequence (e.g. a sequence of SEQ ID NO: 5-17) without abolishing or substantially altering the therapeutic activity of the peptide, whereas an "essential" amino acid residue is a residue that cannot be altered without introducing such a change.
  • nucleic acids or polypeptide sequences refers to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same when compared and aligned for maximum correspondence over a comparison window or designated region. Methods of aligning sequences for comparison are well-known in the art. Mutant humanin-like peptides (MHLPs) and derivates, analogs and variants provided herein may be modified chemically and/or biologically.
  • modifications include, but are not limited to, functional group introduction such as alkylation, acylation, amidation, esterification, halogenation, amination, carboxylation, and pegylation, functional group conversion such as oxidation, reduction, addition, and elimination, glycosylation, lipid compound introduction, phosporylation, and/or biotinylation.
  • modification(s) may for example stabilize and/or enhance the biological activity of mutant-humanin- like peptides (MHLPs) and derivates, analogs and variants thereof.
  • identifying methods for activity of humanin comprising inhibition, and/or stimulation or expression of humanin, such as the activity or expression in the cell is modulated by using mutant-humanin-like peptides (MHLPs).
  • Another aspect is a method for identifying modulation of
  • treating used herein includes, but is not limited to prevention, amelioration, alleviation, and/or eliminations of disease, disorder, or condition being treated or one or more symptoms of the disease, disorder or condition being treated, but also of therapies/treatments/drugs alone or in combination affecting cartilage tissues and/or bone tissues as well as improvement in the overall well being of patient, as measured by objective and/or subjective criteria.
  • Disease refers to a problem affecting cartilage tissues and/or bone tissues in a negative manner, but also of therapies/treatment/drugs alone or in combination affecting cartilage tissues and or bone tissues in a negative manner.
  • disorder that negativly affects cartilage tissues and/or bone tissues refers to a disorder, disease or condition that interact, alter, influences and/or disturbs the normal physiology and/or morphology and/or function of cartilage tissues and/or bone tissues.
  • X-ray examination Dual energy X-ray absorptiometry, Ultrasound, Computer tomography, Peripheral quantitative computer tomography, Magnetic resonance imaging, Visual inspection, Histological examination, Clinical examination, or Analysis of biological markers in the blood.
  • short stature used herein includes, but is not limited to, Familial short stature, Constitutional delay of growth and puberty, Idiopathic short stature, Small for gestational age, Intrauterine growth retardation, Growth hormone deficiency, Insulin-like growth factor-l deficiency, or growth impairment caused by a chronic disease and/or genetically determined disorder and/or syndrome.
  • bone dysplasia used herein includes, but is not limited to,
  • Achondrodysplasia Hypochondrodysplasia or a disorder and/or syndrome affecting cartilage and/or bone development.
  • osteomalacia used herein is defined as a disorder which involves the softening of the bones due to defective bone mineralization which can be caused by, but not limited to, Rickets, Hypoparathyroidism,
  • osteoporosis used herein is defined as a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced and the bone microarchitecture is disrupted, and the amount and variety of proteins in bone may be altered.
  • skin atrophy used herein is defined as a condition when the skin becomes thin which could be secondary to a medical treatment or part of a natural aging process.
  • a “subject” of a method provided herein refers to any mammalian patient to which peptides or compositions of the invention can be beneficially administered.
  • the term “mammal” refers to humans and non-human primates, as well as experimental or veterinary animals, such as rabbits, rats mice, and other animals.
  • an "effective amount" of MHLPs and derivates, analogs and variants thereof is an amount sufficient to provide a measurable reduction in symptoms or other beneficial effect(s) with respect to a disease, therapy, disorder, or condition targeted for treatment.
  • Cancer refers generally to a disease characterized by uncontrolled, abnormal cell growth and proliferation.
  • a “tumor” or “neoplasm” is an abnormal mass of tissue that results from excessive, uncontrolled, and progressive cell division.
  • the present invention also provides methods of treating a subject having a disorder affecting cartilage tissues and/or bone tissues characterized by aberrant activity and/or aberrant expression of humanin or variant thereof, by administering an agent which is a modulator of the activity of humanin or variant or modulator thereof.
  • an agent which is a modulator of the activity of humanin or variant or modulator thereof.
  • pharmaceutical compositions comprising one or more peptides of the invention together with at least one pharmaceutically acceptable carrier or excipient.
  • Peptides of the invention can be incorporated into pharmaceutical
  • compositions suitable for administration typically comprise the peptide and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should 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.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze- drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • compositions can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Phmogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active for transdermal administration, the active
  • the active peptides are prepared with carriers that will protect the peptide against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,
  • polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as
  • the active ingredient of the pharmaceutical composition of the present invention may be DNA encoding the polypeptide of the present invention.
  • examples of administration methods thereof include a method which administers a vector incorporating the DNA therein.
  • the vector include plasmids, adenovirus vectors, adeno- associated virus vectors, herpes virus vectors, vaccinia virus vectors, and retrovirus vectors.
  • the therapeutic agent can be expressed in vivo with efficiency by infecting organisms with the viral vectors.
  • a method which introduces the vector or the DNA into liposomes e.g., positively charged liposomes and positively charged cholesterol
  • administers the liposome can be used as an effective therapy.
  • the pharmaceutical composition of the present invention When used as a preventive and/or therapeutic agent for the diseases described above, it can be administered to mammals such as humans, mice, rats, rabbits, dogs, and cats.
  • the dose and number of doses of the pharmaceutical drug of the present invention may be changed appropriately according to the age, sex, and conditions of a subject to be administered, or administration routes.
  • a therapeutically effective amount of protein or polypeptide provided herein can range from about 0.001 to 500 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • treatment of a subject with a therapeutically effective amount of a protein or polypeptide can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with protein or polypeptide in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks.
  • the effective dosage of antibody, protein, or polypeptide used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays as described herein.
  • doses of protein or polypeptide agents depend upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher.
  • the dose(s) will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable.
  • Exemplary doses include milligram or microgram amounts of the protein or polypeptide per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram.
  • appropriate doses of a protein or polypeptide depend upon the potency of the protein or polypeptide with respect to the expression or activity to be modulated. Such appropriate doses may be determined using the assays described herein.
  • a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific protein or polypeptide employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
  • Human chondrocyte cell line HCS-2/8 (20000 cells/well, in 96 wells plate), was cultured in DMEM/Ham's F12 (Invitrogen) supplemented with 20% FBS Thereafter, cells were treated with dexamethasone (25 ⁇ ) and MHLPs (1 OnM and 1000 nM) in test medium (DMEM-F12 supplemented with 1 % FBS) . Incubation was at 37°C in a humidified atmosphere of 95% air/5%
  • FVB mice female, 4 weeks old were treated with daily injections of dexamethasone (Dexa, 2mg/kg), humanin peptide (HNG, 1 g/mouse) or vehicle (saline) for 4 weeks. Animals were then killed and a skin biopsy (8mm) taken, fixed in 4% formaldehyde, embedded in paraffin, and sectioned. Skin thickness (subcutis and dermis) was measured on digital images captured in the light microscope.
  • dexamethasone Dexa, 2mg/kg
  • HNG humanin peptide
  • vehicle saline
  • HNG S14G-HN
  • MHLPs mutant-humanin-like peptides
  • the MHLPs of the present invention may be compared with the humanin sequence S14G-HN (HNG):
  • HNG Human chondrocytes
  • MHLP1 to MHLP13 were tested in corresponding concentrations, i.e. 10 nM, 100 nM and 1000 nM, respectively.
  • MHLPs protect human chondrocytes from toxic/anti-proliferative effects of GCs
  • the cell proliferation reagent 4-[3- (4-iodophenyl)-2(4-nitrophenyl)-2H-5-tetrazolio]-1 ,3-benzene disulfonate was used, which was purchased from Roche Diagnostics GmbH (Mannheim, Germany).
  • WST-1 is a colorimetric assay for the quantification of cell proliferation and cell viability. This assay is based on a water-soluble tetrazolium salt, which is cleaved to formazan by mitochondrial enzymes. The amount of the formazan dye formed is directly correlated to the number of metabolically active cells.
  • the HCS-2/8 cells were plated in 96-well plates (2 10 4 cells/well), and cultured for 72 hrs in DMEM/F12 with 20% FBS added. The cells were then washed once with 1 ⁇ PBS before the medium was changed to test medium, which contained 1 % FBS and for each experiment specific concentrations of effectors which included Dexamethasone (25 ⁇ , diluted in 99% Ethanol), HNG (10 or 1000 nM diluted in dH 2 O) and MHLPs (10 or 1000 nM diluted in dH 2 O). Control cells were incubated in medium with no effectors added but with corresponding amounts of 99% Ethanol and dH 2 O. After treatment, WST-1 was added, 20 ⁇ /well (final dilution 1 :10), and the reaction mixture was incubated for 1 hr at 37 C before read
  • MHLPs prevent apoptosis caused by dexamethasone in chondrocytes
  • apoptosis was studied with the detection and quantification of cytoplasmic histone-associated DNA fragments (mono- and oligonucleasomes) by photometric enzyme immunoassay (Cell Death Detection ELISA PLUS , Roche Diagnostics).
  • the cells were first treated as described for the proliferation assay and then lysated (100 ⁇ lysis buffer) and centrifuged. The supernatant was removed for analysis of cytoplasmic histone-associated DNA fragments according to the manufacturer's instructions.
  • the cells were treated with dexamethasone (25 ⁇ , diluted in 99% Ethanol), HNG (100 nM diluted in dH 2 O) and MHLPs (100 nM diluted in dH 2 O). Control cells were incubated in medium with no effectors added but with corresponding amounts of 99% Ethanol and dH 2 O.
  • HCS-2/8 chondrocytes (1 x10 6 per Petri-dish) in test medium (DMEM-F12 with 1 % FBS) were treated with Dexamethasone (25 ⁇ , diluted in 99% Ethanol), HNG (100 nM diluted in dH 2 O) and MHLPs (100 nM diluted in dH2O), and lipopolysacharide (LPS, 100 ng/ml).
  • Control cells were incubated in medium with no effectors added but with corresponding amounts of 99% Ethanol and dH 2 O. After 48 hrs, test medium was collected and analysed for release of cytokine (TNF-alpha).
  • TNF-alpha The detection of TNF-alpha was performed by using an ELISA kit (R&D systems, Minneapolis) according to the instructions provided by the manufacturer.
  • the data presented in Table 4 show that selected MHLPs do not interfer with the desired anti-inflammatory effects of GCs (dexamethasone).
  • FVB mice female, 4 weeks old were given a daily injection of
  • dexamethasone (2mg/kg), humanin peptide HNG (1 g/mice) or vehicle (saline). After 4 weeks of treatment, animals were killed and an 8 mm skin biopsy was collected (one from the neck and one from the back near the tail). The skin biopsies were fixed in 4% formladehyde and embedded in paraffin blocks.
  • Figure 1 a the upper left slide represents vehichle; upper right represents HNG (1 g/mouse); lower left represents dexamethasone
  • GCs dihydroxy-3-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)

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Abstract

La présente invention concerne le domaine des agents thérapeutiques médicaux, et plus particulièrement des peptides thérapeutiques actifs dans le traitement de troubles des os ou du cartilage et d'autres maladies. L'invention concerne une série de nouveaux peptides et leurs fragments, analogues, dérivés et variantes, structuralement apparentés à l'humanine, qui ont des activités bénéfiques sur les tissus du cartilage et/ou les tissus des os (y compris la prévention des effets négatifs de médicaments sur les tissus du cartilage et/ou les tissus des os), et dans d'autres maladies, y compris les fractures osseuses, les chondrodysplasies squelettiques, les cancers, les maladies auto-immunes, les maladies fibrotiques, les maladies inflammatoires, l'obésité, les diabètes de type I et de type II, les maladies neurodégénératives, les maladies infectieuses, les maladies pulmonaires, l'infertilité, les troubles musculaires, le vieillissement, les maladies de la peau, les maladies cardiaques et vasculaires, et les maladies métaboliques.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170061084A (ko) * 2015-11-25 2017-06-02 연세대학교 원주산학협력단 휴매닌 또는 이의 유사체를 유효성분으로 함유하는 창상 치료용 약학적 조성물
KR101885591B1 (ko) * 2015-11-25 2018-08-06 주식회사 바이오에프디엔씨 휴매닌 또는 이의 유사체를 유효성분으로 함유하는 창상 치료용 약학적 조성물

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