WO2017032859A2 - Composés pour induire la formation tissulaire et leurs utilisations - Google Patents

Composés pour induire la formation tissulaire et leurs utilisations Download PDF

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WO2017032859A2
WO2017032859A2 PCT/EP2016/070136 EP2016070136W WO2017032859A2 WO 2017032859 A2 WO2017032859 A2 WO 2017032859A2 EP 2016070136 W EP2016070136 W EP 2016070136W WO 2017032859 A2 WO2017032859 A2 WO 2017032859A2
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WO2017032859A3 (fr
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Omar F. ZOUANI
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Histide Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to compounds for inducing tissue formation, biomaterials and medical devices comprising such compounds, such compounds for use in medical methods and use of such compounds in non-medical methods.
  • Tissue regeneration forms an important part of the healing process subsequent to disease, trauma, or surgery.
  • tissue regeneration is a central goal of recovery. It is not, however, a goal that is always or easily achieved and much research has been devoted to newer and more effective ways to promote tissue repair and regeneration.
  • Conventional technics to achieve tissue regeneration involve the activation of tissue-specific stem cells present in adult tissues with repair and/or regenerative capabilities called mesenchymal stem cell(s) or MSC(s) using recombinant proteins called growth factors (GFs).
  • GFs growth factors
  • MSCs or MSC-like cells may be found in the bone marrow, but also in tissues such as fat, umbilical cord blood, amniotic fluid, placenta, dental pulp, tendons, synovial membrane and skeletal muscle.
  • GFs growth factors
  • VEGF vascular endothelial growth factors
  • BMP bone morphogenetic proteins
  • TGF transforming growth factors
  • PDGF-BB platelet-derived growth factor-BB
  • osteoblasts are the cells responsible for bone formation and are derived from osteoblast precursors. Differentiation of human bone marrow mesenchymal stem cells and osteoblast precursors is one of the important processes for bone regeneration. Osteoblasts differentiate from mesenchymal stem cells. Mature osteoblasts differentiate from osteoblast precursors and into osteocytes which are non-dividing cells. Upon cell activation osteoblasts begin to secrete some extracellular matrix around themselves. Calcification, i.e., deposition of insoluble calcium salts in the bone matrix, begins a short time after the matrix has been secreted. Upon termination of bone matrix synthesis, osteoblasts either undergo cell death by apoptosis or differentiate into osteocytes or bone lining cells.
  • Mesenchymal stem cells are found in large numbers in the periosteum, the fibrous-like layer on the outside surface of bones, and in the bone marrow.
  • the developing progenitor cells express the regulatory transcription factor Cbfa1/Runx2.
  • a second important transcription factor required for osteoblastic differentiation is osterix.
  • Osteoprogenitors differentiate under the influence of growth factors.
  • Important growth factors in skeletal differentiation include bone morphogenetic proteins (BMPs), transforming growth factor beta (TG F- ⁇ ) and fibroblast growth factors (FGFs).
  • BMPs bone morphogenetic proteins
  • TG F- ⁇ transforming growth factor beta
  • FGFs fibroblast growth factors
  • Differentiation of osteoblasts is also characterized by the expression of alkaline phosphatase as an early marker of pre-osteoblasts.
  • acting on the differentiation cycle of mammal bone marrow mesenchymal stem cells and osteoblast precursors may have applications in bone tissue regeneration.
  • Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture.
  • the bone mineral density BMD
  • bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered.
  • Osteoporosis is defined by the World Health Organization as a bone mineral density of 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by dual-energy X-ray absorptiometry; the term "established osteoporosis" includes the presence of a fragility fracture.
  • the treatment of osteoporotic fractures is often hindered by reduced bone healing and higher rates of complications.
  • MSCs mesenchymal stem cells
  • BMPs key agents are BMPs.
  • BMP-2 is one of the most potent osteoinductive cytokines which physiologically contributes to the early phase of fracture healing.
  • BMP-2 is already clinically approved for the treatment of distinct fracture entities.
  • genetic polymorphisms in BMP-2 have been identified as risk factors for the development of familial osteoporosis and osteoporotic fractures. All these findings directly link the BMP pathways to osteoporosis.
  • rhBMP-2 increased the volume of trabecular bone and stimulated bone formation in osteoporotic mice.
  • the local application of adenoviral BMP-2 at the site of injury enhanced callus formation and improved mechanical properties of the healing bone in osteoporotic sheep. Stimulating the differentiation of MSCs and/or inducing growth factor activity, in particular of BMPs, may thus lead to the development of new osteoporosis treatments.
  • chondrocytes offer little assistance to injured articular cartilage, these cells are responsible for the synthesis and turnover of the cartilage extracellular matrix (ECM), which provides an environment of nutrition diffusion for chondrocytes and provides the joint surface with biomechanical competence.
  • ECM cartilage extracellular matrix
  • Chondrogenic cells arise from pluripotential adult mesenchymal stem cells (MSCs) through a series of differentiation pathways. Subsequently, it was shown that a number of cytokines and transcription factors are involved in chondrocyte maturation and cartilage formation. Chondrogenic differentiation of MSCs is induced by various intrinsic and extrinsic factors. Growth factors play the most important role in this process.
  • Skeletal muscle is a highly complex and heterogeneous tissue serving a multitude of functions in the organism.
  • the process of generating muscle -myogenesis- can be divided into several distinct phases.
  • mesoderm-derived structures generate the first muscle fibers of the body proper, and in subsequent waves additional fibers are generated along these template fibers.
  • muscle resident myogenic progenitors initially proliferate extensively but, later on, decrease as the number of myonuclei reaches a steady state and myofibrillar protein synthesis peaks. Once the muscle has matured, these progenitors will enter quiescence and henceforth reside within it as satellite cells.
  • the activation of the network of transcription factors that controls skeletal muscle development depends on paracrine factors that are released by adjacent tissues, such as the neural tube, notochord, surface ectoderm and lateral mesoderm.
  • paracrine factors that are released by adjacent tissues, such as the neural tube, notochord, surface ectoderm and lateral mesoderm.
  • Several secreted factors have been identified that determine the spatial and temporal onset of myogenesis.
  • no consensus has been reached as to whether these molecules instruct naive cells (instructive induction), amplify a pool of committed progenitors and/or enable a default differentiation pathway (permissive induction) or primarily prevent programmed cell death of muscle progenitor cells.
  • Sonic hedgehog (SHH) and WNT signaling have been reported to have pivotal roles in the induction of myogenesis.
  • BMPs bone morphogenetic proteins
  • vasculature in the human body forms through two distinct processes: vasculogenesis and angiogenesis.
  • Vasculogenesis is defined as the process of de novo blood vessel formation occurring when endothelial precursor cells (angioblasts) migrate and differentiate into endothelial cells which form the new vessel. These vascular trees are then extended through angiogenesis which is defined as the new vessel formation secondary to proliferation of endothelial cells from pre-existing vessels.
  • Vasculogenesis as well as angiogenesis occur during the embryologic development of the circulatory system but also in the adult organism from circulating endothelial progenitor cells (derivatives of stem cells) able to contribute, albeit to varying degrees, to neovascularization.
  • EPCs endothelial progenitor cells
  • FG F FG F
  • VEGF vascular endothelial growth factor
  • PDGF vascular endothelial growth factor
  • VEG F is a sub-family of growth factors, to be specific, the platelet-derived growth factor family of cystine-knot growth factors. VEG F causes an importantsignaling cascade in endothelial cells. Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability, proliferation/survival, migration and finally differentiation into mature blood vessels. Recent reports have also indicated that different somatic cells (other than the EPCs) could be reprogrammed towards distinct endothelial cell lineages. This somatic reprogramming as well as the stimulation of EPCs differentiation, both represent promising therapeutic targets in regenerative vascular medicine.
  • Wound healing is a complex and dynamic process of replacing devitalized and missing cellular structures and tissue layers.
  • a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage and restore the protective barrier which in the normal skin is formed by the epidermis (outermost layer) and the dermis (inner or deeper layer) which exist in a steady- state equilibrium .
  • the human adult wound healing process can be divided into 4 distinct phases: hemostasis, inflammatory, fibroblastic, and maturation (or remodeling). These phases are initiated and regulated by various secreted factors such as growth factors.
  • the damaged blood vessels are sealed via different substances secreted by the platelets such as the platelet-derived growth factor (PDGF).
  • PDGF platelet-derived growth factor
  • the second phase corresponds to an inflammatory response which causes the blood vessels to become leaky thus releasing plasma and PMN's into the surrounding tissue.
  • the neutrophils phagocytize debris and microorganisms and provide the first line of defence against infection.
  • the cells macrophages are able to phagocytize bacteria and provide a second line of defence. They also secrete a variety of chemotactic and growth factors such as fibroblast growth factor (FG F), epidermal growth factor (EGF), transforming growth factor beta (TG F ⁇ and interleukin-1 (IL-1 ) which appears to direct the next stages of wound healing.
  • the third phase involves the replacement of dermal and subdermal tissues.
  • the fibroblasts secrete the collagen framework onto which further dermal regeneration occurs.
  • the pericytes which regenerate the outer layers of capillaries and the endothelial cells which produce the lining are involved in the angiogenesis.
  • the keratinocytes are responsible for the epithelialization.
  • contracture occurs as the keratinocytes differentiate to form the protective outer layer or stratum corneum.
  • the last and 4th phase of wound healing involves remodeling the dermal tissues to produce greater tensile strength.
  • the principle cells involved in this process are the fibroblasts.
  • hematopoietic progenitor cells may have the ability to de-differentiate back into hematopoietic stem cells and/or trans-differentiate into non-lineage cells, such as fibroblasts. It is thought that the extent of the stem cell involvement in skin wound healing is complex as the epidermis and dermis could be reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or BSC), the bulge of hair follicles (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells).
  • BSC basic stem cells
  • HFSC hair follicular stem cell
  • HFSC hair follicular stem cell
  • the bone marrow may also contain stem cells that could play a major role in cutaneous wound healing. Therefore, activating adult stem cells as well as the different cells and growth factors intervening during the four phases of the skin wound healing process, most certainly represents a promising therapeutic target. Tissue closure
  • Wound healing not only applies to skin tissue repair but also to the closure of all tissue layers damaged e.g. in an injury or during surgery. For instance, during bone repair surgery, the different layers of tissues incised in order for the surgeon to reach the damaged bone part and repair it would all need to be closed for the overall healing process to occur.
  • the mediation of this complex, "multi-layered" healing process involves the participation of many different factors such as growth factors.
  • neural stem cells are self-renewing, multipotent adult stem cells that generate the main phenotype of the nervous system. They undergo asymmetric cell division into two daughter cells, one non-specialized and one specialized. NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes. NSCs are generated throughout an adult's life via the process of neurogenesis. NSCs can be differentiated to replace lost or injured neurons or in many cases even glial cells.
  • NSCs are stimulated to begin differentiation via exogenous cues from their microenvironment, or the neural stem cell niche.
  • This niche defines a zone in which stem cells are retained after embryonic development for the production of new cells of the nervous system. This continual supply of new neurons and glia then provides the postnatal and adult brain with an added capacity for cellular plasticity.
  • Critical to the maintenance of the stem cell niche are microenvironmental cues and cell-cell interactions that act to balance stem cell quiescence with proliferation and to direct neurogenesis versus gliogenesis lineage decisions.
  • proteins like different growth factors are involved in the mechanisms of the neural stem cell niche as well as in the maintenance and growth of the newly formed neurons.
  • Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule. While “nerve growth factor” refers to a single factor, “nerve growth factors” refers to a family of factors also known as neurotrophins. Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5). NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis.
  • BDNF Brain-Derived Neurotrophic Factor
  • NT-3 Neurotrophin-3
  • NT-4/5 Neurotrophin 4/5
  • Nerve growth factor causes axonal growth. Studies have shown that it causes also axonal branching and elongation. Several brain diseases are considered to be caused by disorders in the neural stem cell niche and especially in the precise signaling of this microenvironment. Therefore restoring correct growth factor signaling is a promising target for the treatment of brain diseases.
  • the vertebrate retina is a light-sensitive layer of tissue, lining the inner surface of the eye. Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses. These are sent to various visual centers of the brain through the fibers of the optic nerve. In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, so the retina is considered part of the central nervous system (CNS) and is actually brain tissue. Retinal development involves a complex progression of tissue induction, proliferation of retinal progenitor cell (RPC) populations and terminal differentiation of these cells into specific functional types. Growing evidence indicates that several extrinsic cues play a critical role in the retinal cell development.
  • RPC retinal progenitor cell
  • BMP bone morphogenetic protein
  • TGF transforming growth factor
  • BMP-2, -4, and -7 and their receptors (BMPRs) are expressed in the eye during embryogenesis and are essential for multiple aspects of retinal development.
  • BMPRs transforming growth factor receptors
  • the kidney is a complex tissue consisting of several different cell types including glomerular podocytes, endothelial cells, mesangial cells, interstitial cells, tubular epithelial cells, and connecting duct cells. These cell types interact to establish a precise cellular environment that functions as an efficient tissue. Kidney diseases are currently a global public health problem, with an incidence that has reached epidemic proportions and continues to climb worldwide. Kidney failure can be associated with chronic kidney disease (CKD), which is a progressive loss in renal function over a period of months or years. Renal fibrosis, the common pathological feature of CKDs, is characterized by excessive accumulation of ECM (extracellular matrix).
  • ECM extracellular matrix
  • TGF- ⁇ transforming growth factor- ⁇
  • BMP-7 bone morphogenetic protein-7
  • T/L Tendons and ligaments
  • T/L are dense connective tissues of mesodermal origin. They connect and transmit force from muscle to bone and bone to bone, respectively. Both tissues are able to store elastic energy and withstand hightensile forces, on which locomotion is entirely dependent.
  • T/L are predominantly composed of collagen type I fibrils organized in a highly hierarchical manner that is unique for the T/L.
  • Other collagens types ll l-VI, XI , XI I , XIV, and XV
  • proteoglycans decorin, cartilage oligomeric matrix protein (COMP), byglican, lumican, fibromodulin, tenascin-C, etc.
  • T/L tendon-specific fibroblasts
  • tenocytes tendon-specific fibroblasts
  • MSCs Mesenchymal stem cells
  • Several tendon injuries result from gradual wear and tear to the tendon from overuse or aging.
  • Tendon healing is a complex and highly-regulated process that is initiated, sustained and eventually terminated by a large number and variety of molecules.
  • IGF-I insulinlike growth factor-l
  • TG Fbeta transforming growth factor beta
  • VEG F vascular endothelial growth factor
  • PDG F platelet-derived growth factor
  • bFGF basic fibroblast growth factor
  • Reproduction is the biological process by which new offspring individual organisms are produced from their parents.
  • Sexual reproduction is a biological process by which organisms create descendants that have a combination of genetic material contributed from two (usually) different members of the species.
  • Fertility is the natural capability to produce offspring.
  • the development and physiological functions of basic structures in the mammalian reproductive system are influenced by the tissue-specific expression of members of different growth factors families like the BMP family.
  • the establishment of the germ line is a fundamental aspect of reproduction. Germ cell determination is induced in epiblast cells by the extraembryonic ectoderm, and is not acquired through the inheritance of preformed germ plasma.
  • BMP-4 and -8b play a central role in determining primordial germ cell (PGC) formation in the embryo.
  • PGC primordial germ cell
  • the genes encoding BMP-4 and -8b have overlapping expression in the extraembryonic ectoderm before gastrulation, i.e., before PGCs are seen.
  • PGC formation requires BMP-4 expression.
  • BMP-8b is required for PGC formation.
  • locally produced BMPs play a major role in the differentiation of the pituitary gonadotrope. Restoring the BMPs signaling would thus be an important factor in infertility therapies.
  • Tissue homeostasis and regeneration are regulated through balancing quiescence and activation of quiescent epithelial stem cells (SCs).
  • SCs quiescent epithelial stem cells
  • HFs Hair follicles
  • telogen quiescence
  • anagen anagen
  • telogen which can last for months
  • HFSCs are quiescent and reside within a specialized microenvironment called the bulge.
  • HFSCs surround the hair shaft produced in the previous cycle.
  • the base of the bulge called the secondary hair germ (HG) directly abuts the underlying mesenchymal dermal papillae (DP), a key signaling center for HFSCs.
  • HG secondary hair germ
  • DP mesenchymal dermal papillae
  • telogen/anagen transition relies upon DP-HFSC crosstalk to generate the necessary threshold of activating factors.
  • HFSCs in the HG are the first to proliferate and initiate HF regeneration, whereas HFSCs within the bulge become active several days later.
  • the DP stimulus is pushed increasingly further from niche SCs, which return to quiescence.
  • relatively undifferentiated bulge cell progeny along the outer root sheath (ORS) accelerate proliferation as they approach the DP. This fuels a steady production of transiently amplifying matrix cells, which undergo a few divisions while in contact with DP and then terminally differentiate to form the hair and inner root sheath (I RS).
  • acting on the differentiation cycle of mammal hair follicle mesenchymal stem cells and precursor cells may have applications in hair follicle tissue regeneration thus preventing hair- loss and activating hair-growth, preventing/treating alopecia areata, alopecia totalis, alopecia universalis, androgenic alopecia (male pattern baldness), telogen effluvium , anagen effluvium or chemotherapy- induced alopecia, but is not limited.
  • the skin constantly renews itself throughout adult life.
  • Stem cells (SCs) residing in the epidermis ensure the maintenance of adult skin homeostasis, but they also participate in the repair of the epidermis after injuries.
  • the skin protects the body from dehydration, injury and infection .
  • the skin consists of an underlying dermis, separated by a basement membrane from the multilayered overlaying epidermis.
  • the dermis is of mesodermal embryonic origin and contains as adult stem cells fibroblastic mesenchymal stem-cell-like cells. These cells have a multi-lineage differentiation potential, being also able to form adipose tissue or bones.
  • the stratified epidermis is of ectodermal origin and composed of keratinocytes that differentiate to a water-impermeable stratum corneum.
  • the terminally differentiated cells in the epidermis are shed from the skin, necessitating a continuous delivery of newly differentiating cells.
  • the epidermis is completely renewed about every four weeks. Given that the differentiated cells cannot divide anymore, their replacement depends on epidermal stem cells. There is strong evidence that the hair bulge forms a reservoir of epidermal stem cells.
  • the basal layer of the epidermis contains two different types of cell populations: (I) the slowly dividing epidermal stem cells and (II) their progeny that are rapidly dividing cells in order to supply new cells to replace those that get lost by desquamation.
  • the basal layer of the epidermis contains two different types of cell populations: (I) the slowly dividing epidermal stem cells and (II) their progeny that are rapidly dividing cells in order to supply new cells to replace those that get lost by desquamation.
  • Wnt and ⁇ -catenin play diverse roles in HF (Hair Follicle) morphogenesis, Stem Cells maintenance and/ or activation and hair shaft differentiation.
  • Activation of Wnt ⁇ -catenin signaling is critical during the first stage of HF morphogenesis, as evidenced by the absence of placode formation on conditional ablation of ⁇ -catenin or constitutive expression of a soluble Wnt inhibitor (Dkk1 ).
  • Dkk1 soluble Wnt inhibitor
  • the source and identity of the putative Wnt signal required to induce placode formation remain elusive, it may be the first dermal signal to instruct epidermal cells to make hair.
  • Blood is a bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those cells. When it reaches the lungs, gas exchange occurs wherein carbon dioxide is diffused out of the blood into the alveoli and oxygen is diffused into the blood. This oxygenated blood is pumped to the left hand side of the heart in the pulmonary vein and enters the left atrium. From here it passes through the bicuspid valve, through the ventricle and taken all around the body by the aorta. Blood contains antibodies, nutrients, oxygen and much more to help the body work. In vertebrates, it is composed of blood cells suspended in blood plasma.
  • Plasma which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), and blood cells themselves.
  • Albumin is the main protein in plasma, and it functions to regulate the colloidal osmotic pressure of blood.
  • Hematopoietic stem cells are the blood cells that give rise to all the other blood cells and are derived from the mesoderm. They are located in the red bone marrow, which is contained in the core of most bones.
  • the HSCs give rise to the myeloid lineage (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and to the lymphoid lineages (T-cells, B-cells, NK-cells).
  • the most abundant cells in the vertebrate blood are red blood cells (also called RBSs or erythrocytes). These contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and greatly increasing its solubility in blood.
  • Blood cell degeneration-related diseases, conditions or disorders include, but are not limited to, Anemia, Iron-deficiency anemia, Anemia of chronic disease, Pernicious anemia, Aplastic anemia, Autoimmune hemolytic anemia, Thalassemia, Sickle cell anemia, Polycythemia vera, Vitamin deficiency anemia, Hemolytic anemia, Thrombocytopenia, Idiopathic thrombocytopenic purpura, Heparin-induced thrombocytopenia, Thrombotic thrombocytopenic purpura, Essential thrombocytosis (primary thrombocythemia), Thrombosis, Hemophilia, von Willebrand disease, Hypercoaguable state (hypercoagulable state), Deep venous thrombosis, Disseminated intravascular coagulation (DIC), Thrombocytopenia, Immune Thrombocytopenia (ITP), Drug-induced thrombocytopenia (DITP), Gestational thrombocytop
  • Adipose tissue is loose connective tissue composed mostly of adipocytes.
  • adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells (i.e. adipose tissue macrophages (ATMs)).
  • SVF stromal vascular fraction
  • Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
  • Pre-adipocytes are thought to be undifferentiated fibroblasts that can be stimulated to form adipocytes.
  • the pre-adipocytes originate from mesenchymal stem cells.
  • Areolar connective tissue is composed of adipocytes.
  • the term "lipoblast” is used to describe the precursor of the adult cell.
  • Adipose tissue degeneration-related diseases, conditions or disorders include, but are not limited to, Obesity, Dercum's disease (DD), Multiple symmetric lipomatosis (MSL), Familial multiple lipomatosis (FML), Lipodystrophy, Lipedema, or Atherosclerosis.
  • the lung is the essential respiration organ in many air-breathing animals. In mammals the two lungs are located near the backbone on either side of the heart. Their principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. A large surface area is needed for this exchange of gases, which is accomplished by the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli. Lung cells include, but are not limited to, type I pneumocytes, type II pneumocytes, clara cells and goblet cells.
  • Lung tissue degeneration-related diseases, conditions or disorders include, but are not limited to, Asthma, Chronic obstructive pulmonary disease (COPD), Chronic bronchitis, Emphysema, Cystic fibrosis, Pulmonary edema, Acute respiratory distress syndrome (ARDS), Pneumoconiosis, Interstitial lung disease (ILD), Sarcoidosis, Idiopathic pulmonary fibrosis, Pulmonary embolism (PE), Pulmonary hypertension, Pleural effusion, Pneumothorax, Mesothelioma, Granulomatosis with polyangiitis (GPA), Goodpasture syndrome (G PS), Pulmonary hyperplasia, Infant respiratory distress syndrome (IRDS), Chronic obstructive pulmonary disease (COPD), Silicosis, Sleep Apnea, Severe Acute Respiratory Syndrome (SARS), Pulmonary fibrosis, Primary ciliary dyskinesia (PCD), Pneumoconiosis (Black
  • the present invention thus provides cyclic compounds, compositions, microenvironments, functionalised bioactive carriers, medical devices, and kits comprising them, methods and processes for the design, preparation, manufacture and/or formulation of such cyclic compounds, compositions, functionalised bioactive carriers, medical devices and kits comprising them, and methods and uses thereof for regenerating or recoding mammalian tissues.
  • FIG . 1 is a representation of a relative area of focal adhesion (FA) contacts in human Bone Marrow Mesenchymal Stem Cell cultured with and without G FR-binding compounds as defined herein after 24 hours of incubation.
  • FA focal adhesion
  • FIG . 2 is a diagram representing a commitment of human Bone Marrow Mesenchymal Stem Cells towards osteoblast-like cells after 62 hours of culture on titanium biomaterials covalently modified according to the invention using Runx2 and Osterix immunofluorescent stainings.
  • FIG . 3 is a representation of a fluorescence intensity of osteogenic G FR-binding compounds as defined herein mixed with type-l collagen or with apatite ceramics substrates. The images represent surfaces non-covalently coated with osteogenic G FR-binding compounds-FITC.
  • FIG . 4 is a representation of a fluorescence intensity of G FR-binding compounds-FITC coated on apatite ceramics after incubation in cell culture medium for the indicated times (up to 10 days).
  • FIG . 5 is a diagram representing a quantification of the proliferation of osteoblast precursors after 48 hours of cell culture on apatite ceramics and on collagen coated with osteogenic G FR-binding compounds as defined herein.
  • FIG . 6 is a representation of the commitment of hMSCs towards osteoblast-like cells after 48 hours of culture on collagen and on apatite ceramics coated with osteogenic GFR-binding compounds as defined herein using Runx2 and Osterix immunofluorescent stainings.
  • FIG . 7 is a representation of an immunofluorescent staining of F-actin (green) and Osteopontin (red) for hMSC showing their differentiation into osteoblast cells after 96 hours of culture on a type-l collagen scaffold non-covalently modified with a compound of the invention .
  • FIG . 8 is a representation of a Quantitative Real Time PCR analysis of the expression of Runx2 in cells cultured on native apatite ceramics and on apatite ceramics non-covalently modified with the different osteogenic G FR-binding compounds as defined herein, (P ⁇ 0.005).
  • (b) is the micrographs for Alkaline Phosphatase Activity.
  • FIG . 9 is (a) representation of a quantification of the relative Sox9 intensity on hMSCs cultured with and without G FR-binding compounds as defined herein. hMSCs committed towards chondrocyte differentiation as seen by positive Sox9 (Transcription factor) immunofluorescent staining, (b) is a semi- quantitative RT-PCR analysis for the expression of the Aggrecan gene.
  • FIG. 10 is a representation of a distribution of the endothelial cell adherens junction's size. The results were obtained from immunofluorescence staining with an antibody against CD31 (PECAM1 ).
  • FIG. 1 1 is confocal images of endothelial cells cultured with and without GFR-binding compounds as defined herein.
  • the fluorescence intensities corresponding to F-actin filaments (Phalloidin staining) was represented in green.
  • FIG. 12 is a representation of (a) a Phase-contrast Micrograph showing the progression of migrating cells after scratching and (b) a Mean epithelial cell velocity measured for cells cultured with and without GFR- binding compounds as defined herein.
  • FIG. 13 is (a) a diagram representing the results of a Quantitative Real Time PCR analysis for the expression of Sox2 for cells cultured with or without GFR-binding compounds as defined herein, (b) The total BMP-6 immunofluorescence intensity in the cell culture medium was quantified for Hair Follicle Stem Cells cultured for 96h.
  • FIG. 14 is (a) a quantification of the cell area of hMSCs cultured with or without GFR-binding compounds as defined herein. The average cell area was estimated from approximately 25 cells from 2 different passages, (b) is a Quantitative Real Time PCR analysis for the expression of the COMP gene (Cartilage Oligomeric Matrix Protein, a tendon/ligament lineage gene).
  • COMP gene Cartilage Oligomeric Matrix Protein, a tendon/ligament lineage gene
  • FIG. 15 is a diagram representing the results of a Quantitative Real Time PCR analysis of the expression of the Growth Associated Protein 43 (GAP43) gene for cells cultured with and without GFR-binding compounds as defined herein.
  • GAP43 Growth Associated Protein 43
  • FIG. 16 is diagram representing the amount of STRO-1 (a hMSC sternness marker) present in the cells expressed as an average fluorescence intensity, normalized by the number of cells.
  • osteoblast progenitors are derived from adult bone marrow mesenchymal stem cells, followed by osteoblast precursors, mature osteoblasts and osteocytes.
  • MSCs Mesenchymal stem cells or MSCs are multipotent stromal cells that can differentiate into a variety of cell types including osteoblasts (bone cells), chondrocytes (cartilage cells), neurons, endothelial cells and adipocytes (fat cells). Growth factors generally modulate MSC activity through non-covalent binding to specific receptors called growth factor receptors (GFRs). Growth factors (GF) bind to serine-threonine kinase receptors on the cell surface, triggering specific intracellular pathways that activate and influence gene transcription, having effects in cell proliferation and/or differentiation. There are three or more receptors (types I, II and III) for GF members but only types I and II are required for binding and signalling.
  • GFRs growth factor receptors
  • R-Smads receptor-regulated Smads
  • Co-Smad common-partner Smad
  • This complex is translocated into the nucleus and modulates gene transcription with other transcription factors required for chondrogenic differentiation. Modulation of such an activity may typically be performed using recombinant growth factors.
  • Preventing/treating alopecia areata, alopecia totalis, alopecia universalis, androgenic alopecia (male pattern baldness), telogen effluvium, anagen effluvium or chemotherapy-induced alopecia, Modifying and/or enhancing and/or modulating and/or promoting and/or activating the osteogenicity, and/or the chondrogenecity, and/or the endothelization and vascularization ability, and/or hair growth ability, and/or the wound healing ability, and/or the skin repair ability, and/or the tissue defect closure ability, and/or the neuroregeneration ability, and/or the ligament/tendon tissue regeneration ability, and/or the female fertility ability, of a bioactive carrier such as a biomaterial which may be useful in the manufacturing of medical devices;
  • Stem cells preferably adult stem cells, more preferably mesenchymal stem cells, commitment and/or differentiation in a specific lineage of cells;
  • articles such as “a”, “an”, and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of the stated reference value unless otherwise indicated, self-evident or contradictory in context (e.g. except where such number would exceed 100% of a possible value).
  • (Ca-Cb)alkyl indicates an alkyl moiety of the integer "a” to the integer "b” carbon atoms, inclusive.
  • substituents of compounds of the present disclosure may be disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges.
  • the term "C1 -C5 alkyl” is an abbreviation for (and thus is specifically intended to individually disclose) C1 -alkyl (i.e. methyl), C2-alkyl (i.e. ethyl), C3-alkyl (i.e. 1 -propyl and 2-propyl), C4- alkyl (i.e.
  • alkyl and (Ca- Cb)alkyl refer to monovalent hydrocarbon radicals containing the requisite number of carbon atoms as described above, having straight or branched moieties or combinations thereof.
  • alkyl groups may be optionally substituted with between one to four substitutes.
  • Non-limiting examples of alkyl groups include, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.
  • alkyl groups will be readily apparent to those of skilled in the art given the benefit of the present disclosure.
  • a disclosed 0-10 range would, for example, in certain embodiments, also specifically and individually disclose the following values and ranges: 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6,
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims using the appropriate disclaimer(s) or proviso(s). Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production ; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
  • molecular weights should be understood in the present description as being number averaged molecular weights.
  • the N-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid.
  • the C-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid.
  • NAIS N-terminal or C-terminal
  • S N-terminal or C-terminal.
  • a certain peptide e.g. a cyclic GFR-binding compound as provided herein
  • said one or more other peptide(s) is(are) understood to be stably (in most cases, covalently) attached/bound to at least one part of said peptide.
  • the attachment/binding may be located anywhere on the peptide unless indicated otherwise, contradictory in context or contradictory to general scientific rules. No specific attachment/binding location of said one or more other peptide(s) to said peptide shall be assumed unless specifically mentioned.
  • Peptide or polypeptide As used herein, the term “peptide” or “polypeptide” are used interchangeably and refers to a polymer of less than or equal to 100 amino acids long, e.g., about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 amino acids long.
  • 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, non- naturally occurring amino acid polymers, peptide analogs, peptide variants and peptide mimetics.
  • peptide analogs refers to polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting peptide.
  • Peptide variants As used herein, unless indicated otherwise or contradictory in context, the term "peptide variants" refers to a peptide which has a certain identity with a native or reference compound sequence. In one example, the peptide variant refers to any post- administration, application, injection modified peptide.
  • Such post- administration, application, injection modifications include, but are not limited to, phosphorylation, acetylation, glutamylation, tyrosination, palmitoylation, glycosylation, myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, phosphopantetheinylation, acylation, alkylation, amidation, arginylation, polyglutamylation, polyglycylation, butyrylation, gamma-carboxylation, glycosylation, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition, oxidation, adenylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, succinylation, sulfation, glycation, biotinylation, pegylation, ISGylation, SUMOylation, ubiquitination,
  • peptido-mimetic refers to a synthetic chemical compound which comprises amino acids but not only and that is able to mimic the biological action of a peptide, often because the mimetic has a basic structure that mimics the basic structure of the peptide and/or has the salient biological properties of that peptide.
  • a peptidomimetic is a hybrid molecule containing both, at least one peptide, and at least one of a polysaccharide, a polynucleotide or a linear or branched, saturated or unsaturated, hydrocarbon chain.
  • Linear peptide As used herein, unless indicated otherwise or contradictory in context, the term "linear peptide” means a peptide in which the C-terminal and the N-terminal amino acid residues do not covalently interact with each other and none of the C-terminal or the N-terminal amino acid residues covalently interacts with another amino acid residue of the peptide chain.
  • cyclic peptide As used herein, unless indicated otherwise or contradictory in context, the term “cyclic peptide” means peptide in which the C-terminal and N-terminal amino acid residues do covalently interact with each other or the C-terminal and/or the N-terminal amino acid residues covalently interact with at least one other amino acid residue of the peptide chain so as to form a ring-like structure.
  • Amino acid As used herein, unless indicated otherwise or contradictory in context, the term “amino acid” refers to naturally occurring and non-naturally occurring amino acids including amino acid analogs.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, [gamma]-carboxyglutamate, and O-phosphoserine.
  • Naturally encoded amino acids are the 20 common amino acids glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), isoleucine (lie, I), serine (Ser, S), threonine (Thr, T), phenylalanine (Phe, F), tyrosine (Tyr, Y), tryptophane (Trp, W), cysteine (Cys, C), methionine (Met, M), proline (Pro, P), aspartic acid (Asp, D), asparagine (Asn, N), glutamine (Gin, Q), glutamic acid (Glu, E), histidine (His, H), arginine (Arg, R)
  • Non-naturally occurring amino acids include, but are not limited to, the dextrogyre (D) isomers of the above-cited naturally-occurring amino acids.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid i.e., an [alpha] carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group (i.e. side chain), and which may be used in replacement thereof without substantially affecting the overall function of the peptide to which it belongs.
  • Amino acid analogs that may be suitable for implementing embodiments of the present invention include, but are not limited to, amino acids comprising a photoactivatable cross-linker, spin-labeled amino acids, fluorescent amino acids, metal binding amino acids, metal-containing amino acids, radioactive amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and/or photoisomerizable amino acids, amino acids comprising biotin or a biotin analogue, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and/or photocleavable amino acids, amino acids with an elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons,
  • amino acid side chain As used herein, unless indicated otherwise or contradictory in context, the term "amino acid side chain” means the functional group of an amino acid that differentiates it from other amino acids. All amino acid structures have a carboxyl group, an amine group and a specific side chain.
  • polar amino acid or “AA” means amino acids having a polar, non-charged group-containing side chain.
  • Polar amino acids are protonated at physiological pH (about 7). Examples of polar amino acids include, but are not limited to, Cys (C), Asn (N), Gin (Q), Ser (S), Thr (T), or Tyr (Y).
  • AA 1 " (AA roman numeral three): As used herein, unless indicated otherwise or contradictory in context, the terms "acidic amino acid” or “AA 1 "” means amino acids having an acidic group-containing side chain. Acidic amino acid deprotonated forms predominate at physiological pH (about 7). Examples of acidic amino acids include, but are not limited to, Asn (N) and Glu (E).
  • aliphatic amino acid or “AA IV” means amino acids having an aliphatic side chain.
  • aliphatic amino acids include, but are not limited to, Ala (A), Leu (L), lie (I), Gly (G), Val (V) and any analogs and derivatives thereof.
  • apolar amino acid or “AA V” means amino acids having an apolar side chain.
  • apolar amino acids include, but are not limited to, Ala (A), Phe (F), Gly (G), lie (I), Leu (L), Met (M), Pro (P), Val (V) or Trp (W).
  • AA VI (AA roman numeral six): As used herein, unless indicated otherwise or contradictory in context, the term "aromatic amino acid” or "AA VI " means amino acids having an aromatic group-containing side chain. Examples of aromatic amino acids include, but are not limited to, Trp (W), Tyr (Y) or Phe (F).
  • AA V " (AA roman numeral seven): As used herein, unless indicated otherwise or contradictory in context, the term "basic amino acid” or “AA V “” means amino acids having a basic group-containing side chain. Basic amino acid protonated forms predominate at physiological pH (about 7). Examples of basic amino acids include, but are not limited to, Arg (R), His (H), or Lys (K).
  • AA VI (AA roman numeral eight): As used herein, unless indicated otherwise or contradictory in context, the term “AA VI "” means Leu (L) or lie (I) and any analogs and derivatives thereof.
  • AA AA roman numeral nine: As used herein, unless indicated otherwise or contradictory in context, the term “charged amino acid” or “AA” means amino acids having either an acidic group-containing side chain or an basic group-containing side chain. Charged amino acid charged forms predominate at physiological pH (about 7). Examples of charged amino acids include, but are not limited to, Asn (N), Glu (E), His (H), Lys (K) or Arg (R).
  • AA As used herein, unless indicated otherwise or contradictory in context, the term “AA n ", in which n is a positive integer arbitrarily chosen to identify a specific position within the primary sequence of a peptide. For instance, AA 13 means the amino acid of position 13.
  • amino acid and “AA” are interchangeably used in the present description.
  • N-terminal As used herein, unless indicated otherwise or contradictory in context, the term "N-terminal” means the amine (-NH 2 ) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only amine group which is not engage in n amide peptide bond.
  • C-terminal As used herein, unless indicated otherwise or contradictory in context, the term "C-terminal” means the carboxylate (-C0 2 H) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only carboxylic acid group which is not engage in n amide peptide bond.
  • Naturally-occurring peptide As used herein, unless indicated otherwise or contradictory in context, the terms “naturally-occurring peptide” or “natural peptide” means a peptide which may be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Synthetic peptide As used herein, unless indicated otherwise or contradictory in context, the terms "synthetic peptide” or “non-natural peptide” means a peptide which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • a synthetic peptide may have the amino acid sequence of a natural peptide except for at least one amino acid deletion or substitution relative to the natural sequence. In the case of a substitution, an amino acid from the natural sequence is replaced by another, different, naturally-occurring or non- naturally occurring amino acid.
  • a synthetic peptide may not possess a post-translational modification of the natural peptide such as the attachment of an acetate group, a phosphate group, a lipid, a carbohydrate, or the formation of a disulfide bridge.
  • Covalent interaction As used herein, unless indicated otherwise or contradictory in context, the term “interact covalently”, “covalent interaction” or “covalent bond” are interchangeably used and means a chemical bond or interaction that involves the sharing of electron pairs between atoms. Examples of such interactions are ⁇ -bonding and ⁇ -bonding.
  • Non-covalent interaction As used herein , unless indicated otherwise or contradictory in context, the term "interact non-covalently”, “non-covalent interaction” or “non-covalent bond” are interchangeably used and means a chemical bond or interaction that does not involve the sharing of electron pairs between atoms but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. Non-covalent interactions can be generally classified into four categories, electrostatic interactions, ⁇ -interactions, van der Waals forces, and hydrophobic interactions.
  • Electrophile As used herein, unless indicated otherwise or contradictory in context, the term "electrophile” means an organic molecule attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.
  • nucleophile As used herein, unless indicated otherwise or contradictory in context, the term “nucleophile” means an organic molecule that donates an electron pair to an electrophile to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles.
  • polysaccharide As used herein, unless indicated otherwise or contradictory in context, the term “polysaccharide” means polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages and which upon hydrolysis provide monosaccharides or oligosaccharides. They range in structure from linear to highly branched polymers.
  • polynucleotide refers to the phosphate ester polymeric form of nbonucleosides ("RNA molecules”) or deoxyribonucleosides ("DNA molecules”), or any phosphoester analogs thereof, such as phosphorothioates and thioesters, in either single stranded form , or a double-stranded helix.
  • RNA molecules nbonucleosides
  • DNA molecules deoxyribonucleosides
  • nucleic acid includes double-stranded DNA round, inter alia, in linear (e.g., restriction fragments) or circular DNA molecules.
  • nucleic acids as used herein refer to nucleic acids such as RNAs encoding for agonist of growth factor receptors as defined herein.
  • nucleoside refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”).
  • a sugar molecule e.g., a pentose or ribose
  • an organic base e.g., a purine or pyrimidine
  • nucleobase also referred to herein as “nucleobase”
  • nucleotide refers to a nucleoside including a phosphate group.
  • Dendrimer As used herein, unless indicated otherwise or contradictory in context, the term “dendrimer” means any repetitively branched molecules. Examples of dendrimers are phosphorous dendrimers, polylysine dendrimers, polypropylenimine dendrimers and PAMAM dendrimers, such as the ones described, for instance, in Scientific World Journal. 2013; 2013:732340; Curr Opin Chem Biol. 1998; 2(6) :733-42; J Pept Sci. 1999; 5(5) :203-20 ; and J Pept Sci. 2008; 14(1 ) :2-43, which may be used for implementing embodiments of the present invention, each of which being herein incorporated by reference in its entirety.
  • Synthetic molecule As used herein, unless indicated otherwise or contradictory in context, the term "synthetic molecule” means a molecule which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Synthetic polymers As used herein, unless indicated otherwise or contradictory in context, the term “synthetic polymer” refers to a macromolecule or polymer which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Biocompatible As used herein, unless indicated otherwise or contradictory in context, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system .
  • biologically active refers to a characteristic of any substance that has activity in a biological system and/or organism .
  • a substance that, when administered to an organism , has a biological effect on that organism is considered to be biologically active.
  • a compound, substance or pharmaceutical composition of the present disclosure may be considered biologically active even if a portion of the compound, substance or pharmaceutical composition is biologically active or mimics an activity considered biologically relevant.
  • stem cells As used herein, unless indicated otherwise or contradictory in context, the term “stem cell” refers to the term as it is generally understood in the art. For example, in certain embodiments, stem cells, regardless of their source, are cells that are capable of dividing and renewing themselves for long periods, are at least to a degree unspecialized (undifferentiated), and can give rise to (differentiate into) specialized cell types (i.e., they are progenitor or precursor cells for a variety of different, specialized cell types).
  • Mesenchymal stem cells As used herein , unless indicated otherwise or contradictory in context, the term “mesenchymal stem cells” generally means multipotent adult stromal cells that can differentiate into a variety of cell types, such as osteoblasts, chondrocytes, and adipocytes.
  • Stem cell-like refers to a cell which is not a stem cell by its origin but functions as a stem cell and presents similar characteristics such as, for example, the expression of sternness markers like Stro-1 and/or is multipotent thus has the ability to differentiate into various cell types.
  • Progenitor cells As used herein, unless indicated otherwise or contradictory in context, the term “progenitor cells” generally means a biological cell that, like any stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target” cell. Stem cells can generally replicate indefinitely, whereas progenitor cells can divide only a limited number of times.
  • adult stem cells As used herein, unless indicated otherwise or contradictory in context, the term “adult stem cells” means undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile as well as adult animals and human bodies.
  • Differentiation refers to the process by which a less specialized cell becomes a more specialized cell type and involves a switch from one gene expression pattern to another.
  • Differentiated cells As used herein, unless indicated otherwise or contradictory in context, the term “differentiated cells” generally means any cell of a specific lineage at the exception of cells containing stem cell specific markers.
  • Non-terminally differentiated As used herein, unless indicated otherwise or contradictory in context, the term “non-terminally differentiated”, when used in relation to a cell, refers to a differentiated cell as defined herein which has not reached its final state of differentiation. For example, in certain embodiments, in the Osteoblast cell lineage, a non-terminally differentiated cell is any differentiated cell of the lineage at the exception of an osteocyte.
  • Terminally differentiated when used in relation to a cell, refers to a differentiated cell as defined herein which has reached its final state of differentiation.
  • a terminally differentiated cell in the Osteoblast cell lineage, is an osteocyte.
  • Methods for obtaining stem cells are known in the art.
  • the cells are initially expanded in vivo or in vitro, by contacting the source of the stem cells with a suitable reagent that expands or enriches such cells in the tissue source or in culture.
  • a suitable reagent that expands or enriches such cells in the tissue source or in culture.
  • adult stem cells are isolated from a tissue source and then expanded or enriched in vitro by exposure to a suitable agent.
  • Cells are obtained from an individual by any suitable method for obtaining a cell sample from an animal, including, but not limited, to, collection of bone marrow collection of a bodily fluid (e.g., blood), collection of umbilical cord blood, tissue punch, and tissue dissection, including particularly, but not limited to, any biopsies of skin, intestine, cornea, spinal cord, brain tissue, scalp, stomach, breast, lung (e.g., including lavage and bronchioschopy) , fine needle aspirates of the bone marrow, amniotic fluid, placenta and yolk sac.
  • a bodily fluid e.g., blood
  • umbilical cord blood e.g., umbilical cord blood
  • tissue punch e.g., a cell punch
  • tissue dissection including particularly, but not limited to, any biopsies of skin, intestine, cornea, spinal cord, brain tissue, scalp, stomach, breast, lung (e.g., including lavage and bronchioschopy)
  • Osteogenesis refers to the process by which bone is produced.
  • An entity, molecule, compound, association, combination or composition may be said to be “osteogenic” when it has an effect on the development, growth, or repair of bone.
  • This process involves the participation of stem cells.
  • Chondrogenesis As used herein, unless indicated otherwise or contradictory in context, the term “chondrogenesis” refers to the process by which cartilage is produced.
  • An entity, molecule, compound, association, combination or composition may be said to be “chondrogenic” when it has an effect on the development, growth, or repair of cartilage. This process involves the participation of stem cells.
  • Endothelialisation refers to the process that maintains or restores normal vascular homeostasis and regulates neointimal hyperplasia.
  • endothelium maintains vessel integrity with dynamic mechanisms that prevent thrombosis and intimal hyperplasia.
  • the endothelial progenitor cells are an important component of the response to vascular injury, having the potential to accelerate vascular repair through rapid re-endothelialization.
  • drug-eluting stents are generally implanted during angioplasty into patients suffering from atherosclerosis and resulting in stenosis or restenosis.
  • the drug is typically coated onto a metal alloy framework and is mainly employed to inhibit neointimal growth (due to proliferation of smooth muscle cells) which would cause restenosis. Because much of the neointimal hyperplasia seems to be caused by inflammation, immunosuppressive and antiproliferative drugs are conventionally used. Drugs such as sirolimus and paclitaxel are currently used.
  • Vascularization/angiogenesis As used herein, unless indicated otherwise or contradictory in context, the term "vascularization/angiogenesis" refers to a physiological process through which new blood vessels are produced from pre-existing vessels. This process involves the participation of stem cells.
  • wound healing refers to a process whereby the skin (or another organ-tissue) repairs itself after injury. This process involves the participation of stem cells.
  • Skin repair As used herein, unless indicated otherwise or contradictory in context, the term “skin repair” means the reparation of the dermis through the participation of stem cells. These active cells produce collagenous fibers and ground substance. Blood vessels soon grow into the dermis, restoring circulation.
  • Neuron-regeneration As used herein, unless indicated otherwise or contradictory in context, the term “neuron-regeneration” or “neuroregeneration” refers to the regrowth or repair of nervous tissues, cells or cell products involving the participation of stem cells. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses.
  • tissue closure refers to the closure of all tissue layers damaged e.g. in an injury or during surgery. For instance, during bone repair surgery, the different layers of tissues incised in order for the surgeon to reach the damaged bone part and repair it would all need to be closed for the overall healing process to occur.
  • Cell lineage As used herein, unless indicated otherwise or contradictory in context, the term “cell lineage” refers to the developmental history of a particular cell from its primary state in the fertilized egg or embryo through to its fully differentiated state. The different steps and phases involved in the development of a cell produces many intermediate cells which may be referred to as progenitor or precursor cells in the present application and form an integral part of the cell lineage.
  • Osteoblast cell lineage refers to bone cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, osteoblasts, osteocytes or any precursors thereof.
  • Chondrocytic cell lineage As used herein, unless indicated otherwise or contradictory in context, the term “chondrocytic cell lineage” refers to cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells,
  • Muscle cell lineage refers to muscle cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, myoblasts, myocytes or any precursors thereof.
  • vascular cell lineage refers to vascular cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, angioblast, pericytes and endothelial cells or any precursors thereof.
  • Neuronal cell lineage refers to brain cells at any stage of their development and thus include, but are not limited to, neural stem cells, neuroblast, neurocyte and neuroglial cells or any precursors thereof.
  • Retinal cell lineage refers to eye retina cells at any stage of their development and thus include, but are not limited to, photoreceptor, bipolar cells, rod and cone cells or any precursors thereof.
  • Renal cell lineage As used herein, unless indicated otherwise or contradictory in context, the term “renal cell lineage” refers to renal cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, podocytes, or any precursors thereof.
  • Ligament and tendon cell lineage As used herein, unless indicated otherwise or contradictory in context, the term “ligament and tendon cell lineage” or “L/T cell lineage” refers to bone or cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, fibrocytes, or any precursors thereof.
  • Fibroblast lineage refers to skin cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, keratinocytes, Merkel cells, melanocytes, Langerhans cells, and any precursor cells thereof.
  • Reproduction system lineage As used herein, unless indicated otherwise or contradictory in context, the term “reproduction system lineage” refers to Sertoli cells, Leydig cell and Germ cell at any stage of their development, in particular, mesenchymal stem cells.
  • Blood cell lineages refers to blood cells at any stage of their development from the myeloid or from the lymphoid lineage, and thus include, but are not limited to, hematopoietic stem cells (HSC), myeloid progenitors, lymphoid progenitors, mast cells, myeloblasts, monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, thrombocytes, dendritic cells, small lymphocytes, T-lymphocytes (T-cells), B-lymphocytes (B-cells), natural killer (NK)-cells, and any precursor cells thereof.
  • HSC hematopoietic stem cells
  • myeloid progenitors myeloid progenitors
  • lymphoid progenitors mast cells
  • myeloblasts monocytes
  • macrophages neutrophils
  • basophils basophils
  • eosinophils neutrophils
  • Adipocyte lineage refers to adipocyte cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, areolar connective cells, adipocytes, pre- adipocytes/lipoblasts, and any precursor cells thereof.
  • Lung cell Lineages As used herein, unless indicated otherwise or contradictory in context, the term “lung cell Lineage” refers to lung cells at any stage of their development and thus include, but are not limited to, epithelial cells, erythrocytes, alveolar cells and any precursor cells thereof.
  • ratio when used in relation to cyclic GFR-binding compound with respect to the bioactive carrier in the pharmaceutical association or composition disclosed herein, refers to the (molar, weight or part as specified) ratio between the quantity of cyclic GFR-binding compound and the quantity of bioactive carrier.
  • the ratio may be a molar ratio, a weight ratio or a part ratio and will be specified as needed on a case by case basis.
  • Quantity units may conventionally be mole, millimole, gram, milligram or parts.
  • Density when used in relation to cyclic GFR-binding compound with respect to the bioactive carrier in the pharmaceutical composition disclosed herein, refers to the quantity of cyclic GFR-binding compounds, expressed in e.g. mole, millimole, gram, or milligram, with respect to one standardised surface unit e.g. squared millimetre (mm 2 ), squared micrometre ( ⁇ 2 ), or squared nanometre (nm 2 )).
  • the ratio between a cyclic GFR-binding compound and a bioactive carrier in the pharmaceutical association or composition disclosed herein may be expressed in pmol per mm 2 or pmol/mm 2 .
  • Recoding when used in relation to a cell (in particular a mesenchymal stem cell or progenitor stem cell), refers to the action of contacting (in-vitro, ex-vivo or in-vivo) a stem cell to be treated with a suitable extracellular micro-environment (e.g. containing a peptide, variant or analog thereof, peptidomimetic, a biomaterial, a medical device, or a medical or cosmetic composition as defined herein) thus providing appropriate extracellular signals so that the cell may undergo efficient differentiation into a more specialised cell type.
  • a suitable extracellular micro-environment e.g. containing a peptide, variant or analog thereof, peptidomimetic, a biomaterial, a medical device, or a medical or cosmetic composition as defined herein
  • Recoding therapy refers to a therapy that promotes efficient stem cell differentiation in an aim to regenerate mammalian tissues.
  • Extracellular micro-environment refers to the environment surrounding (in functional proximity with) a specific stem cell which is characterized by biophysical, mechanical and biochemical properties specific for each tissue and is able to regulate cell behavior. Modification of the extracellular micro-environment of a specific mesenchymal stem cell using, for instance, a peptide, variant or analog thereof, peptidomimetic, a biomaterial, a medical device, or a medical or cosmetic composition as defined herein, allows for the efficient differentiation of this cell into a more specialised cell type.
  • Physiologically functional cell refers to a cell which is able to perform normally all of the cell functions associated with a particular cell type and necessary for the normal physiology of a cell. These functions include all of the intracellular molecular mechanisms but also all of the activities necessary for a normal communication between the cell and its microenvironment.
  • One method which may be used to verify if a cell is physiologically functional is the grafting of the cell, after the introduction of fluorescent markers, in other mammalian model organisms such as mouse models. The cell is grafted in the tissue corresponding to its cell type.
  • the cell characteristics and normal functions are monitored after a period of time with various methods such as in vivo microscopy or histological staining.
  • the term "functional" when used in relation to a molecule, compound or substance refers to a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.
  • Shorter period of time when used in relation to differentiation or recoding duration, means substantially shorter to provide a substantial benefit for the treated patient in comparison with existing treatments.
  • a shorter period of time includes at least 1 .5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold or at least 10-fold reduction with respect to an existing treatment.
  • exogenous refers to a substance coming from outside a living system such as a cell, an organ, or an individual organism.
  • exogenous factors in medicine include pathogens and therapeutics.
  • DNA introduced into a cell via transfection or viral infection may be considered as an exogenous factor.
  • Carcinogens are also commonly referred to as exogenous factors.
  • Endogenous refers to substances that originate from within an organism, tissue, or cell.
  • Intracellular As used herein, unless indicated otherwise or contradictory in context, the term “intracellular” generally means “inside the cell”. In vertebrates, such as animals, the cell membrane is the barrier between the inside of the cell and the outside of the cell (the extracellular milieu). Thus, treatments and therapies in which at least one substance, compound, pharmaceutical association, combination or composition penetrates the cell wall of a cell to be treated in order to produce/deliver its (effective) biological effect are considered as intracellular treatments and therapies.
  • extracellular means “outside the cell”.
  • the cell membrane is the barrier between the inside of the cell (the intracellular milieu) and the outside of the cell.
  • treatments and therapies in which no substance, compound, pharmaceutical association, combination or composition requires penetration of the cell membrane in order to produce/deliver its (effective) biological effect (e.g. by interacting with trans-membrane receptors) are considered as extracellular treatments and therapies.
  • a therapy using a plurality of substances in order to provide the desired biological effect wherein one or more of these substances require the entry into the intracellular compartment to provide
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish , etc. , rather than within an organism (e.g., animal, plant, or microbe).
  • in vivo refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).
  • Ex vivo refers to events that occur in an external environment on tissues sourced from an organism (e.g., animal, plant, or microbe) in an attempt to replicate natural living conditions outside such an organism.
  • Patient/subject refers to any organism to which a composition in accordance with the invention may be administered, e.g. , for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.
  • patients/subjects include those individuals who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.
  • purify As used herein, unless indicated otherwise or contradictory in context, the term “purify,” “purified,” “purification” means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.
  • Targeted cells refers to any one or more cells of interest.
  • the cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism.
  • the organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.
  • Molecule length As used herein, unless indicated otherwise or contradictory in context, the term molecule or peptide "length” or “size” means the longest 2D or 3D distance which may possibly be measured within the molecule. For cyclic molecules, “length” or “size” means the longest measurable distance across the cyclic structure. Throughout the present disclosure, when a molecule size or length is given (in general using the nanometre, nm, unit), the following procedures were used to calculate them :
  • the present disclosure provides for cyclic growth factor receptor-binding compounds having the ability to induce stem cell differentiation and promote tissue regeneration.
  • cyclic growth factor receptor-binding compound refers to an exogenous or endogenous cyclic compound, molecule or substance having an (binding) affinity for a growth factor receptor as defined herein, and optionally comprising the ability to associate or combine with a bioactive carrier as defined herein.
  • the (binding) affinity values of a given cyclic GFR-binding compound to a given GFR are provided using the method of fluorescence anisotropy.
  • a cyclic GFR-binding compound is fluorescently labelled using technics well established in the art. Binding of the resulting labelled compound to a growth factor receptor results in a fluctuation of fluorescence anisotropy which is used to construct an affinity binding curve from which the cyclic GFR-binding compound binding affinity value is derived.
  • cyclic GFR- binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) picomolar (pM). In certain embodiments, cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) nanomolar (nM). In certain embodiments, cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) nanomolar (nM).
  • cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) nanomolar (nM). In certain embodiments, cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) micromolar ( ⁇ ). In certain embodiments, cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) micromolar ( ⁇ ). In certain embodiments, cyclic GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) micromolar ( ⁇ ).
  • a cyclic GFR-binding compound is said to possess the ability to associate or combine with a bioactive carrier if it comprises a functional chemical element, function or group allowing for the covalent or non- covalent assembly of the cyclic GFR-binding compound and the bioactive carrier.
  • a functional chemical element, function or group also referred to as a bioactive carrier-affinity-contaning group or bioactive carrier-high-affinity-containing group, include, but is not limited to, a thiol-containing compound, a cysteine-containing compound, a cysteine, or a GTPGP or a WWFWG peptide fragment.
  • Growth factor receptor As used herein, unless indicated otherwise or contradictory in context, the term “growth factor receptor” or “GFR” is a receptor which binds to growth factors which are naturally occurring substances capable of stimulating, for instance, cellular growth, proliferation, healing, and cellular differentiation.
  • Suitable as growth factor receptors for implementing embodiments of the present invention include epidermal growth factor receptors (EGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptors (VEGFR), nerve growth factor receptors (NGFR), Insulin receptor family, Trk receptor family, Eph receptor family, AXL receptor family, LTK receptor family, TIE receptor family, ROR receptor family, DDR receptor family, RET receptor family, KLG receptor family, RYK receptor family, MuSK receptor family, hepatocyte growth factor receptors (HGFR), somatomedin or insulin-like growth factor receptors (SGFR), platelet-derived growth factor receptors (PDGFR), transforming growth factor beta (TGF- ⁇ ) superfamily proteins such as AMH, ARTN, BMP10, BMP15, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, G DF1 , G DF10, G DF1 1 , G DF15, GDF2,
  • growth factor refers to any substance(s) having the ability to bind to a growth factor receptor and produce (a) biological effect(s) or reaction(s), such as promoting the growth of tissues, by activating such a growth factor receptor.
  • Exemplary growth factors include, but are not limited to, platelet-derived growth factor (PDGF), platelet-derived angiogenesis factor (PDAF) , vascular endotheial growth factor (VEGF), platelet- derived epidermal growth factor (PDEG F), transforming growth factor beta (TGF- ⁇ ), transforming growth factor A (TGF-A), epidermal growth factor (EGF), fibroblast growth factor (FGF), acidic fibroblast growth factor (FG F-A), basic fibroblast growth factor (FG F-B), insulin-like growth factors 1 and 2 (IGF-I and IG F- 2), keratinocyte growth factor (KG F), tumor necrosis factor (TNF), fibroblast growth factor (FGF) and interleukin-1 (IL-I), Keratinocyte Growth Factor-2 (KGF-2), and combinations thereof.
  • PDGF platelet-derived growth factor
  • PDAF platelet-derived angiogenesis factor
  • VEGF vascular endotheial growth factor
  • PDEG F platelet-
  • Activation of growth factor receptors refers to the phosphorylation of the tyrosine kinase domain of such a growth factor receptor.
  • the present disclosure provides a cyclic G FR-binding compound having mesenchymal stem cell and progenitor cell commitment and/or differentiation and/or maturation capacities resulting in tissue regeneration.
  • said cyclic G FR-binding compound has a molecular weight of less than 5,000 Daltons. In one particular example, said cyclic GFR-binding compound has a molecular weight of less than 4,000 Daltons. In one particular example, said cyclic G FR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons. In one particular example, said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 4,000 Daltons.
  • the growth factor receptor involved in the interaction with said cyclic G FR- binding compound is an epidermal growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic G FR-binding compound is a fibroblast growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a vascular endothelial growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic G FR-binding compound is a nerve growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a hepatocyte growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a somatomedin or insulin-like growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a platelet-derived growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a protein from the transforming growth factor beta (TGF- ⁇ ) superfamily.
  • the growth factor receptor(s) involved in the interaction with said cyclic GFR- binding compound is (are) preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF- ⁇ ) superfamily proteins.
  • epidermal growth factor receptors preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF- ⁇ ) superfamily proteins.
  • TGF- ⁇ transforming growth factor beta
  • said cyclic GFR-binding compound is a peptide, or a variant or analog thereof, having growth factor receptor-binding capability or capabilities, with (exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids.
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; wherein said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons (in particular, between 1 ,000 and 4,000 Da).
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; and containing at least one peptide portion or fragment with between 5-20 amino acids (in particular containing one peptide portion or fragment with between 5-20 amino acids); wherein said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons (in particular, between 1 ,000 and 4,000 Da).
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, having a molecular weight of less than 5,000 Da, in particular of between 1 ,000 and 5,000 Da, more particularly of between 1 ,000 and 4,000 Da.
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2).
  • PEP2 five amino acids
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4).
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PE
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between six and eleven amino acids (PEP10).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between six and eleven amino acids (PE
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
  • LINKER-PEP(B) (I) wherein one end of LINKER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da.
  • Mw molecular weight
  • the molecular weight of LINKER refer to the calculated molecular weight prior to being connected to / reacted with any of the elements it is configured to connect to or react with e.g. PEP(B) or any other groups defined herein.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (I), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (I), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (I), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP10. In one aspect, the present disclosure provides a cyclic GFR-binding compound comprising compound (I), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (I), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
  • LINKER-PEP2-PEP(D) (II) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of PEP(D) interacts covalently with one end of PEP2; wherein one end of LINKER interacts covalently with one end of PEP2; wherein PEP(D) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 1 1 amino acids.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) comprises PEP4.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) comprises PEP6.
  • PEP(D) is PEP6.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) comprises PEP10. In one particular example, PEP(D) is PEP10. In one aspect, the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) comprises PEP4 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) comprises PEP6 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (II), wherein PEP(D) is PEP6 or PEP10.
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)):
  • LINKER-PEP2-PEP6-PEP8 (III) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein PEP6 is a peptide with between five and seven amino acids as already defined herein; wherein PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein; wherein one end of LINKER interacts covalently with one end of PEP2 via AA 21 ; wherein one end of PEP6 interacts covalently with another end of PEP2 via AA 26 ; wherein another end of PEP6 interacts covalently with one end of PEP8 via AA 32 .
  • Mw mole
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (IV) (hereinafter may also be referred to as compound (IV) or peptide (IV)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 21 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 31 -AA 32 is PEP4 as defined herein; wherein AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 is PEP8 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein AA 21 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA 38 may be an N-terminal amino acid
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising two LINKERS.
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, having any one of the following schematic general formulae (V) to (IX) (hereinafter may also be referred to as compounds (V) to (IX) or peptides (V) to (IX)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da;
  • PEP2 is a peptide with five amino acids as already defined herein;
  • PEP6 is a peptide with between five and seven amino acids as already defined herein;
  • PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein;
  • PEP10 is a peptide with between six and eleven amino acids;
  • curved lines represents covalent bonds between LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' lengths may not be representative of the actual relative distance between the LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' length
  • the present disclosure provides a cyclic GFR-binding compound, wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, having any one of the following schematic general formulae (X) or (XI) (hereinafter may also be referred to as compounds (X) and (XI) or peptides (X) and (XI)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 21 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 31 -AA 32 is PEP4 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein another end of LINKER interacts covalently with AA 25 ; and wherein curved lines represents covalent bonds between LINKERS and AAs "boxes". Curved lines' lengths may not be representative of the actual relative distance between the LINKERS and AAs.
  • PEP2 is selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH.
  • PEP6 is a peptide of general formula AA -AA -AA -AA -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA 1 " and AA V amino acids; and wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably is absent or is S.
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, MIVEE, MIVRS, MIVKS, MVVKS, FLQHN, LEEHS, RLEEH and TLEDH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33 , AA 34 , AA 35 , AA 36 , AA 37 or AA 38 is not absent.
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL, XKXS, KXEXR, QXEXR, LEX AX A and LAXKXE.
  • PEP10 is a peptide of general formula PEP6-PEP8; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or is E; wherein AA 27 and
  • AA are independently selected from the group consisting of AA and AA amino acids; and wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably is absent or is S; wherein PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVE SXAXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • the pair PEP2:PEP4 is selected from the group consisting of LKNYQ:VVE, LKNYQ:TVE, LKNYQ:VVR, LKNYQ:VVK, LKNYQ:VAE, LKNYQ:AVS, LKNYQ:VVD, LKNYQ:VEE, LKNYQ:VRS, LKNYQ:VKS, LKNYQ:QHN, LKNYQ:EHS, LKNYQ:EEH, LKNYQ:EDH, LKVYP:TVE, LKVYP:VVE, LKVYP:VVR, LKVYP:VVK, LKVYP:VAE, LKVYP:AVS, LKVYP:VVD, LKVYP:VEE, LKVYP:VRS, LKVYP:VKS, LKVYP:QHN, LKVYP:EHS, LKVYP:
  • KFKYE:AVS KFKYE:VVE, KFKYE:TVE, KFKYE:VVR, KFKYE:VVK KFKYE:VAE KFKYE:VVD,
  • DHHKD:VEE DHHKD:VVE
  • DHHKD:TVE DHHKD:VVR
  • DHHKD:VVK DHHKD:VAE DHHKD:AVS
  • IGEMS:QHN IGEMS:VVE
  • IGEMS:TVE IGEMS:VVR
  • IGEMS:VVK IGEMS:VAE IGEMS:AVS
  • LGEMS:VVD LGEMS:VEE
  • LGEMS:VRS LGEMS:VKS
  • LGEMS:QHN LGEMS:EEH
  • LGEMS:EDH
  • KEVQV:EEH KEVQV:VVE, KEVQV:TVE, KEVQV:VVR, KEVQV:VVK KEVQV:VAE KEVQV:AVS,
  • KEVQV:VVD KEVQV:VEE, KEVQV:VRS, KEVQV:VKS, KEVQV:QHN KEVQV:EHS KEVQV:EDH,
  • KKATV:EDH KKATV:VVE, KKATV:TVE, KKATV:VVR, KKATV:VVK KKATV:VAE KKATV:AVS,
  • KKATV:VVD KKATV:VEE, KKATV:VRS, KKATV:VKS, KKATV:QHN, KKATV:EHS and KKATV:EEH.
  • the pair PEP2:PEP6 is selected from the group consisting of LKNYQ:NMVVE, LKNYQ:EGMSVVE, LKNYQ:GMVVE, LKNYQ:DMVVE, LKNYQ:MIVVE, LKNYQ:MVVVE, LKNYQ:NMTVE, LKNYQ:NMVVR, LKNYQ:NMVVK, LKNYQ:EGMSVAE, LKNYQ:GMAVS, LKNYQ:GMVVD, LKNYQ:MIVEE, LKNYQ:MIVRS, LKNYQ:MIVKS, LKNYQ:MVVKS, LKNYQ:FLQHN, LKNYQ EEHS, LKNYQ:RLEEH, LKNYQ:TLEDH, LKVYP:DMTVE, LKVYP:EMTVE, LKVYP:NMTVE, LKVYP:EGMSTVE, LKVYP
  • the pair PEP2:PEP8 is selected from the group consisting of LKNYQ:SXAXR, LKNYQ:SXGXH, LKNYQ:AXGXH, LKNYQ:XGXR, LKNYQ:EXGXR, LKNYQ:RXGXS, LKNYQ:AXGXR, LKNYQ:SXGXR, LKNYQ:XGXL, LKNYQ:XKXS, LKNYQ:KXEXR, LKNYQ:QXEXR, LKNYQ:LEXAXA, LKNYQ:LAXKXE, LKVYP:GXGXR, LKVYP:SXGXH, LKVYP:AXGXH, LKVYP:XGXR, LKVYP:EXGXR, LKVYP:RXGXS, LKVYP:AXGXS, LKV
  • the pair PEP2:PEP10 is selected from the group consisting of LKNYQ:NMVVESXAXR, LKNYQ:NMVVESXGXH, LKNYQ:NMVVEAXGXH, LKNYQ:EGMSVVEXGXR, LKNYQ:GMVVEEXGXR, LKNYQ:GMVVERXGXS, LKNYQ:DMVVEAXGXR, LKNYQ:DMVVESXGXR, LKNYQ:MIVVEXGXL, LKNYQ:MIVVEXKXS, LKNYQ:MVVVEXKXS, LKNYQ:NMTVESXAXR, LKNYQ:NMVVRSXGXH, LKNYQ:NMVVRAXGXH, LKNYQ:NMVVKAXGXH, LKNYQ:EGMSVAEXGXR, LKNYQ:GMAVSEXGX
  • the triplet PEP2:PEP4:PEP8 is selected from the group consisting of LKNYQ:VVE:SXAXR, LKN YQ :VVE :SXGXH , LKNYQ:VVE:AXGXH, LKNYQ:VVE:XGXR LKNYQ:VVE:EXGXR, LKNYQ:VVE:RXGXS, LKNYQ:VVE:AXGXR, LKNYQ:VVE:SXGXR LKNYQ:VVE:XGXL, LKNYQ:VVE:XKXS, LKNYQ:TVE:SXAXR, LKNYQ:VVR:SXGXH LKNYQ:VVR:AXGXH, LKN YQ : VVK : AXGXH , LKNYQ:VAE:XGXR, LKNYQ:AVS:EXG
  • the triplet PEP2:PEP6:PEP8 is selected from the group consisting of LKNYQ:NMVVE:SXAXR, LKNYQ:NMVVE:SXGXH, LKNYQ:NMVVE:AXGXH,
  • EQLSN:GMVVD:RXGXS EQLSN:DMVVE:AXGXR, EQLSN:DMVVE:SXGXR, EQLSN:MIVEE:XGXL EQLSN:MIVKS:XKXS, EQLSN:MVVKS:XKXS, EQLSN:FLQHN:KXEXR, EQLSN:LEEHS:QXEXR EQLSN:RLEEH:LEXAXA, EQLSN:TLEDH:LAXKXE, EQLSN:DMVKS:GXGXR, EQLSN:NMVKS:SXAXR EQLSN:EMVKS:GXGXR, EQLSN:NMVKS:SXGXH, EQLSN:NMVKS:AXGXH, EQLSN:EGMSVKS:XGXR EQLSN:GMVKS:EXGXR, EQLSN:
  • said cyclic G FR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said cyclic GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a cyclic peptidomimetic.
  • a length of said cyclic G FR-binding compound, in solution, such as in a physiologically acceptable solvent such as water or PBS, is comprised between about 6 and about 20 nm , preferably between about 6 and about 16 nm , as determined using the standard « 3D » procedure described above.
  • said cyclic G FR-binding compounds may be any one of peptides of SEQ I D NO: 1 to 14868.
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da.
  • Mw molecular weight
  • LINKER is not meant to be particularly limited and may be any organic molecule capable of covalently connecting two ends of a peptide or a peptidomimetic such as PEP(B) or PEP2-PEP(D) so as to form a cyclic compound and so long as LINKER provides sufficient cycle stability to provide or conserve the required tissue regeneration activity.
  • LINKER may thus be, for example, in certain embodiments, a peptide, or variant, analog or peptidomimetic thereof, a polysaccharide, a polynucleotide, a saturated or unsaturated hydrocarbon chain, or a mixture thereof.
  • LINKER is a peptide with 6 to 30 amino acids. In one particular example, LINKER is a peptide with 6 to 25 amino acids. In one particular example, LINKER is a peptide with 6 to 20 amino acids. In one most particular example, LINKER is a peptide with 7 to 20 amino acids.
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof of general formula (I); wherein one end of LINKER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids).
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof of general formula (II); wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids); wherein PEP2 and PEP(D) are as already defined herein; wherein one end of LINKER interacts covalently with one end of PEP2 via AA 21 ; wherein another end of PEP2 interacts covalently with PEP(D) via AA 25 .
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, having any one of the general formula (V) to (XI); wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids).
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, of general formula (II); wherein LINKER is not a peptide but may comprise amino acids or peptides in covalent or non-covalent (preferably covalent) association with other groups or residues other than amino acids or peptides.
  • LINKER comprises (or is) a peptide of general formula (XII): wherein said peptide of formula (XII) may be selected from the group consisting of * AA -AA -AA -AA -
  • AA 202 -AA 203 -AA 204 AA 201 -AA 202 -AA 203 -AA 204 , AA 201 -AA 202 -AA 203 -AA 204 -AA 205 , AA 201 -AA 202 -AA 203 -AA 204 -AA 205 -AA 206 , AA 201 -AA 202 -
  • AA 208 -AA 209 , AA 205 -AA 206 -AA 207 -AA 208 -AA 209 , AA 206 -AA 207 -AA 208 -AA 209 , AA 207 -AA 208 -AA 209 , AA 208 -AA 209 or AA 209 may be absent.
  • any one of the amino acid labelled " * " or the amino acid labelled " ** " is an N-terminal amino acid and the other is a C-terminal amino acid.
  • AA occupies position AA
  • * AA occupies position AA
  • AA occupies position AA
  • AA occupies position AA 204
  • AA V occupies position AA 205
  • AA X occupies position AA 206
  • AA X occupies position AA 207
  • AA XI occupies position AA 208
  • AA XI occupies position AA 209 .
  • LINKER may thus comprise or be any one of the following peptides:
  • said peptide of formulae (XII-1 ) may thus be selected from the group consisting of * AA I "-AA I -AA I -AA"-AA V "-AA X "-AA X "- AA XI " ** , *AA I "-AA I -AA VI -AA”-AA V "-AA X "-AA X "-AA XI "**, *AA I II -AA I -AA I -AA I I -AA II -AA XII -AA XI I -AA XIM** , * AA'"-
  • LINKER comprises a peptide of formula (XII), (XII -2) or (XII -4).
  • LINKER comprises (or is) a poly-(aliphatic amino acid) peptide such as poly-alanine peptide (A) n , or a poly-glycine (G) n , n being an integer comprised between 2 and 30, in particular between 2 to 25, more particularly between 2 and 20, such as A-A-A-A-A-A-A-A-A, A-A-A-A-A-A-A, A-A-A-A-A-A, G- G-G-G-G-G-G-G, G-G-G-G-G-G-G or G-G-G-G-G-G.
  • LINKER comprises (or is) a peptide of general formulae (XII) to (XII-14), more particularly (XII), (XII-2) or (XII-4), and/or a poly-(aliphatic amino acid) n peptide as defined herein.
  • LINKER is a polysaccharide comprising 6 to 30 saccharides.
  • LINKER is a polysaccharide comprising 6 to 25 saccharides.
  • LINKER is a polysaccharide comprising 6 to 20 saccharides.
  • LINKER is a polysaccharide comprising 7 to 20 saccharides.
  • Suitable monosaccharides include, but are not limited to, glucose (dextrose), fructose (levulose) and galactose.
  • Monosaccharides are the building blocks of disaccharides (such as sucrose) and polysaccharides (such as celluloses, chitosans, ulvanes and starches). Further, each carbon atom that supports a hydroxyl group (except for the first and last) is chiral, giving rise to a number of isomeric forms all with the same chemical formula.
  • a large number of biologically important modified monosaccharides exists e.g.
  • amino sugars such as Galactosamine, Glucosamine, Sialic acid, N-Acetylglucosamine, and sulfosugars such as Sulfoquinovose. All of these monosaccharide and polysaccharide derivatives may be used as LINKER in the present invention.
  • LINKER is a polynucleotide comprising 6 to 30 nucleotides. In one particular example, LINKER is a polynucleotide comprising 6 to 25 nucleotides. In one particular example, LINKER is a polynucleotide comprising 6 to 20 nucleotides. In one most particular example, LINKER is a polynucleotide comprising 7 to 20 nucleotides. Suitable nucleotides include adenine (A), guanine (G), thymine (T), cytosine (C), uracil (U) and derivatives, analogues and/or mimetic thereof.
  • A adenine
  • G guanine
  • T thymine
  • C cytosine
  • U uracil
  • LINKER is a saturated or unsaturated hydrocarbon chain of at most 10 nanometres (nm) in length, preferably at most 144 nanometres (nm) in length, in particular at most 120 nm, 96nm, 84 nm or 72 nm as determined using the standard « 2D » procedure described above.
  • saturated or unsaturated hydrocarbon chains include polyethylene glycol (PEG) or any one of its derivatives.
  • LINKER is a hexapeptide (6 amino acids). More particularly, LINKER is a heptapeptide (7 amino acids). More particularly, LINKER is a octapeptide (8 amino acids). More particularly, LINKER is a nonapeptide (9 amino acids). More particularly, LINKER is a decapeptide (10 amino acids). More particularly, LINKER is a hendecapeptide (1 1 amino acids). More particularly, LINKER is a dodecapeptide (12 amino acids). More particularly, LINKER is a tridecapeptideo (13 amino acids). More particularly, LINKER is a tetradecapeptide (14 amino acids). More particularly, LINKER is a pentadecapeptide (15 amino acids).
  • LINKER is a hexadecapeptide (16 amino acids). More particularly, LINKER is a heptadecapeptide (17 amino acids). More particularly, LINKER is an octadecapeptide (18 amino acids). More particularly, LINKER is an enneadecapeptide (19 amino acids). More particularly, LINKER is an icosapeptide (20 amino acids).
  • LINKER comprises one or more of a peptide selected from the group consisting of DENEKVV, DENKNVV, DEYDKVV, DDSSNVI , DSSNNVI , DDMGVPT, DKGVVTY, NDKQQII , DAANNVV, DSANNVV, DDSSNVI, DNGRVLL, VGRKPKV, IGKTPKI , VG RTPKV, RIKPHQGQH, EYVRKKPKL, EIVRKKPI F, EYVRKKP, EIVRKKP, polyalanine (A L12 ) (preferably A 2 . 8 ) and polyglycine (G M 2 ) (preferably G 2 . 8 ).
  • a L12 preferably A 2 . 8
  • G M 2 polyglycine
  • the covalent bonds between e.g. LINKER, PEP(B), PEP(D) or PEP2, PEP4, PEP6, PEP8 and PEP10 may be created through the chemical reaction between a free amine moiety e.g. of a N-terminal amino acid (-NH 2 or -NH 3 X, X generally being a halide anion selected from the group consisting of F " , CI " and Br " ), typically acting as a nucleophile, and an electrophile moiety of e.g. a C-terminal amino acid.
  • a free amine moiety e.g. of a N-terminal amino acid (-NH 2 or -NH 3 X, X generally being a halide anion selected from the group consisting of F " , CI " and Br " ), typically acting as a nucleophile, and an electrophile moiety of e.g. a C-terminal amino acid.
  • the covalent bonds between e.g. LINKER, PEP(B), PEP(D) or PEP2, PEP4, PEP6, PEP8 and PEP10 may be created through the chemical reaction between a free carboxylic acid moiety e.g. of a C- terminal amino acid (-C0 2 H or -C0 2 X, X generally being an inorganic cation such as alkaline cations (e.g. Li + , Na + or K + ) or an organic cation such as ammonium cations), typically acting as an electrophile, and a nucleophile moiety of e.g.
  • a free carboxylic acid moiety e.g. of a C- terminal amino acid (-C0 2 H or -C0 2 X
  • X generally being an inorganic cation such as alkaline cations (e.g. Li + , Na + or K + ) or an organic cation such as ammonium cations), typically acting as an electro
  • nucleophile moiety includes, but is not limited to, alcohols (-OH), amines (-NH 2 ), phosphines (-PR 3 ), thiols (-SH). More particularly, this covalent interaction is a peptide bond formed through conventional peptide synthesis using conventional coupling reagents as already defined herein.
  • Cyclisation of a cyclic G FR-binding compound of the present disclosure may be carried out as described above using conventional peptide bond formation procedures, click chemistry, formation of disulphide bonds, etc.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis.
  • PEP2 is selected from the group consisting of LKNYQ, LKKYR, LRKHR and LKYHY.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G, M and T, preferably AA 28 is selected from the group consisting of M, I, V and L; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 - AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, XKXS and LAXKXE.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH ; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably E; wherein AA 27 and AA 28 are independently selected from the group consisting of
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDHLAXKXE.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present bone section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis.
  • PEP2 is selected from the group consisting of LKNYQ, LKKYR, YKQYE and EQLSN.
  • PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of
  • AA amino acids preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA" amino acids, preferably absent.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, DMVVE, MIVRS, MIVKS and MVVKS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 - AA -AA ; wherein AA is absent or is selected from the group consisting of AA amino acids at the exception of AA VI amino acids, preferably absent, G, S or A; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, preferably absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids,
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N and M,
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, DMVVESXGXR, MIVRSXKXS, MIVKSXKXS and MVVKSXKXS.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present cartilage section.
  • said GFR- binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR- binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vasculanzation/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies.
  • PEP2 is selected from the group consisting of IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of
  • AA amino acids preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA is L or E; wherein AA is absent or selected from the group consisting of AA amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of LEEHS, FLQHN, RLEEH and TLEDH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 - AA -AA ; wherein AA is absent or is selected from the group consisting of AA amino acids at the exception of AA VI amino acids, in particular is selected from the group consisting of K, Q and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent, E or A; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA 28 is L or E;
  • PEP10 is selected from the group consisting of FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP is selected from the group consisting of FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vasculanzation/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present vascular tissue section.
  • said GFR- binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR- binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases.
  • PEP2 is selected from the group consisting of LKKYR, LKYHY, YKQYE and KFKYE.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E; wherein
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A and E; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is G or K; wherein AA 37 is absent or is
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 - AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVR AXGXH, NMVVKAXGXH, EGMSVAEXGXR, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDHLAXKXE.
  • PEP is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVR AXGXH, NMVVKAXGXH, EGMSVAEXGXR, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDHLAXKXE.
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVR AXGXH, NMVVKAXG
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present neurogeneration section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases such as macular degeneration.
  • PEP2 is YGKIP.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 - PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 - AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I ; wherein AA 29 is
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration- related conditions or diseases, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present eye retina section.
  • said G FR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said G FR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases such as chronic kidney disease or renal fibrosis.
  • PEP2 is YGKI P.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 - AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E ; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I ; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMV
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G , S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C ; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 - AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I ; wherein AA
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP is selected from the group consisting of DMVVEGX
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present renal tissue section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies.
  • L/T ligament and tendon
  • PEP2 is selected from the group consisting of LKKYR, YKQYE and EQLSN.
  • PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably is
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S and A; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, SXGXR, XKXS and SXKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids,
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, DMVVESXGXR, MIVRSXKXS, MIVKSXKXS and MVVKSXKXS.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present L/T section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • PEP2 is YKQYE.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E; wherein AA 27 and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA" amino acids,
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present L/T section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration.
  • PEP2 is selected from the group consisting of IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA 28 is L or E; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of LEEHS, FLQHN, RLEEH and TLEDH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is selected from the group consisting of K, Q and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent, E or A; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is selected from the group consisting of E, A and K; wherein AA 37 is absent
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of
  • AA amino acids preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA is L or E; wherein AA is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is selected from the group consisting of K, Q and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent, E or A; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is selected from the group consisting of E, A and K; wherein AA 37 is absent or is selected from
  • PEP PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present wound healing section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies.
  • PEP2 is selected from the group consisting of EQLSN, IGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N, E, M, F, T and R, preferably AA 28 is selected from the
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, K and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent, A or E; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA 1 " and
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present skin section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies.
  • PEP2 is LKVYP.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN and EEH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN and EEH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or is E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N, E, G, M, F and R, preferably AA 28 is selected from the group consisting of M, I, V
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, MIVEE, MIVRS, MIVKS, MVVKS, FLQHN and RLEEH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA is absent or is selected from the group consisting of AA amino acids at the exception of AA amino acids, in particular is absent or is selected from the group consisting of G, S, A, E, R, K and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent or E; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA
  • PEP8 is selected from the group consisting of GXGXR, SXASR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL, XKXS, KXEXR and LEXAXA.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 - PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN and EEH ; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA 1 " and AA V amino acids,
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXASR, EMVVEGXGXR, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR and RLEEHLEXAXA.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present hair section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof.
  • PEP2 is LKKYR.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N, E, M and G, preferably AA 28 is M or I ; wherein AA 29 is absent or selected from the group consisting of AA" amino acids, preferably is absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD and MIVEE.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 - AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N, E, M and G,
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present fertility and reproduction section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies.
  • PEP2 is selected from the group consisting of LKKYR, LRKHR, LKYHY, KFKYE and YGKIP.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 - AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA" amino acids
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, DMVVE, MIVEE, MIVRS, MIVKS and MVVKS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL and XKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 - AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS and MVVKSXKXS.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present lung section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies.
  • PEP2 is KEVQV or KKATV.
  • PEP4 is selected from the group consisting of VRS, VKS, QHN and EHS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VRS, VKS, QHN and EHS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of M, F and L, preferably AA 28 is selected from the group consisting of I, V, L and E; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent.
  • PEP6 is selected from the group consisting of MIVRS, MIVKS, MVVKS, FLQHN and LEEHS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 - PEP4; wherein PEP4 is selected from the group consisting of VRS, VKS, QHN and EHS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent; wherein AA 27 and
  • AA are independently selected from the group consisting of AA and AA amino acids, preferably AA is selected from the group consisting of M, F and L, preferably AA 28 is selected from the group consisting of I, V, L and E; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 .
  • PEP10 is selected from the group consisting of MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR and LEEHSQXEXR.
  • PEP is selected from the group consisting of MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR and LEEHSQXEXR.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present muscle section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies.
  • PEP2 is IGEMS or LGEMS.
  • PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, EEH and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 - AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent; wherein AA are independently selected from the group consisting of AA and AA V amino acids, preferably AA 27 is selected from the group consisting of G, D, N, M, R and T, preferably AA 28 is selected from the group consisting of M, I, V and L; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably is absent.
  • PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, EEH and EDH
  • AA 26 is absent or selected from the group consisting of AA 1 " amino acids,
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected
  • PEP8 is selected from the group consisting of RXGXS, AXGXR, SXGXR, SXGXH, XGXL, XKXS, LEX AX A and LAXKXE.
  • PEP10 is a peptide of general formula PEP6-AA 33 - AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent; wherein
  • AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of G, D, N, M, R and T, preferably AA 28 is selected from the group consisting of M, I, V and L; wherein AA 29 is absent or selected from the group consisting of
  • AA amino acids preferably is absent; wherein AA is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 .
  • PEP10 is selected from the group consisting of GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present blood section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies.
  • PEP2 is LKNYQ or LKKYR.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, DMVVE, MIVEE, MIVRS, MIVKS and MVVKS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA" amino acids, preferably is S or C
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL and XKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 - PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably is absent or E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA 1 " and AA V amino acids, preferably AA 27 is selected from the group consist
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH, NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS and MVVKSXKXS.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present adipose tissue section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • PEP2, PEP4, PEP6, PEP8, and PEP10 will depend on the type of specific tissue closure to be performed and may include any of the suitable amino acids, peptides, analog or variant thereof, or peptidomimetic, already disclosed herein with respect to the bone, cartilage, vascular, wound healing, neuronal, eye-retinal, kidneys, liver, L/T and skin applications.
  • suitable amino acids, peptides, analog or variant thereof, or peptidomimetic already disclosed herein with respect to the bone, cartilage, vascular, wound healing, neuronal, eye-retinal, kidneys, liver, L/T and skin applications.
  • different layers of tissue such as skin, muscle and blood vessel are incised in order to reach the damaged bone part.
  • suitable PEP2, PEP4, PEP6, PEP8, and PEP10 for implementing embodiments of the invention in this specific situation may include such amino acids, peptides, analog or variant thereof, or peptidomimetic, already described herein with respect to skin, muscle, vascular and bone tissue regeneration/formation and cell migration.
  • suitable PEP2, PEP4, PEP6, PEP8, and PEP10 for implementing embodiments of the invention in this specific situation may include such amino acids, peptides, analog or variant thereof, or peptidomimetic, already described herein with respect to skin, muscle, vascular and bone tissue regeneration/formation and cell migration.
  • different layers of tissue such as skin, muscle and blood vessel, are incised in order to reach the patient's heart.
  • suitable PEP2, PEP4, PEP6, PEP8, and PEP10 for implementing embodiments of the invention in this specific situation include such amino acids, peptides, analog or variant thereof, or peptidomimetic, already described herein with respect to the skin, muscle and blood vessel tissue regeneration/formation and cell migration.
  • the present invention may achieve its intended therapeutic and/or cosmetic action(s) e.g. through efficient tissue induction, by functional combination (or association) with a bioactive carrier.
  • said cyclic GFR-binding compound and said bioactive carrier are thus operably associated, combined, linked or connected as defined herein and thus may form a pharmaceutical, dermatological, prophylactic, diagnostic, imaging or cosmetic association or combination for uses and methods as defined herein.
  • bioactive carrier As may be used herein, the term “bioactive carrier”, “biocompatible carrier”, “bioactive material”, “biocompatible material”, “bioactive substance”, “bio-substance”, “biocompatible substance”, are used interchangeably.
  • Bioactive carriers suitable for implementing embodiments of the present invention include, but are not limited to, (a) a biopolymer such as (a1 ) collagen, (a2) fibrin; (b) a synthetic polymer such as (b1 ) ultra-high molecular weight polyethylene (UHMWPE), (b2) polyurethane (PE), (b3) polyurethane (PU), (b4) polytetrafuoroethylene (PTFE), (b5) polyacetal (PA), (b6) polymethylmethacrylate (PMMA), (b7) polyethylene terepthalate (PET), (b8) silicone rubber (SR), (b9) polyetheretherketone (PEEK), (b10) poly(lactic acid) (PLA), (b1 1 ) polysulfone (PS), (b12) PLLA, (b13) PLGA or (b14) PLDA; (c) a biopolymer such as (a1 ) collagen, (a2) fibrin; (b) a synthetic polymer such as (b1
  • polysaccharides such as alginates, chitosans, chitins, guar gums, pectins, gellan gums, heparins, carrageenans, hyaluronans, starches, agars, xanthan gums, methylcellulose, carboxymethylcellulose, hydroxypropyl methyl cellulose, (i3) polyglycols such as polyethyleneglycol or polypropyleneglycol, (i4) polyvinylpyrrolidone, (i5) poly(vinylalcohol), (i6) polyacrylic acids, (i7) glycerophosphates, (i8) 2-acrylamido-2-methylpropanesulfonic acid, (i9) polyphosphazenes; (j) other suitable materials such as demineralized bone matrix; and any combinations thereof.
  • polysaccharides such as alginates, chitosans, chitins, guar gums, pectins, gellan gums,
  • Suitable sources of bioactive carriers for implementing embodiments of the present invention include, but are not limited to, autographs, allographs, xenographs, plants, solutions, excipients, ceramics, metals, metal alloys, organic and inorganic polymers, bioglasses, carbon-containing structures, or combination thereof.
  • bioactive carriers for implementing embodiments of the present invention include bioactive carriers comprising at least one naturally occurring hydroxyl group on at least one surface thereof and bioactive carriers which do not naturally comprise at least one hydroxyl group on a surface thereof but which have been modified using conventional surface treatment techniques such that at least one hydroxyl group is present on a surface of the bioactive carrier.
  • said hydroxyl group is an available hydroxyl group i.e. it is not prevented from interacting and/or reacting with a compound of the present disclosure.
  • Suitable as bioactive carriers naturally containing hydroxyl groups on a surface thereof for implementing embodiments of the invention specifically include metal oxides such as titanium oxides and non-metal oxides such ceramics.
  • bioactive carriers comprising at least one naturally occurring carboxylate group (-COOH) or amine group (-NH 2 ) on at least one of a surface thereof and bioactive carriers which do not naturally comprise at least one carboxylate group (-COOH) or amine group (-NH 2 ) onto a surface thereof but which have been modified using conventional surface treatment techniques such that at least one carboxylate group (-COOH) or amine group (-NH 2 ) is present on a surface of the bioactive carrier.
  • bioactive carriers comprising at least one naturally occurring carboxylate group (-COOH) or amine group (-NH 2 ) on at least one of a surface thereof and bioactive carriers which do not naturally comprise at least one carboxylate group (-COOH) or amine group (-NH 2 ) onto a surface thereof but which have been modified using conventional surface treatment techniques such that at least one carboxylate group (-COOH) or amine group (-NH 2 ) is present on a surface of the bioactive carrier.
  • said bioactive carrier includes a biomaterial.
  • Suitable biomaterials for implementing certain embodiments of the present disclosure may be derived from nature or synthesized in the laboratory using a variety of chemical approaches utilizing metallic components, polymers, ceramics or composite materials. They are often used and/or adapted for a medical application, and thus comprise whole or part of a living structure or biomedical device.
  • Suitable biomaterials for implementing certain embodiments of the present disclosure are commonly used in joint replacements, bone plates, bone cement, artificial ligaments and tendons, dental implants for tooth fixation, blood vessel prostheses, heart valves, skin repair devices (artificial tissue), cochlear replacements, contact lenses, breast implants, drug delivery mechanisms, sustainable materials, vascular grafts, stents, nerve conduits.
  • biomaterials for implementing certain embodiments of the present disclosure such as metals and alloys (pages 94-95), ceramics (pages 95-97), polymeric biomaterials (pages 97-98) and biocomposite materials (pages 98-99) are described in Nitesh et al., International Journal of Emerging Technology and Advanced Engineering, ISSN 2250-2459, Volume 2, Issue 4, 2012, which is herein incorporated by reference in its entirety.
  • said bioactive carrier is a biomaterial.
  • particularly suitable bioactive carriers are selected from the group consisting of bioinert biomaterials, bioactive biomaterials and bioresorbable biomaterials.
  • biomaterial is an important parameter. Particularly good results have been obtained using bioactive carriers composed mostly with the main material component of the tissue to be regenerated and/or repaired. This generally allows for a better integration of the bioactive carrier, a better resorption from the surrounding cells already present and therefore a better regeneration or repair of the targeted tissue to be achieved. For example, it was discovered that particularly good results may be obtained when a solid ceramic component (granulated ceramic powder or ceramic scaffolds) or a gel ceramic component is used in combination of a GFR-binding peptide of the present disclosure to regenerate bone and protect from osteoporosis.
  • a solid ceramic component granulated ceramic powder or ceramic scaffolds
  • a gel ceramic component is used in combination of a GFR-binding peptide of the present disclosure to regenerate bone and protect from osteoporosis.
  • collagen in particular collagen types I, II, III and XI
  • a GFR-binding peptide of the present disclosure to regenerate cartilage.
  • particularly good results may be obtained when collagen, in particular collagen types I and III, or a biodegradable hydrogel is used in combination of a GFR-binding peptide of the present disclosure to regenerate muscle, skin, tendons and ligaments.
  • a collagen or a biodegradable hydrogel is used in combination of a GFR-binding peptide of the present disclosure to regenerate tissues and/or functions of vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, and adipose tissues.
  • Bioinert biomaterials As used herein, unless indicated otherwise or contradictory in context, the term “bioinert biomaterials” refers to any material that once placed in the human body has minimal interaction with its surrounding tissue. Examples of these are stainless steel, titanium, alumina, partially stabilised zirconia, and ultra-high molecular weight polyethylene. Generally a fibrous capsule might form around bioinert implants hence its biofunctionality relies on tissue integration through the implant.
  • Bioactive biomaterial refers to a material which, upon being placed within the human body, interacts with the surrounding bone and in some cases, even soft tissue. This occurs through a time-dependent kinetic modification of the surface, triggered by their implantation within the living bone. An ion-exchange reaction between the bioactive implant and surrounding body fluids, results in the formation of a biologically active carbonate apatite (CHAp) layer on the implant that is chemically and crystallographically equivalent to the mineral phase in bone. Examples of these materials are synthetic hydroxyapatite [Ca 10 (PO 4 )6(OH) 2 ], glass ceramic A-W and bioglass®.
  • Bioresorbable Biomaterials As used herein, unless indicated otherwise or contradictory in context, the term “bioresorbable biomaterials” refers to a material which, upon placement within the human body, starts to dissolve (resorbed) and slowly replaced by advancing tissue (such as bone). Examples of bioresorbable materials include, but are not limited to, tricalcium phosphate [Ca 3 (P0 4 ) 2 ], polylactic- polyglycolic acid copolymers, calcium oxide, calcium carbonate and gypsum.
  • bioactive carrier has a stiffness of at least 5 kPa, more preferably at least 35 kPa and preferably not more than 3 or 5 G Pa as measured using conventional Dynamic Mechanical Analysis such as described in details in Gong JP et ai, Double- network hydrogels with extremely high mechanical strength, Adv Mater 2003, 15(14), 1 155e8, which is incorporated herein by reference.
  • a biomaterial as defined herein for use in neuron-related applications has a stiffness comprised between about 0.01 kPa and about 3 kPa, preferably between about 0.01 kPa and about 1 kPa.
  • a biomaterial as defined herein for use in muscle, cartilage and tendon/ligament -related applications has a stiffness comprised between about 3 kPa and about 200 kPa, preferably between about 10 kPa and about 30 kPa.
  • a biomaterial as defined herein for use in bone-related applications has a stiffness comprised between about 30 kPa and about 3 GPa, preferably between about 70 kPa and about 200 kPa for instance in applications such as the treatment or prevention of osteoporosis and bone tissue regeneration.
  • a biomaterial as defined herein for use in hair-related applications has a stiffness comprised between about 0.01 kPa and about 200 kPa, preferably between about 3 kPa and about 70 kPa.
  • a biomaterial as defined herein for use in endothelization-related applications has a stiffness comprised between about 500 kPa and about 2.5 GPa.
  • a biomaterial as defined herein for use in angiogenesis-related applications has a stiffness comprised between about 0.01 kPa and about 100 kPa. In one particular example, a biomaterial as defined herein for use in wound healing and skin-related applications has a stiffness comprised between about 0.01 kPa and about 70 kPa.
  • available hydroxyl groups As used herein, unless indicated otherwise or contradictory in context, the term “free hydroxyl” or “available hydroxyl” means an hydroxyl group, which may be -OH or a radical (-0 * ) or an anion (-0 ) fully or partially ionised, which is able to / free to act as a nucleophile in a reaction with an electrophile such as compound (A) or compound (B) defined below.
  • Available hydroxyl-containing surface As used herein, unless indicated otherwise or contradictory in context, the term “available hydroxyl-containing surface” or “free hydroxyl-containing surface” means a surface containing at least one free or available hydroxyl group as defined herein.
  • Ceramics As used herein, unless indicated otherwise or contradictory in context, the term “ceramic” refers to an inorganic material with a high melting point, above 1000°C. Most typically, materials referred to as “ceramics” are obtained by a process in which raw material solid particles are heated in order to sinter them. Materials referred to as “ceramics” may broadly be split into two groups, these being “oxide ceramics” and “non-oxide ceramics”. “Oxide ceramics” include, but are not limited to, alkaline earth oxides such as MgO and BaO, Al 2 0 3 and aluminates, Ti0 2 and titanates, Zr0 2 and zirconates, silicates such as clays and clay-derived materials.
  • Non-oxide ceramics include, but are not limited to, carbides and nitrides, and also borides and silicides, for example silicon carbide and silicon nitride, and also metal carbides and nitrides.
  • solid ceramics e.g. in granulated powder or as a scaffold, is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications.
  • gel ceramics is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications.
  • Metal oxides As used herein, unless indicated otherwise or contradictory in context, the term "metal oxide” means a chemical compound that contains at least one oxygen atom and one other element in its chemical formula. Metal oxides typically contain an anion of oxygen in the oxidation state of -2. They can be obtained by hydrolysis or air/oxygen oxidation. Examples of such metal oxides are titanium oxides (e.g. TiO, Ti 2 0 3 , Ti0 2 ), silicon oxide (Si0 2 ), aluminum oxide (Al 2 0 3 ), iron (II, III) oxides such as Fe 2 0 3 , and zinc oxide (ZnO).
  • TiO titanium oxides
  • Ti 2 0 3 silicon oxide
  • Si0 2 silicon oxide
  • Al 2 0 3 aluminum oxide
  • iron oxides such as Fe 2 0 3
  • ZnO zinc oxide
  • Biopolymer refers to a polymer produced by living organisms and includes, but is not limited to, polypeptides and proteins (such as collagen and fibrin), polysaccharides (such as cellulose, starch, chitin and chitosan), nucleic acids (such as DNA and RNA), and hydrides thereof.
  • polypeptides and proteins such as collagen and fibrin
  • polysaccharides such as cellulose, starch, chitin and chitosan
  • nucleic acids such as DNA and RNA
  • Hydrogel As used herein, unless indicated otherwise or contradictory in context, the term “hydrogel” refers to "Hydrogel” refers to a class of polymeric materials which are swollen in an aqueous medium, but which do not dissolve in water. Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content.
  • U.S. Patent No. 6,475,516, for example provides hydrogels being covalently bound to the surface of an in-dwelling medical device such as an implant, which may be functionalized with a GFR-binding compound of the present disclosure using, for instance, a process as described herein. In one particular example, biodegradable hydrogels are used as bioactive carriers in the meaning of the present disclosure.
  • Collagen As used herein, unless indicated otherwise or contradictory in context, the term “collagen” refers to the main structural protein of the various connective tissues in animals which is mostly found in fibrous tissues such as tendons, ligaments and skin, and is also abundant in corneas, cartilage, bones, blood vessels, the gut, and intervertebral discs. Collagen is typically composed of a triple helix and generally contains high hydroxyproline content. The most common motifs in its amino acid sequence glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.
  • Collagen I which may be found in skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)
  • Collagen I I which may be found in cartilage (main component of cartilage)
  • Collagen II I which may be found in reticulate (main component of reticular fibers)
  • Collagen IV which may be found in the basal lamina, the epithelium-secreted layer of the basement membrane
  • Collagen V which may be found on cell surfaces, hair and placenta.
  • suitable collagens for implementing embodiments of the present invention particularly include collagen type-l and type-IV.
  • collagen in particular collagen types I , I I, III and XI
  • cartilage-related applications is used as cartilage-related applications.
  • collagen, in particular collagen types I and I II is used as a bioactive carrier in the meaning of the present disclosure in muscle-related applications, skin-related applications, and T/L-related applications.
  • any type of collagen is used as a bioactive carrier in the meaning of the present disclosure in vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, adipose -related applications.
  • said association, combination, linkage or connection between said cyclic GFR- binding compound and a bioactive carrier may occur via a bioactive carrier-affinity-containing group as defined herein.
  • the present disclosure provides a cyclic GFR-binding compound as already defined herein modified or functionalised with at least one bioactive carrier-affinity-containing group.
  • Said at least one bioactive carrier-affinity-containing group provides said cyclic GFR-binding compound with the ability to, covalently or non-covalently, interact with, or be connected to, a bioactive carrier as defined herein (in particular, a biomaterial as defined herein).
  • said bioactive carrier- affinity-containing group may be a thiol (SH)-containing group or a cysteine-containing group, in particular, a thiol (SH)-containing peptide or a cysteine-containing peptide.
  • said bioactive carrier-affinity-containing group may particularly be a cysteine.
  • said bioactive carrier-affinity-containing group may comprise (or be) a peptide group such as any one of the peptide groups disclosed in US patent application No. 2008/0268015 A1 , which is hereby incorporated by reference in its entirety.
  • peptides containing amino acid sequences rich in large aromatic amino acid residues that include one or more of Phe, Trp, Tyr such as sequences no: 1 to 45 described in US 2008/0268015 A1 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention.
  • Said fragment may also be a peptide fragment such as any one of the peptide fragments disclosed in US patent No. 6,818,620 B2, which is hereby incorporated by reference in its entirety.
  • peptides of sequences no: 1 to 7 described in US 6,818,620 B2 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention.
  • said bioactive carrier-affinity-containing group is a bioactive carrier high- affinity-containing group such as a biomaterial high-affinity-containing group.
  • said bioactive carrier-affinity-containing group has some affinity (preferably high affinity) with a given bioactive carrier (in particular, a biomaterial) such as collagen, apatite, titanium or any of those listed in e.g. US patent application No. 2008/0268015 A1 , which is incorporated herein by reference.
  • a group having some affinity with a biomaterial is any group capable to non- covalently interact/bind to a biomaterial with an affinity/specificity selected from at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, or a higher percentage, with respect to an affinity where said group binds to an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.
  • an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.
  • a biomaterial-affinity-containing group has a binding specificity that is characterized by a relative binding affinity as measured by an EC50 of 10 DM or less, and in certain emdiments, less than 1 ⁇ M.
  • a relative affinity comprised between 1 pM and 100 DM, between 1 pM and 10 D M, or between 1 pM and 1 DM is particularly suitable.
  • the EC50 is determined using any number of methods known in the art. In this case, the EC50 represents the concentration of fragment producing 50% of the maximal binding observed for that fragment in the assay.
  • said bioactive carrier-affinity-containing group is selected from the group consisting of GTPGP, which may preferably non-covalently interact with a bioactive carrier such as an apatite, and WWFWG, which may preferably non-covalently interact with a bioactive carrier such as a collagen.
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity- containing group.
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • a thiol-containing group in particular, a thiol-containing peptide
  • cysteine-containing group in particular, a cysteine-containing peptide and more particularly, a cysteine
  • an aromatic amino acid-containing peptide or peptidomimetic an aromatic amino acid-containing peptide or peptidomimetic.
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; comprising a peptide with five amino acids (PEP2) selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV and KKATV; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of LKNY
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids, having the following general formula
  • LINKER-PEP(B) (I) wherein one end of LINKER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • Mw molecular weight
  • said bioactive carrier-affinity-containing group is selected from the group consisting of a thi
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
  • LINKER-PEP2-PEP(D) (II) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of PEP(D) interacts covalently with one end of PEP2; wherein one end of LINKER interacts covalently with one end of PEP2; wherein PEP(D) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 1 1 amino acids; wherein said bioactive carrier-affinity- containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol- containing peptide), a cysteine-containing group (
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)):
  • LINKER-PEP2-PEP6-PEP8 (III) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein PEP6 is a peptide with between five and seven amino acids as already defined herein; wherein PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein; wherein one end of LINKER interacts covalently with one end of PEP2 via AA 21 ; wherein one end of PEP6 interacts covalently with another end of PEP2 via AA 26 ; wherein another end of PEP6 interacts covalently with one end of PEP8 via AA 32 ; wherein said bioactive carrier
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (IV) (hereinafter may also be referred to as compound (IV) or peptide (IV)): LINKER-AA 21 -AA 22 -AA 23 -AA 24 -AA 25 -AA 26 -AA 27 -AA 28 -AA 29 -AA 30 -AA 31 -AA 32 -AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA ;
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 21 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 31 -AA 32 is PEP4 as defined herein; wherein AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 is PEP8 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein AA 21 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA 38 may be an N-terminal amino acid
  • said bioactive carrier-affinity-containing group is comprised within said cyclic GFR-binding compound e.g. is comprised in said LINKER, or is said LINKER.
  • said modified cyclic GFR-binding compound may have any one of the following general schematic formulae:
  • the present disclosure provides a functionalised bioactive carrier, which may be used for inducing, in-vitro, ex-vivo or in-vivo, tissue regeneration, comprising at least one cyclic GFR-binding compound (in particular, at least one modified cyclic GFR-binding compound) as defined in the present disclosure.
  • said (modified) cyclic GFR-binding compound and bioactive carrier are both active principles/ingredients.
  • said functionalised bioactive carrier is a modified, functionalised, coated or grafted biomaterial as defined herein, in particular, a modified, functionalised, coated or grafted tissue regeneration compatible-biomaterial.
  • said functionalised bioactive carrier comprises one (modified) cyclic GFR-binding compound. In one example, said functionalised bioactive carrier comprises two or more distinct (modified) cyclic GFR-binding compounds. In one example, said functionalised bioactive carrier comprises three or more distinct (modified) cyclic GFR-binding compounds. In one example, said functionalised bioactive carrier comprises four or more distinct (modified) cyclic GFR-binding compounds.
  • (bio)active principle” or “(bio)active ingredient” generally refers to a molecule, compound or substance which is responsible for providing the desired biological effect. Without said active ingredient, the formulation or composition containing it, would not provide the desired biological effect. For example, in certain embodiments, formulation excipients are not considered as active ingredients in the pharmaceutical composition as defined herein.
  • said functionalised bioactive carrier is formed using a method comprising, or exclusively consisting of, contacting a bioactive carrier as defined herein and a (modified) cyclic GFR-binding compound under reacting conditions thereby functionalizing at least one part (or at least one part of a surface) of said bioactive carrier and thus forming a functional association, interaction or bond between said bioactive carrier and said (modified) cyclic GFR-binding compound.
  • the terms “functionally associated”, “functionally combined”, “functionalized”, “immobilized”, “deposited”, “coated”, or “grafted” all refer to the action of associating or functionalising at least one part of a bioactive carrier with a (modified) cyclic GFR-binding compound so that the desired biological, therapeutic and/or cosmetic effect e.g. inducing tissue formation, is obtained.
  • the association or combination may be covalent and form, between said (modified) cyclic GFR-binding compound and said bioactive carrier, a covalent interaction as already defined herein, or, the association or combination may be non-covalent and form, between said (modified) cyclic GFR-binding compound and said bioactive carrier, a non-covalent interaction as already defined herein.
  • a (modified) cyclic GFR-binding compound interacts covalently (makes at least one functional covalent interaction) with said bioactive carrier.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a peptide, or a variant or analog thereof, having growth factor receptor-binding capability or capabilities, with (exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; wherein said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons (in particular, between 1 ,000 and 4,000 Da).
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28)
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between six and eleven amino acids (PEP10).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein,
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (I):
  • LINKER-PEP(B) (I) wherein one end of LINKER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da.
  • Mw molecular weight
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (I), and wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (I), and wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (I), and wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP10.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (I), and wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4 and PEP8.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (I), and wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6 and PEP8.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (II): LINKER-PEP2-PEP(D) (II) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) comprises PEP4.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) comprises PEP6.
  • PEP(D) is PEP6.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) comprises PEP10.
  • PEP(D) is PEP10.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) comprises PEP4 and PEP8.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) comprises PEP6 and PEP8.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound comprises compound (II), and wherein PEP(D) is PEP6 or PEP10.
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (III):
  • LINKER-PEP2-PEP6-PEP8 wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein PEP6 is a peptide with between five and seven amino acids as already defined herein; wherein PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein; wherein one end of LINKER interacts covalently with one end of PEP2 via AA 21 ; wherein one end of PEP6 interacts covalently with another end of PEP2 via AA 26 ; wherein another end of PEP6 interacts covalently with one end of PEP8 via AA 32 .
  • Mw molecular weight
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (IV):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 21 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 31 -AA 32 is PEP4 as defined herein; wherein AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 is PEP8 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein AA 21 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA 38 may be an N-terminal amino acid
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, having any one of the following schematic general formulae (V) to (IX) (hereinafter may also be referred to as compounds (V) to (IX) or peptides (V) to (IX)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da;
  • PEP2 is a peptide with five amino acids as already defined herein;
  • PEP6 is a peptide with between five and seven amino acids as already defined herein;
  • PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein;
  • PEP10 is a peptide with between six and eleven amino acids;
  • curved lines represents covalent bonds between LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' lengths may not be representative of the actual relative distance between the LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' length
  • the present disclosure thus provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10- 35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12- 28) amino acids, having any one of the following schematic general formulae (XX) and (XI) (hereinafter may also be referred to as compounds (XX) and (XI) or peptides (XX) and (XI)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 21 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 31 -AA 32 is PEP4 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein another end of LINKER interacts covalently with AA 25 ; and wherein curved lines represents covalent bonds between LINKERS and AAs "boxes". Curved lines' lengths may not be representative of the actual relative distance between the LINKERS and AAs.
  • the present disclosure provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compound (before any modifications) is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, having any one of the following schematic general formulae (XIII) to (XXII):
  • the present disclosure provides a functionalised bioactive carrier comprising a (modified) cyclic GFR-binding compound, wherein said (modified) cyclic GFR-binding compounds may be any one of SEQ ID NO: 1 to 14868.
  • the present disclosure provides a functionalised bioactive carrier comprising a (modified) cyclic GFR- binding compound, wherein all of PEP2, PEP4, PEP6, PEP10, pairs and triplets thereof, disclaimers and provisos, are as already defined herein.
  • Suitable covalent association or functionalization techniques for implementing embodiments of the present invention include, but are not limited to, reductive amination coupling or photo-grafting such as described in H. Freichel et al., Macromol. Rapid Commun. 201 1 , 32, 616-621 and V. Pourcelle et al., Biomacromol. 2009, 10, 966-974, the content of which is hereby incorporated by reference in its entirety.
  • the present disclosure provides a production method or process useful for producing a functionalised bioactive carrier according to the present disclosure wherein said bioactive carrier is a biomaterial such as a ceramic or a titanium, comprising, or exclusively consisting of, the contacting of a compound of formula (C-l) and a bioactive carrier as defined herein under suitable covalent-bond formation conditions thereby forming at least one covalent bond between said compound (C-l) and said bioactive carrier thus forming a functionalised bioactive carrier according to the present disclosure: wherein X is Si; wherein Y is a divalent organic linker; wherein A is a (modified) cyclic GFR-binding compound according to the present disclosure, wherein R 1 and R 2 are both independently an organic spacing-compound other than a leaving group as defined herein, and wherein R 3 is a leaving group as defined herein;
  • Such syntheses involve the formation of a covalent interaction (or association) between a (modified) cyclic GFR-binding compound (represented as (A)-SH in Scheme 1 ) and a bioactive carrier as defined herein.
  • a process or method which may be used to functionally associate or combine a (modified) cyclic GFR-binding compound with a bioactive carrier is a method for covalent functionalization or depositing of a (modified) cyclic GFR-binding compound onto a polylactic acid (PLLA) polymer wherein (i) the polymer is immersed in a solution containing, for instance, (dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride + N-hydroxysuccinimide in (2-(N-morpholino)-ethanesulfonic acid and then (ii) rinsed using e.g. MilliQ water.
  • PLLA polylactic acid
  • leaving groups As used herein, unless indicated otherwise or contradictory in context, the term "leaving group” means a molecular fragment which possesses the ability to depart with a pair of electrons in a heterolytic bond cleavage. Leaving groups are anions or neutral molecules and possess the ability to stabilize the additional electron density that results from bond heterolysis. Common anionic leaving groups are halogen atoms such as chlorine (CI), bromine (Br), and iodine (I), which leaves as a chloride ion (CI ), a bromide ion (Br ) and an iodide ion ( ⁇ ), respectively. Other leaving groups include sulfonate esters, such as tosylate (TsO ).
  • Suitable as leaving groups for implementing embodiments of the invention preferably include the group consisting of a halogen, a substituted or unsubstituted alkoxy group (-OR), a substituted or unsubstituted aryloxy or heteroaryloxy group (-OAr), a substituted or unsubstituted alkylcarbonyloxy group (-0 2 CR), a substituted or unsubstituted arylcarbonyloxy or heteroarylcarbonyloxy group (-0 2 CAr), a substituted or unsubstituted alkylsulfonyloxy group (-0 3 SR), a substituted or unsubstituted arylsulfonyloxy or heteroarylsulfonyloxy group (-0 3 SAr).
  • Substituents of leaving groups include halogens, alkyl (preferably C1 to C5-alkyl) groups and alkoxy (preferably C1 to
  • the Y group is not aimed at being particularly limited and any moiety comprising at least one atom and having the ability to covalently or non-covalently, preferably covalently, link or interact with the X and A groups as defined herein thereby providing a stable connection between an active substance A and the X group as defined herein, is, unless contradictory or non-adapted in context, suitable for implementing embodiments of the present disclosure and is comprised within the scope of the invention.
  • linker when used in relation to a Y group, means any organic moiety comprising at least one atom and having the ability to interact covalently or non-covalently with an active substance A and covalently interact with an X group as defined herein.
  • Ri is selected from the group consisting of a hydrogen atom, a C1 -C6 alkyl group and a aryl group, and wherein said hydrocarbon chain is non-substituted or substituted, by at least one radical selected from the group consisting of a halogen, a hydroxyl group, a C1 -C20 alkyl group and a aryl group.
  • Suitable as Y groups for implementing embodiments of the invention include saturated or unsaturated hydrocarbon chains comprising between 1 and 20 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 10 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 5 carbon atoms, saturated or unsaturated hydrocarbon chains comprising 1 , 2 or 3 carbon atoms, all of which being specifically and individually preferred.
  • suitable covalent-bond formation conditions means reaction conditions such as pressure, temperature, reagent quantities, solvent's type and quantity, or stirring, under which starting materials may contact and provide at least one further material resulting from the formation of at least one covalent bond between said starting materials.
  • suitable as covalent-bond formation conditions for implementing embodiments of the present invention preferably include substantially atmospheric conditions.
  • organic spacing-compound means an organic chemical radical (preferably monofunctional radical) having the ability to create a steric effect/hindrance and/or electronic effect/hindrance in a direct vicinity of a (modified) cyclic GFR-binding compound of the present disclosure.
  • organic spacing compounds include saturated or unsaturated hydrocarbon chains comprising between 1 and 80 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 60 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 40 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 20 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 10 carbon atoms, saturated hydrocarbon chains comprising 1 , 2, 3, 4, 5 or 6 carbon atoms, all of which being specifically and individually preferred.
  • the saturated hydrocarbon chain may be methyl, ethyl, propyl, butyl or pentyl.
  • said unsaturated hydrocarbon chain may be ethylene, propene, 1 - or 2-butene, 1 -, 2- or 3-pentene, acetylene, propyne, 1 - or 2-butyne, 1 -, 2- or 3-pentyne.
  • saturated hydrocarbon chain means a chain of carbon atoms linked together by single bonds and has hydrogen atoms filling all of the other bonding orbitals of the carbon atoms.
  • Unsaturated hydrocarbon chain In the present description and unless otherwise indicated, the terms "unsaturated hydrocarbon chain” means a chain of carbon that contains carbon-carbon double bonds or triple bonds, such as those found in alkenes or alkynes, respectively.
  • Atmospheric conditions As used herein, unless indicated otherwise or contradictory in context, the term “atmospheric conditions” or “ambient conditions”, which are interchangeably used, refers to conditions which may be found naturally at an experimentation location. For example, in certain embodiments, typical atmospheric conditions in a chemistry/biology laboratory are a temperature of between about 15°C and about 35°C and a pressure of about 1 atm.
  • solution means a homogeneous mixture composed of only one phase, which is stable, which does not allow beam of light to scatter, in which the particles of solute cannot be seen by naked eye and from which a solute cannot be separated by filtration.
  • Suspension As used herein, unless indicated otherwise or contradictory in context, the term "suspension” means a heterogeneous mixture containing solid particles that are sufficiently large for sedimentation. Typically, said solid particles are larger than one micrometer.
  • the internal phase solid
  • the external phase fluid
  • Suitable non-covalent association or functionalization techniques for implementing embodiments of the present invention include, but are not limited to, association(s) between a bioactive carrier-affinity containing group as already defined herein and at least part of a bioactive carrier.
  • association(s) involves the formation of at least one non-covalent interaction (or attachment) between a (modified) cyclic GFR-binding compound and a bioactive carrier as defined herein.
  • said functionalised bioactive carrier is functionally associated with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten (modified) cyclic GFR-binding compounds, each possessing a different and distinct chemical structure.
  • said functionalised bioactive carrier does not comprise a layer of polysiloxane.
  • a functionalised bioactive carrier as defined herein comprises at least one (modified) cyclic GFR-binding compound, and at least one bioactive carrier, wherein said bioactive carrier:
  • a porosity or average pore diameter
  • a porosity comprised between 1 nm and 1000 ⁇ , as measured by scanning electronic microscopy for pore sizes within the supra-nanometre range and by atomic force microscopy for pore sizes within the nanometre range, and/or comprises a stiffness of at least 5 kPa, preferably at least 35 kPa, as measured by Dynamic Mechanical Analysis, and/or
  • biopolymers collagen, fibrin, ...etc
  • synthetic polymers PEEK, PET, ...etc
  • solid materials Tianium, Metals ...etc
  • ceramics Hadroxyapatite, Beta-tricalcium Phosphate, Biphasic Calcium Phosphate ...etc
  • - comprises a density or concentration of associated compound (I) comprised between 0.05 ⁇
  • Porosity refers to the measure of the void spaces in a substance or material, and is a fraction of the volume of voids over the total volume, between 0 and 1 , or as a percentage between 0 and 100%.
  • porosity values are provided in manometers (nm) as obtained using atomic force microscopy for small pore diameters (up to 100 nm) and scanning electron microscopy for larger pore sizes.
  • Stiffness refers to the rigidity of a substance or material i.e. the extent to which it resists deformation in response to an applied force. There are many ways to test and measure the stiffness of a substance or material, but for the purpose of the present disclosure, and for the avoidance of any doubts, stiffness values are provided in Pascal (Pa) as obtained using Dynamic Mechanical Analysis (DMA). Particularly preferred stiffness values are comprised between 1 kPa and 100 kPa and not more than 5 GPa depending on the tissue to be regenerated or repaired.
  • DMA Dynamic Mechanical Analysis
  • bioactive carriers composed mostly with the main material component of the tissue to be regenerated and/or repaired. This generally allows for a better integration of the bioactive carrier, a better resorption from the surrounding cells already present and therefore a better regeneration or repair of the targeted tissue to be achieved.
  • said bioactive carrier for use in neuroregeneration-related applications has a stiffness comprised between about 0.01 kPa and about 3 kPa, preferably between about 0.01 kPa and about 1 kPa. In one example, said bioactive carrier for use in muscle, cartilage and T/L -related applications has a stiffness comprised between about 3 kPa and about 200 kPa, preferably between about 10 kPa and about 30 kPa.
  • said bioactive carrier for use in bone-related applications has a stiffness comprised between about 30 kPa and about 3 GPa, preferably between about 70 kPa and about 200 kPa for instance in applications such as the treatment or prevention of osteoporosis and bone tissue regeneration.
  • said bioactive carrier for use in hair-related applications has a stiffness comprised between about 0.01 kPa and about 200 kPa, preferably between about 3 kPa and about 70 kPa.
  • said bioactive carrier for use in endothelization-related applications has a stiffness comprised between about 500 kPa and about 2.5 GPa.
  • said bioactive carrier for use in angiogenesis-related applications has a stiffness comprised between about 0.01 kPa and about 100 kPa. In one example, said bioactive carrier for use in wound healing and skin -related applications has a stiffness comprised between about 0.01 kPa and about 70 kPa.
  • a pharmaceutical, dermatological or cosmetic association or combination of the present invention may be in the form of a dry, sterile powder.
  • the concentration or density (as defined herein) of a (modified) cyclic GFR- binding compound in, or on the surface of, a bioactive carrier as defined herein is comprised between 0.05 and 50 pmol/mm 2 , in particular comprised between 0.1 and 30 pmol/mm 2 , comprised between 0.1 and 10 pmol/mm 2 , comprised between 0.1 and 5 pmol/mm 2 , or comprised between 0.1 and 2 pmol/mm 2 , each range being preferred and specifically contemplated to be combined with any other numerical or non-numerical ranges as described herein.
  • the density is comprised between 0.2 and 2 pmol/mm 2 . VII. Medical devices
  • cyclic GFR-binding compounds, modified cyclic GFR-binding compounds or functionalised bioactive carriers of the present invention may be injected e.g. using an appropriate syringe, to a specific target site so that they may be delivered directly to the interior of e.g. a body articulation or under the skin in close proximity with the cells to be treated via, for instance, a PTD or cell- permeable peptide.
  • a medical device or implant (or implantable medical device) comprising such cyclic GFR-binding compounds, modified cyclic GFR-binding compounds or functionalised bioactive carriers may be used.
  • Implants may contain reservoirs in which to place the cyclic GFR-binding compound, modified cyclic GFR-binding compound or functionalised bioactive carrier of the invention for release into the surrounding tissue, or may comprise a porous composition which may be soaked in a solution containing one or more cyclic GFR-binding compounds or modified cyclic GFR-binding compounds of the present disclosure prior to implantation.
  • Hydrogels, time-release capsules or spheres, liposomes, microspheres, nanospheres, biodegradable polymers, or other such drug delivery systems may also be employed to deliver cyclic GFR-binding compounds of the present invention to target cells and tissues.
  • U.S. Patent No. 6,475,516, for example, provides hydrogels being covalently bound to the surface of an in-dwelling medical device such as an implant, which may be used with cyclic GFR-binding compounds of the present disclosure.
  • the present disclosure provides a medical device comprising at least one GFR-compound, modified cyclic GFR-binding compound or functionalised bioactive carrier as defined herein.
  • the medical device of the invention may be, partly or entirely, made of a functionalised bioactive carrier as defined herein or contain, for example, in certain embodiments, within a cavity thereof, said functionalised bioactive carrier.
  • said medical device may comprise between 1 wt% and 100 wt% of a functionalised bioactive carrier of the invention with respect to the total weight of the medical device.
  • said medical device comprises between about 50 wt% and 100 wt%, between about 60 wt% and 100 wt%, between about 70 wt% and 100 wt%, between about 80 wt% and 100 wt%, between about 90 wt% and 100 wt% of a functionalised bioactive carrier of the invention with respect to the total weight of the medical device, all of which being specifically and individually preferred.
  • at least one part of a surface of said medical device comprises a cyclic GFR-binding compound, a modified cyclic GFR-binding compound or a functionalised bioactive carrier of the invention.
  • said medical device is preferably an implantable medical device.
  • stents include stents, stiches, powders, granules, sponges, putties, injectable and non-injectable liquids, curable compositions, moldable compositions, membranes, glues, sprays, pills, filaments, prosthesis, or combinations thereof.
  • the present disclosure provides a bone graft material comprising a cyclic GFR-binding compound or a modified cyclic G FR-binding compound of the invention and a collagen as defined herein.
  • a bone graft material means a material suitable for bone grafting.
  • the present disclosure provides an antibody:cyclic G FR-binding compound complex comprising at least one (modified) cyclic GFR-binding compound and at least one antibody or any functional fragment thereof; wherein said (modified) cyclic GFR-binding compound is as defined herein.
  • Antibody refers to a light chain and heavy chain protein of an antibody that are encoded by a gene or genes that are either a naturally occurring gene or a codon-optimized gene.
  • the antibody light chain and heavy chain genes may be human antibody light chain and heavy chain genes.
  • Antibodies, or immunoglobulins are proteins produced by cells of the immune system to identify and neutralize foreign substances, such as bacteria, viruses, or improperly proliferating native cells.
  • Immunoglobulins are one class of desired globulin molecules and include, but are not limited to, IgG , IgM, IgA, IgD, IgE, IgY, lambda chains, kappa chains and fragments thereof; bi-specific antibodies, and fragments thereof; scFv fragments, Fc fragments, and Fab fragments as well as dimeric, trimeric and oligomeric forms of antibody fragments.
  • Suitable antibodies include, but are not limited to, naturally occurring antibodies, animal- specific antibodies, human antibodies, humanized antibodies, autoantibodies and hybrid antibodies. Suitable antibodies also include antibodies with the ability to bind specific ligands.
  • Suitable antibodies also include, but are not limited to, primary antibodies, secondary antibodies, designer antibodies, anti- protein antibodies, anti-peptide antibodies, anti-DNA antibodies, anti-RNA antibodies, anti-hormone antibodies, anti-hypophysiotropic peptides, antibodies against non-natural antigens, anti-anterior pituitary hormone antibodies, anti-posterior pituitary hormone antibodies, anti-venom antibodies, anti-tumor marker antibodies, antibodies directed against epitopes associated with infectious disease, including, anti-viral, anti-bacterial, anti-protozoal, anti-fungal, anti-parasitic, anti-receptor, anti-lipid, anti- phospholipid, anti-growth factor, anti-cytokine, anti-monokine, antiidiotype, and anti-accessory (presentation) protein antibodies.
  • Suitable antibodies also include, but are not limited to, 3F8, 8H9, Abagovomab, Abciximab, Abituzumab, Abrilumab, Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afelimomab, Afutuzumab, Alacizumab pegol, ALD518, Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Anatumomab mafenatox, Anetumab ravtansine, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab, Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Atlizumab, Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab,
  • said antibody:cyclic GFR-binding compound complex is a covalent complex. In certain embodiments, said antibody:cyclic GFR-binding compound complex is a non-covalent complex. IX. Dendrimencvclic GFR-binding compound complex
  • the present disclosure provides a dendrimer:cyclic GFR-binding compound complex comprising at least one (modified) cyclic GFR-binding compound and at least one dendrimer or any functional fragment thereof; wherein said (modified) cyclic GFR-binding compound is as defined herein; and wherein said dendrimer is as already defined herein.
  • said dendrimer:cyclic GFR-binding compound complex is a covalent complex. In certain embodiments, said dendrimer:cyclic GFR-binding compound complex is a non-covalent complex.
  • the extracellular biological action of the cyclic G FR-binding peptides may also be conveyed via expression, by a cell, of the appropriate polynucleotide sequence engineered to encode a particular non- cyclic, cyclizable-GFR-binding peptide having the same sequence as the cyclic GFR-binding peptide of interest and having the relevant N- and C- terminal modifications so that, once expressed by the cell, the non-cyclic sequence is able to appropriately cyclize to form, in-situ, the desired cyclic GFR-binding peptide.
  • N- and C- terminal modifications is the sulfide modification in which the polynucleotide sequence encoding the peptide sequence of interest also contains, as part of its coding region, nucleotides encoding for an N-terminal cysteine and a C-terminal cysteine, so that the peptide sequence is expressed with two termini cysteines capable of forming, under appropriate conditions, a disulfide bond (S-S) resulting in the formation of a cyclic GFR-binding peptide.
  • S-S disulfide bond
  • GFR-binding peptides may be produced ex-vivo (e.g. using a peptide synthesizer) or in-vivo (e.g. via cell expression of a cyclizable GFR-binding-peptide-encoding polynucleotide), and in all cases have an extracellular biological action of activation of growth factor receptors to induce cell differentiation and/or tissue regeneration.
  • the present disclosure provides a polynucleotide encoding at least one peptide as disclosed herein together with the appropriate termini modifications as described above.
  • said polynucleotide is a messenger RNA or a primary construct thereof.
  • Said messenger RNA may additionally have a 5' cap structure chosen from the group consisting of m 7 G(5')ppp (5')A,G(5')ppp(5')A and G(5')ppp(5')G.
  • the messenger RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides.
  • the messenger RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides.
  • the messenger RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S- transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Myc tag, a Swal 1 epitope, a FLAG tag or an HA tag.
  • the messenger RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence.
  • said polynucleotide is a complementary DNA of said messenger RNA or a primary construct thereof.
  • the present disclosure also provides a vector comprising a polynucleotide as defined in the present disclosure. In one aspect, the present disclosure also provides a cultured cell comprising a vector as defined in the present disclosure.
  • the present disclosure also provides a method of expressing a peptide of interest, variant or analog thereof, in a mammalian cell, said method comprising: (i) providing an mRNA as defined in the present disclosure; and (ii) introducing said mRNA to a mammalian cell under conditions that permit the expression of the peptide of interest by the mammalian cell.
  • the present disclosure also provides a mRNA as disclosed herein for use in a medical treatment or prophylactic method.
  • said medical treatment method is a therapeutic, surgical, or diagnostic method.
  • said method is a method for treating or preventing cell-degeneration-associated diseases, disorders, conditions, or pathologies as defined in the present disclosure.
  • said method is a method for regenerating mammalian tissues as disclosed herein.
  • the present disclosure also provides a use of a RNA or mRNA as defined in the present disclosure for the preparation of a pharmaceutical composition for the treatment or prevention of cell- degeneration-associated diseases, disorders, conditions, or pathologies as disclosed herein.
  • the present disclosure also provides a medical composition comprising a polynucleotide, a vector, or a transfected eel, all as defined in the present disclosure, and a medically acceptable excipient or carrier.
  • expression of a nucleic acid sequence refers to one or more of the following events: (1 ) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5' cap formation, and/or 3' end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.
  • mRNA As used herein, the term "mRNA” refers to messenger RNA. Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5'UTR, a 3'UTR, a 5'cap and a poly-A tail.
  • the 5'UTR, 3'UTR, 5'cap and the poly-A tail are usually required to improve e.g. stability, translation and/or recognition by the ribosome, it is the coding region which comprises the sequence encoding the protein(s), polypeptide(s), or peptide(s) of (therapeutic) interest. Therefore, when the mRNA molecule as disclosed herein is conventionally described with reference to its coding region, any mRNA molecule also comprising at least one of a 5'UTR, a 3'UTR, a 5'cap or a poly-A tail forms an integral part of the present disclosure.
  • Coding region As used herein, the term “coding region” or “coding sequence” refers to a portion of a polynucleotide that codes for a peptide or peptides of interest.
  • Primary RNA construct or transcript refers to any precursor RNA molecule from a mature and functional (i.e. translatable) RNA molecule may be obtained.
  • a precursor messenger RNA pre-mRNA
  • mRNA messenger RNA
  • Newly synthesized primary transcripts are modified in several ways to yield their mature form before they can be translated into a protein of interest. Such modifications include, but are not limited to, excision of introns, splicing of exons, addition of 5'cap and poly-A tail.
  • RNA molecules aims to cover all RNA molecules including, but not limited to, primary RNA transcripts or constructs at any stage of the modification process leading to a mature and functional RNA molecule e.g. with or without introns, exons, 5'cap, poly- A tail and/or any other conventional modifications, insofar as the RNA molecule contains a coding region or a precursor thereof allowing for a peptide of interest encoded by said coding region or precursor thereof to be expressed.
  • 5' Capping As used herein, unless indicated otherwise or contradictory in context, the term “5' Capping” ou “5' Cap” refers to a 5' cap structure of a mRNA that is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5' proximal introns removal during mRNA splicing.
  • CBP mRNA Cap Binding Protein
  • Endogenous mRNA molecules may be 5 '-end capped generating a 5'-ppp-5'- triphosphate linkage between a terminal guanosine cap residue and the 5 '-terminal transcribed sense nucleotide of the mRNA molecule. This 5'-guanylate cap may then be methylated to generate an N7- methyl-guanylate residue.
  • Poly-A tails During RNA processing, a long chain of adenine nucleotides (poly-A tail) may be added to a polynucleotide such as an m RNA molecules in order to increase stability. Immediately after transcription, the 3' end of the transcript may be cleaved to free a 3' hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 100 and 250 residues long.
  • Untranslated regions As used herein, the term "Untranslated regions" or UTRs of a gene refers to regions that are transcribed but not translated. The 5'UTR starts at the transcription start site and continues to the start codon but does not include the start codon ; whereas, the 3'UTR starts immediately following the stop codon and continues until the transcriptional termination signal.
  • the regulatory features of a UTR can be incorporated into the polynucleotides, primary constructs and/or m RNA of the present disclosure to enhance the stability of the molecule.
  • 3'UTR As used herein, unless indicated otherwise or contradictory in context, the term “3'UTR” or “three prime untranslated region” refers to the section of messenger RNA that immediately follows the translation termination codon. The 3'-UTR often contains regulatory regions that post-transcriptionally influence gene expression.
  • 5'UTR As used herein, unless indicated otherwise or contradictory in context, the term “5'UTR” or “five prime untranslated region” refers to the section of mRNA that starts at the transcription start site and continues to the start codon but does not include the start codon. There is growing body of evidence about the regulatory roles played by the UTRs in terms of stability of the nucleic acid molecule and translation. Natural 5'UTRs bear features which play roles in for translation initiation. 5 'UTR also have been known to form secondary structures which are involved in elongation factor binding.
  • Complementary DNA refers to a DNA molecule containing an eukaryote gene which has been tailored or engineered to be expressed in a prokaryote host cell. cDNA is also called “intron-free” DNA as it lacks the gene regions encoding introns, its transcription yielding an intron-free mRNA molecule.
  • the present disclosure provides a vector comprising a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein.
  • Vector As used herein, unless indicated otherwise or contradictory in context, the term "vector” is used in its most general meaning and refers to any intermediary vehicle for a nucleic acid which enables said nucleic acid, for example, to be introduced into prokaryotic and/or eukaryotic cells and, where appropriate, to be integrated into a genome. Vectors of this kind are preferably replicated and/or expressed in the cells. Vectors may comprise plasmids, phagemids, bacteriophages or viral genomes.
  • Plasmid As used herein, unless indicated otherwise or contradictory in context, the term “plasmid” refers to a double-stranded (which may be circular) DNA sequence that is capable of automatically replicating in a host cell.
  • the present disclosure provides a cultured cell (or transfected cell) comprising a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor- binding capability or capabilities, as defined herein.
  • the present disclosure provides a medical composition comprising at least one of a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor- binding capability or capabilities, as defined herein, a vector comprising such a polynucleotide, or a transfected cell comprising such a vector, and a medically acceptable carrier.
  • the present disclosure provides methods and uses for inducing cell differentiation, regenerating tissues and protecting a patient from cell-degeneration-related diseases, conditions, disorders or pathologies, using at least one of a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein, a vector comprising such a polynucleotide, a transfected cell comprising such a vector, or a medical composition comprising them.
  • the present disclosure provides cyclic GFR-binding compounds, modified cyclic GFR-binding compounds and functionalised bioactive carrier, which may be used for inducing stem cell differentiation and tissue regeneration.
  • the present disclosure provides a composition such as a pharmaceutical, prophylactic, surgical, diagnostic, or imaging composition (hereinafter shorten as pharmaceutical or medical composition) comprising at least one (modified) cyclic GFR-binding compound or a functionalised bioactive carrier as defined herein and further comprising at least one pharmaceutically acceptable excipient carriers and/or vehicles.
  • a composition such as a pharmaceutical, prophylactic, surgical, diagnostic, or imaging composition (hereinafter shorten as pharmaceutical or medical composition) comprising at least one (modified) cyclic GFR-binding compound or a functionalised bioactive carrier as defined herein and further comprising at least one pharmaceutically acceptable excipient carriers and/or vehicles.
  • Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. Generally, such methods of preparation include the step of bringing the active ingredient(s) into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product
  • a pharmaceutical composition as defined herein may contain between 0.01 % and 100% by weight (over the total weight of the pharmaceutical composition) of a (modified) cyclic GFR-binding compound or a functionalised bioactive carrier, both as defined herein, as a pharmaceutically effective amount.
  • the pharmaceutical composition particularly comprises between 0.01 % and 95%, between 0.01 % and 90%, between 0.01 % and 85%, between 0.01 % and 80%, between 0.01 % and 75%, between 0.01 % and 70%, between 0.01 % and 65%, between 0.01 % and 60%, between 0.01 % and 55%, between 0.01 % and 50%, between 0.01 % and 45%, between 0.01 % and 40%, between 0.01 % and 35%, between 0.01 % and 30%, between 0.01 % and 25%, between 0.01 % and 20%, between 0.01 % and 15%, between 0.01 % and 10%, between 0.01 % and 5%, between 0.1 % and 100%, between 0.1 % and 95%, between 0.1 % and 90%, between 0.1 % and 85%, between 0.1 % and 80%, between 0.1 % and 75%, between 0.1 % and 70%, between 0.1 % and 65%, between 0.1 % and 60%, between 0.1 % and 55%, between
  • the (modified) cyclic GFR-binding compounds or functionalised bioactive carriers as defined herein may thus be administered as such or as part of a formulation in association with one or more pharmaceutically acceptable excipients, carriers and/or vehicles so as to form what is generally referred to as a pharmaceutical composition or pharmaceutical formulation.
  • pharmaceutical effective amount refers to an amount of an agent to be delivered (e.g., nucleic acid, protein, peptide, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, condition and/or pathology, to produce/provide a therapeutically effective outcome.
  • an agent to be delivered e.g., nucleic acid, protein, peptide, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.
  • a “pharmaceutical effective amount” depends upon the context in which it is being applied.
  • a pharmaceutical effective amount of a composition is provided based, at least in part, on the target tissue, target cell type, means of administration, physical characteristics of the pharmaceutical association or composition (e.g., size, 3D shape, etc.), and other determinants.
  • a pharmaceutical effective amount of an agent in the context of providing an agent that induces tissue regeneration, is, for example, in certain embodiments, an amount sufficient to achieve tissue regeneration, as compared to the response obtained without provision of the agent.
  • a therapeutically effective amount as used herein is any of the herein disclosed weight or molar amounts, ratios or ranges of the (modified) cyclic GFR-binding compound or functionalised bioactive carrier.
  • therapeutically effective outcome refers to an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, condition and/or pathology, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, condition and/or pathology.
  • therapeutic agent refers to any agent that, when administered to a subject/patient/individual, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the ambit of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions refers to any ingredient other than the compounds described herein (i.e. cyclic GFR-binding compounds, bioactive carriers as defined herein or any further active principles) and satisfying to the herein defined definition of pharmaceutically acceptable for a patient.
  • Excipients may include, for example: inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, printing inks, sweeteners, and/or waters of hydration.
  • excipient(s) will largely depend on factors such as the particular mode of administration, the effect of the excipient(s) on solubility and stability, and the nature of the dosage form.
  • the pharmaceutically acceptable excipient is not a naturally occurring excipient.
  • Diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, powdered sugar and/or any combinations thereof.
  • buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, potassium acetate, potassium chloride, monobasic potassium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, phosphoric acid, calcium hydroxide phosphate, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and any combinations thereof.
  • Granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone), sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, methylcellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds and/or any combinations thereof.
  • surface active agents and/or emulsifiers include, but are not limited to, colloidal clays (such as aluminum silicates and magnesium aluminum silicates), natural emulsifiers (such as acacia, agar, sodium alginate, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (such as stearyl, cetyl and oleyl alcohols, triacetin monostearate, ethylene glycol distearate and glyceryl monostearate), carbomers (such as carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, o
  • binding agents include, but are not limited to, natural and synthetic gums (such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate and poly(vinyl-pyrrolidone), gelatin, starch, sugars (such as sucrose, dextrose, glucose, dextrin, lactose, and mannitol), alignates, magnesium aluminum silicates, polyethylene glycol, polyethylene oxide, inorganic calcium salts, water, alcohol, silicic acid, waxes, and any combinations thereof.
  • natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate and poly(vinyl-pyrrolidon
  • preservatives include, but are not limited to, antioxidants, chelating agents, antifungal preservatives, antimicrobial preservatives, acidic preservatives, and alcohol preservatives.
  • antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, propionic acid, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium ascorbate, and sodium sulfite.
  • chelating agents include ethylenediaminetetraacetic acid (EDTA), fumaric acid, malic acid, phosphoric acid, citric acid monohydrate and tartaric acid.
  • EDTA ethylenediaminetetraacetic acid
  • Antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, benzyl alcohol, bronopol, cetylpyridinium chloride, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenoxyethanol, phenylmercuric nitrate, phenylethyl alcohol, phenol, and propylene glycol.
  • Antifungal preservatives include, but are not limited to, benzoic acid, hydroxybenzoic acid, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, potassium benzoate, sodium propionate, potassium sorbate, and/or sorbic acid.
  • Alcohol preservatives include, but are not limited to, phenol, phenolic compounds, bisphenol, ethanol, polyethylene glycol, chlorobutanol and hydroxybenzoate.
  • Acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, acetic acid, citric acid, dehydroacetic acid, and sorbic acid.
  • Lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, magnesium lauryl sulphate and any combinations thereof.
  • sweeteners include, but are not limited to, any natural or synthetic sugar substitutes. Natural sugar substitutes include, but are not limited to, brazzein, curculin, erythritol, glycyrrhizin , glycerol, hydrogenated starch hydrolysates, inulin, isomalt, lactitol, mogroside mix, mabinlin, maltitol, malto-oligosaccharide, mannitol, miraculin, monatin, monellin, osladin , pentadin, sorbitol, stevia, tagatose, thaumatin, and xylitol.
  • Synthetic sugar substitutes include, but are not limited to, acesulfame potassium, advantame, alitame, aspartame, salt of aspartame- acesulfame, sodium cyclamate, dulcin, glucin, neohesperidin dihydrochalcone, neotame, P-4000, saccharin, Sucralose.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and
  • Suitable excipients for use in the present invention also include, but are not limited to, water, phosphate buffered saline (PBS), Ringer's solution, dextrose solution, serum- containing solutions, Hank's solution, other aqueous physiologically balanced solutions, oils, esters and glycols.
  • PBS phosphate buffered saline
  • Aqueous excipients can contain suitable auxiliary substances required to approximate the physiological conditions of the recipient, for example, in certain embodiments, by enhancing chemical stability and isotonicity.
  • pharmaceutically acceptable carriers refers to pharmaceutically acceptable excipients and/or delivery vehicles suitable for delivering a pharmaceutical or therapeutic composition useful in a therapeutic method and uses of the present invention to a suitable in-vivo or ex- vivo site.
  • Preferred pharmaceutically acceptable carriers are capable of maintaining a composition containing an active combination or association of a (modified) cyclic GFR-binding compound and a bioactive carrier as defined herein, in a form that, upon arrival of the combination to a target cell, site or tissue, the active combination is capable of performing one or more biological functions thereof the protein at the cell or tissue site.
  • a controlled release formulation that is capable of slowly releasing a composition or combination into an animal.
  • a controlled release formulation comprises an active combination or association as defined herein in a controlled release vehicle.
  • Suitable controlled release vehicles include, but are not limited to, microparticles, biocompatible polymers, other polymeric matrices, capsules, microcapsules, osmotic pumps, bolus preparations, diffusion devices, liposomes, lipospheres, and transdermal delivery systems.
  • Such suitable controlled release vehicle may be combined with at least one targeting moiety.
  • the pharmaceutically acceptable carrier is not a naturally occurring carrier.
  • the functionalised bioactive carrier disclosed herein includes at least one binding partner which functions to target the cell to a specific tissue space or to interact with a specific moiety, either in-vivo, ex-vivo or in-vitro.
  • Suitable binding partners include antibodies and functional fragments thereof, scaffold proteins, or peptides.
  • said excipients, carriers or vehicles are compatible with the (modified) cyclic GFR- binding compounds or functionalised bioactive carriers defined herein so that they do not disrupt, tamper, modify, de-organise, de-combine or de-associate said the (modified) cyclic GFR-binding compounds or functionalised bioactive carriers.
  • said excipients, carriers or vehicles preserves, maintains or reinforces the stability of the (modified) cyclic GFR-binding compounds or functionalised bioactive carriers so as to preserve their biological activity.
  • the present pharmaceutical compositions also include pharmaceutically acceptable salts and/or solvates and/or prodrugs and/or isotopically-labelled derivatives of the substances and compounds described herein such as the (modified) cyclic GFR-binding compounds or any other active principles.
  • compositions As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable salts” refers to derivatives of the disclosed substances and compounds wherein the parent substance or compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, in certain embodiments, from non- toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are generally found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in Pharmaceutical Salts: Properties, Selection, and Use, P.H. Stahl and C.G. Wermuth (eds.), Wiley- VCH, 2008, each of which being incorporated herein by reference in its entirety.
  • the pharmaceutically acceptable salt is not a naturally occurring salt.
  • solvate refers to a compound, substance, association or combination wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered.
  • solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
  • solvents examples include ethanol, water (For example, in certain embodiments, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), [Nu],[Nu]'-dimethylacetamide (DMAC), 1 ,3-dimethyl-2- imidazolidinone (DMEU), 1 ,3-dimethyl-3,4,5,6-tetrahydro-2-(1 H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like.
  • NMP N-methylpyrrolidinone
  • DMSO dimethyl sulfoxide
  • DMAC dimethylformamide
  • DMAC dimethylformamide
  • DMAC dimethyl-2- imidazolidinone
  • DMEU 1,3-dimethyl-3,4,5,6-t
  • the solvate When water is the solvent, the solvate is referred to as a "hydrate". In one embodiment, the pharmaceutically acceptable solvate is not a naturally occurring solvate.
  • Pharmaceutically acceptable isotopically-labelled compounds In one example, the present invention also includes all pharmaceutically acceptable isotopically-labelled derivatives, which are identical to the compounds, substances, combinations or associations described herein but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into cyclic G FR-binding compound(s) as defined herein include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur, such as 2 H, 3 H, 1 1 C, 13 C, 14 C, 36 CI, 18 F, 123 l, 13 N, 15 N, 17 0, 18 0, and 35 S, respectively. It should be understood that compounds, substances, combinations, associations, prodrugs, and pharmaceutical acceptable salts thereof described herein which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically labeled of the compounds, substances, combinations, associations, prodrugs, and salts thereof such as, for example, in certain embodiments, those incorporating a radioactive isotope such as 3 H and 14 C, are useful in drug and/or substrate tissue distribution studies.
  • Tritium i.e. 3 H
  • carbon-14 i.e. 14 C
  • substitution with heavier isotopes such as deuterium , i.e. 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example, in certain embodiments, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically labeled compounds, substances, combinations, associations, prodrugs, and salts thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples by substituting a readily available non-isotopically labeled reagent for an isotopically labeled reagent.
  • prodrugs As used herein, unless indicated otherwise or contradictory in context, the term “prodrug” refers to a compound, substance, combination or association that is transformed in vivo to yield a compound, substance, combination or association as defined herein or a pharmaceutically acceptable salt or solvate thereof. The transformation may occur by various mechanisms, such as via hydrolysis in blood.
  • a prodrug of a compound, substance, combination or association defined herein may be formed in a conventional manner with one or more functional groups in the compound, such as an amino, hydroxyl or carboxyl group.
  • a prodrug can comprise: (1 ) an ester formed by the replacement of a hydrogen of the acid group with a group such as (C1 -C6)alkyl or (C6-C10) aryl; (2) an activated ester formed by the replacement of the hydrogen of the acid group with groups such as -(CR 2 )COOR', where CR 2 is a spacer and R can be groups such as H or methyl and R' can be groups such as (C1 -C6)alkyl or (C6-C10) aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with groups such as CHROCOOR' where R can be groups such as H or methyl and R' can be groups such as (C1 - C6)alkyl or (C6-C10)aryl.
  • a prodrug can be formed via the replacement of the hydrogen of the alcohol with groups such as (C1 - C6)alkanoyloxymethyl or (C1 -C6)alkanoyloxyaryl or by forming an ester via condensation with, for example, in certain embodiments, an amino acid.
  • a prodrug may comprise, for example, in certain embodiments, an amide formed by the replacement of one or both of the hydrogen atoms of the amino group with (C1 - C10)alkanoyl or (C6-C10)aroyl.
  • Other prodrugs of amines are well known to those skilled in the art.
  • certain compounds defined herein may themselves act as prodrugs of other compounds defined herein.
  • Discussions regarding prodrugs and their use can be found in , for example, in certain embodiments, "Prodrugs as Novel Delivery Systems," T. Higuchi and W. Stella, Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Examples of other prodrug types may be found in the aforementioned reference which is hereby incorporated by reference.
  • cyclic GFR-binding compounds, substances, functionalised bioactive carrier to be delivered and/or pharmaceutical, dermatological, prophylactic, diagnostic, or imaging compositions or formulations thereof in accordance with the present disclosure may be administered by any route of administration effective for preventing, treating, diagnosing, or imaging a disease, disorder, or condition and/or treating or alleviating at least one symptoms thereof and/or inducing tissue formation/regeneration and/or reducing or preventing tissue degeneration.
  • Suitable administration protocols include any in-vitro, in-vivo or ex-vivo administration protocol.
  • the preferred types and routes of administration will be apparent to those of skill in the art, depending on the type of condition or disease to be prevented or treated or the nature of tissue to regenerate; whether the composition is nucleic acid based, protein based, cell based or combinations or mixtures thereof; and/or the target cell/tissue.
  • Ex-vivo and in-vitro administration refers to performing the regulatory step outside of the subject/patient, such as administering a (modified) cyclic GFR-binding compounds, functionalised bioactive carrier or medical compositions as defined herein to a population of cells (e.g., mesenchymal stem cells) removed from a subject/patient for e.g. diagnostic, analysis and/or academic purposes.
  • a (modified) cyclic GFR-binding compounds, functionalised bioactive carrier or medical compositions as defined herein to a population of cells (e.g., mesenchymal stem cells) removed from a subject/patient for e.g. diagnostic, analysis and/or academic purposes.
  • Cells, tissues or organs can be contacted ex vivo or in vitro with a (modified) cyclic GFR-binding compound or a functionalised bioactive carrier by any suitable method, including mixing or the use of a delivery vehicle.
  • Effective in vitro or ex vivo culture conditions include, but are not limited to, effective media, bioreactor, temperature, pH and oxygen conditions that permit cell culture.
  • An effective medium refers to any medium in which a given host cell or tissue is typically cultured. Such medium typically comprises an aqueous medium having assimilable carbon, nitrogen and phosphate sources, and appropriate salts, minerals, metals and other nutrients, such as vitamins.
  • Cells can be cultured in conventional fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and petri plates. Culturing can be carried out at a temperature, pH and oxygen content appropriate for a cell or tissue. Such culturing conditions are within the expertise of one of ordinary skill in the art.
  • the present disclosure thus also provides a method for inducing tissue formation, in-vitro or ex-vivo, said method comprising the administration to a cell (e.g. a non-fully differentiated cell) of an effective amount of a cyclic GFR-binding compound, a functionalised bioactive carrier or a composition thereof as defined herein.
  • a cell e.g. a non-fully differentiated cell
  • a functionalised bioactive carrier e.g. a cell
  • cyclic GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions are administered by one or more of a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, rectal, intravaginal, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, intraperitoneal, topical (e.g.
  • cyclic GFR-binding compounds are administered by systemic intravenous injection.
  • (modified) cyclic GFR-binding compounds, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier.
  • delivery refers to the act or manner of delivering a compound, substance, composition, entity, moiety, cargo or payload.
  • delivery agent refers to any substance which facilitates, at least in part, the in vivo delivery of a (modified) cyclic GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions defined herein to targeted cells.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions of the invention includes forms suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, or for parenteral injection as a sterile solution, suspension or emulsion.
  • Pharmaceutical compositions suitable for the delivery of (modified) cyclic GFR-binding compounds, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions defined herein and methods for their preparation will be readily apparent to those skilled in the art.
  • compositions and methods for their preparation may be found, for example, in certain embodiments, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), which is hereby incorporated by reference in its entirety.
  • Oral administration may involve swallowing, so that the compounds or associations enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, in certain embodiments, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, in certain embodiments, from a sachet.
  • the pharmaceutical associations or compositions defined herein may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in the art.
  • parenteral administration forms include sterile solutions, suspensions or emulsions of the pharmaceutical association defined herein in sterile aqueous media, for example, in certain embodiments, aqueous propylene glycol or dextrose.
  • the parenteral administration form is a solution.
  • Such parenteral dosage forms can be suitably buffered, if desired.
  • Preferred sterile solutions include sodium chloride, 0.9%, UPS solution.
  • Injectable formulations can be sterilized, for example, in certain embodiments, by filtration through a bacterial- retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Dosage forms for topical and/or transdermal administration of a composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • an active ingredient is admixed under sterile conditions with a pharmaceutically acceptable excipient and/or any needed preservatives and/or buffers as may be required.
  • Dosage forms for pulmonary administration via the buccal cavity may comprise dry particles which comprise the active ingredient (e.g. the pharmaceutical association defined herein) and which have a diameter in the range from about 0.5 nm to about 7 nm.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Pharmaceutical compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium , a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • Formulations suitable for nasal administration are also useful for intranasal delivery of a pharmaceutical composition.
  • Formulations suitable for nasal administration may, for example, in certain embodiments, comprise from about as little as 0.1 % (w/w) and as much as 100% (w/w) of active ingredient (e.g. the pharmaceutical association defined herein), and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration.
  • formulations may, for example, in certain embodiments, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, in certain embodiments, 0.1 % to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.
  • Dosage forms for ophthalmic administration include, for example, in certain embodiments, eye drops including, for example, in certain embodiments, a 0.1 /1 .0% (w/w) solution and/or suspension of the active ingredient (e.g. the pharmaceutical association defined herein) in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein.
  • Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this present disclosure.
  • Direct injection One preferred administration method for delivering (modified) cyclic G FR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions as defined herein is by local administration, in particular, by direct injection. Direct injection techniques are particularly useful for administering a composition to a cell or tissue that is accessible by surgery, and particularly, on or near the surface of the body. Administration of a composition locally within the area of a target cell refers to injecting the composition centimeters and preferably, millimeters from the target cell or tissue.
  • Dosage regimens The dosage regimen of the (modified) cyclic GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions as defined herein may be adjusted to provide the optimum desired response. For example, in certain embodiments, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the appropriate dosing regimen, the amount of each dose administered and/or the intervals between doses will depend upon the pharmaceutical association being used, the type of pharmaceutical composition, the characteristics of the subject in need of treatment and the severity of the condition being treated.
  • the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
  • compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect.
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the present invention.
  • doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • Effective dose parameters The dosage regimen of the (modified) cyclic GFR-binding compounds or functionalised bioactive carriers and/or pharmaceutical compositions as defined herein may be adjusted to obtain effective dose parameters. Effective dose parameters can be determined using methods standard in the art for a particular disease or condition. In particular, the effectiveness of dose parameters of a therapeutic composition as defined herein can be determined by assessing response rates. Such response rates refer to the percentage of treated patients in a population of patients that respond with either partial or complete remission.
  • a pharmaceutical composition as defined herein may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • Unit dose refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, in certain embodiments, one-half or one-third of such a dosage.
  • Single unit dose refers to a dose of any therapeutic association or composition administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
  • split dose refers to the division of single unit dose or total daily dose into two or more doses.
  • Total daily dose refers to an amount given or prescribed in 24hr period. It may be administered as a single unit dose.
  • a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.
  • Combination therapy Compounds, associations, compositions or formulations defined herein may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents.
  • the term "in combination with” is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure.
  • Compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In some embodiments, they are administered within about 90, 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the present disclosure encompasses the delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • therapeutically, prophylactically, diagnostically, or imaging active agents used in combination may be administered together in a single composition or administered separately in different compositions.
  • agents used in combination with be used at levels that do not exceed the levels at which they are used individually. In one example, the levels used in combination will be lower than those utilized individually.
  • the particular combination of therapies to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to mammals, in particular humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts, in particular to any member of the Vertebrate class. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys.
  • the pharmaceutical composition defined herein may be a dermatological composition comprising at least one (modified) cyclic GFR-binding compound or at least one functionalised bioactive carrier, as all defined herein, and at least one dermatologically acceptable excipient.
  • a dermatological composition for the uses of the invention may contain between 0.01 % and 100% by weight (over the total weight of the dermatological composition) of a cyclic GFR-binding compound or functionalised bioactive carrier, both as defined herein, as a dermatological effective amount.
  • the dermatological composition particularly comprises between 0.01 % and 95%, between 0.01 % and 90%, between 0.01 % and 85%, between 0.01 % and 80%, between 0.01 % and 75%, between 0.01 % and 70%, between 0.01 % and 65%, between 0.01 % and 60%, between 0.01 % and 55%, between 0.01 % and 50%, between 0.01 % and 45%, between 0.01 % and 40%, between 0.01 % and 35%, between 0.01 % and 30%, between 0.01 % and 25%, between 0.01 % and 20%, between 0.01 % and 15%, between 0.01 % and 10%, between 0.01 % and 5%, between 0.1 % and 100%, between 0.1 % and 95%, between 0.1 % and 90%, between 0.1 % and 85%, between 0.1 % and 80%, between 0.1 % and 75%, between 0.1 % and 70%, between 0.1 % and 65%, between 0.1 % and 60%, between 0.1 % and 55%, between
  • Dermatologically acceptable means that the compound(s) or pharmaceutical association(s) used are adapted for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, or their equivalents.
  • Suitable formulation for implementing dermatological embodiments of the invention include an aqueous or oil-based solution, a water-based cream or gel or an oily gel, usually in a jar or a tube, particularly a shower gel, shampoo, milk, emulsion, microemulsion or nanoemulsion, particularly oil-in-water or water-in-oil or multiple of silicone-based; a lotion, particularly in a glass or plastic bottle of a spray or aerosol bottle, a blister-pack, liquid soap, a dermatological bar of soap, a pomade, mousse, an anhydrous product, preferably liquid, cream or solid, for example in the form of a stick, particularly in the form of lipstick, a cataplasm or a patch.
  • Preferred administration routes include, but are not limited to, oral, topical or intradermal as already defined herein.
  • Suitable dermatologically acceptable excipients for implementing embodiments of the invention include, but are not limited to, preservatives, emollients, emulsifiers, surfactants, moisturizers, thickeners, conditioners, mattifying agents, stabilizers, antioxidants, texturizing agents, shine agents, filmogenic agents, solubilizers, pigments, colorants, perfumes, and solar filters.
  • excipients are preferably chosen from among the group consisting of amino acids and their derivatives, polyglycerols, esters, polymers and cellulose derivatives, lanoline derivatives, phospholipids, lactoferrins, lactoperoxidases, sucrose-based stabilizers, vitamin E and its derivatives, natural and synthetic waxes, vegetable oils, triglycerides, Méponifiables, phytosterols, plant esters, silicones and their derivatives, protein hydrolysates, jojoba oil and its derivatives, lipo/hydrosoluble esters, betaines, aminoxides, saccharose ester plant extracts, titanium dioxides, glycines, parabens, and even more preferably from among the group consisting of butylene glycol, glycol-15 stearyl ether, cetearyl alcohol, phenoxyethanol, methylparaben, propylparaben, butylparaben, butylenes glycol, natural tocopherols, gly
  • the dermatological composition as defined herein may contain at least one other active agents and/or excipients and/or additives of pharmaceutical, especially dermatological, interest such as agents with the following properties:
  • wound-healing properties such as panthenol and derivatives thereof, for example ethyl panthenol, aloe vera, pantothenic acid and derivatives thereof, allantoin, bisabolol, and dipotassium glycyrrhizinate;
  • anti-inflammatory properties such as steroidal and non-steroidal antiinflammatories, in particular Inhibitors of the production of cytokines and chemokines, of cyclooxygenase, of nitric oxide (NO) and nitric oxide synthase (NOS).
  • cytokines and chemokines of cytokines and chemokines
  • cyclooxygenase of cyclooxygenase
  • NOS nitric oxide synthase
  • anti-inflammatory products mention may be made of extracts of Ginkgo biloba, trilactone terpenes such as ginkgolides, especially ginkgolide B and bilobalide known for their platelet- activating factor (PAF) antagonist properties.
  • PAF platelet- activating factor
  • CTFA Cosmetic Ingredient Handbook Second Edition (1992), which is hereby incorporated by reference in its entirety, describes different cosmetic and pharmaceutical ingredients currently used in the cosmetic and pharmaceutical industry that are particularly adapted to topical use and which may be used in a dermatological composition of the invention.
  • these types of ingredients include but are not limited to the following compounds: abrasives, absorbent compounds, compounds with aesthetic purposes such as perfumes, pigments, colorants, essential oils, astringents, etc.
  • anti-acne agents for example: clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, and hamelis distillate
  • anti-acne agents for example: clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, and hamelis distillate
  • anti-acne agents for example: clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, and hamelis distillate
  • anti-microbial agents for example iodopropyl butylcarbamate
  • les antioxidants bonding agents, biological additives, tampon agents, swelling agents, chelatants, additives, biocidal agents, denaturants, external analgesics, film-forming materials, polymers, opacifying agents, pH adjusters, reducing agents, depigmenting or lightening agents (for example
  • the present disclosure provides a (modified) cyclic G FR-binding compound, a functionalised bioactive carrier, or a dermatological composition, all as defined herein, for use in preventing and/or treating scars and/or inflammations such as gingivitis.
  • the dermatological composition is intended for treating skin in which the dermis is at least partially damaged, especially in subjects who have undergone a surgical operation , or who have been burned and/or injured.
  • This treatment makes it possible to stimulate the proliferation and/or the activity of fibroblasts, in order to stimulate tissue repair and/or dermal reconstruction.
  • the present disclosure provides a (modified) cyclic G FR-binding compound, a functionalised bioactive carrier, or a dermatological composition, all as defined herein, for use in preventing and/or treating at least one of acne, alopecia areata, bowen's disease, congenital erythropoietic porphyria, contact dermatitis, darier's disease, eczema (atopic eczema), epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infections of nails, hailey-hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melasma, pemphigus vulgaris, plantar warts (
  • the present disclosure also provides a dermatological care or treatment method for a subject having need thereof, said method comprising the topical application, intradermal injection or oral administration, preferably the topical application or the intradermal injection, of a (suitable amount of) at least one (modified) cyclic G FR-binding compound, functionalised bioactive carrier, or dermatological composition, all as defined herein.
  • Such a dermatological care or treatment method includes the applications cited herein.
  • Suitable as amounts of (modified) cyclic G FR-binding compounds or functionalised bioactive carrier for implementing embodiments of the invention in the dermatological field include the group consisting of between about 0.0001 ⁇ g/day to about 5000 mg/day, between about 0.0001 ⁇ g/day to about 1000 mg/day, between about 0.0001 ⁇ g/day to about 10 mg/day, between about 0.0001 ⁇ g/day to about 1 mg/day, or between about 0.0001 ⁇ g/day to about 100 ⁇ g/day, all being preferred for implementing embodiments of the invention.
  • the subject who has need thereof is a subject chosen from a population having an average age of more than 30 years old or who has had sunlight over-exposure, has a family history of skin conditions.
  • Preferable dosage forms for the (modified) cyclic G FR-binding compound functionalised bioactive carrier or pharmaceutical composition, all as defined herein, for treating eye retina diseases, disorders or conditions include, for example, in certain embodiments, eye drops and eye ointments. These can be prepared using conventional techniques. For instance, eye drops may be prepared, using isotonic agents such as sodium chloride, buffers such as sodium phosphate, and preservatives such as benzalkonium chloride. A suitable pH is within an ophthalmologically acceptable range. Preferred pH is within pH 4 to 8.
  • Particularly preferred administration routes include vitreal and intraocular.
  • a suitable dose of (modified) cyclic G FR-binding compound, functionalised bioactive carrier, or pharmaceutical composition for treating eye disorders is appropriately selected, depending on the symptoms, age of patients, dosage form and the like.
  • suitable concentration may be 0.0001 to 10 w/v %, preferably 0.0001 to 0.01 w/v % for administration into eyes once or several times a day.
  • the (modified) cyclic G FR-binding compounds, functionalised bioactive carriers, and pharmaceutical compositions, all as defined herein, may be used in surgical methods suitable for protecting (e.g. treating or preventing) a patient or subject from a disease, condition, disorder or pathology to whom a surgical intervention would be beneficial.
  • said surgical method may be selected from the group consisting of bone-repair surgery, cartilage-repair surgery, heart surgery, kidneys or lung surgery, eye surgery, muscle- repair surgery, and tendon/ligament -repair surgery.
  • the present invention thus discloses a surgical method for surgical treatment comprising the contacting of at least one (modified) cyclic G FR-binding compound, at least one functionalised bioactive carrier, a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, or medical device, all as defined herein, with a body part of a patient to be treated, wherein said contacting induces stem cell differentiation and tissue formation.
  • said surgical method comprises the placement or implantation of an implantable medical device comprising a (modified) cyclic G FR-binding compound, a functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, all as defined herein, inside a patient or subject in need of such a surgical treatment.
  • the surgical treatment of the invention may include the use of a placement, insertion or depositing device for contacting said cyclic GFR-binding compound, said functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof with a body part of a patient or subject in need of such a treatment.
  • said placement, insertion or depositing device comprises an injection device such as a syringe.
  • said surgical method comprises the positioning of a cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, all as defined herein, inside said injection device for injection into a patient or into a body part of a patient.
  • said medical device comprises titanium and/or PEEK and/or PET and/or hydrogel and/or ceramic.
  • said medical device replaces part of or all of a body part of a patient or subject.
  • said body part is a malfunctioning or damaged body part such as, for instance, a bone, the skin, the hair scalp, an eye, etc.
  • type I and II growth factor receptors belonging to the serine threonine kinase family.
  • growth factors interact with these receptors by forming specific dimeric or oligomeric structures.
  • the type-ll receptor which is constitutively active, phosphorylates the type-l receptor, which then activates the transduction pathway Smad1/5/8.
  • Receptors of both types are thus conventionally needed to form a functional complex in order to initiate further signaling events.
  • Phosphorylated Smads then dissociate from the receptors and bind Smad4, a common mediator, leading to nuclear translocation, regulation of specific genes, and eventually may induce tissue regeneration.
  • a (modified) cyclic GFR-binding compound or a functionalised bioactive carrier of the present disclosure may be one such exogenous entity or molecule.
  • medical treatments may demonstrate the effect of the influence of an exogenous entity or molecule on human mesenchymal stem cells using a medical device onto or into which such an exogenous entity or molecule has been reversibly or irreversibly incorporated or deposited, both being equally preferred, and placed into a patient in need thereof.
  • medical treatments may provide the effect of the influence of an exogenous entity or molecule on human mesenchymal stem cells using a pharmaceutical composition containing such an exogenous entity or molecule and a pharmaceutically acceptable excipient or carrier, administered, for instance, orally, enterically, intravenously, peritoneally, subcutaneously, transdermal ⁇ , parenterally, or rectally, to a patient in need of such a treatment.
  • compounds or compositions of the present invention may be injected at a target site so that they can be delivered in close proximity to the cells to be treated via, e.g. a PTD or cell-permeable peptide.
  • a PTD or cell-permeable peptide e.g. a PTD or cell-permeable peptide.
  • an implant or medical device or implantable medical device comprising a PTD/cyclic GFR-binding compound complex may be used.
  • the present invention generally provides for uses and methods of inducing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation and/or inducing, promoting, enhancing, controlling or regulating tissue regeneration/formation in-vitro, ex-vivo and in-vivo.
  • such a tissue formation process is generally achieved within less than 7 days.
  • such a tissue formation process is generally achieved within less than 6 days.
  • such a tissue formation process is generally achieved within less than 5 days.
  • such a tissue formation process is generally achieved within less than 4 days.
  • such a tissue formation process is generally achieved within less than 3 days.
  • such a tissue formation process is generally achieved within less than 2 days.
  • such a tissue formation process is generally achieved within less than 24 hours.
  • such a tissue formation process is generally achieved within less than 18 hours.
  • the present disclosure provides a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein for use in a method of non-mutagenically inducing tissue formation i.e. without modifying or altering the genome of the treated cells, in-vitro, ex-vivo or in-vivo.
  • a method of inducing tissue formation i.e. without modifying or altering the genome of the treated cells, comprising the in-vitro, ex-vivo or in-vivo administration of an effective amount of a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein.
  • the present disclosure provides a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein for use in a method of extracellular induction of tissue formation.
  • a method of extracellular tissue formation induction comprising the in-vitro, ex-vivo or in-vivo administration of an effective amount of a (modified) cyclic GFR- binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein.
  • an extracellular treatment as used herein implies a biological action/effect to be provided or to occur outside the cell to be treated (i.e. a mesenchymal stem cell).
  • the biologically active agent e.g. the cyclic GFR-binding compound or the pharmaceutical composition as defined herein
  • said active agent may be, for instance, excreted from the host organism with or without being metabolised, and/or tagged to be destroyed through apoptotic routes, and/or internalised by nearby cells, etc...
  • the present disclosure provides a method of producing a physiologically functional and healthy cell, comprising the administration in-vitro, ex-vivo or in-vivo to a mesenchymal stem cell or progenitor cell (at any stage of differentiation) of an effective amount of a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein and wherein said physiologically functional and healthy cell is selected from the group consisting of an osteoblast, osteocyte, chondroblast, chondrocyte, neuroblast, neurocyte, Sertoli cells, Leydig cell, Germ cell, Myoblast, Myocyte, keratinocyte, endothelial cells, angioblast, fibroblast, fibrocyte, podocyte, areolar connective cells, adipocytes, pre- adipocytes/lipoblasts, epithelial cells, erythrocytes, alveolar
  • the present disclosure provides methods to activate a growth factor receptor present on the surface of a mesenchymal stem cell or progenitor cell (at any stage of differentiation), said method comprising administering to said mesenchymal stem cell or progenitor cell (at any stage of differentiation) an effective amount of a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein, wherein administering said cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein activates the growth factor receptor present on the surface of the mesenchymal stem cell or progenitor cell (at any stage of differentiation).
  • the present disclosure provides methods of delivering a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, in-vitro, ex-vivo or in-vivo to a mesenchymal stem cell or progenitor cell (at any stage of differentiation), comprising the contacting of said mesenchymal stem cell or progenitor cell (at any stage of differentiation) with said (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition.
  • the present disclosure provides methods of administering a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, to a patient or subject comprising the contacting of at least one body part of said patient or subject with said (modified) cyclic GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition.
  • the (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a mammal (preferably a human) tissue-inductive compound, bioactive carrier or composition, which has demonstrated the ability to induce tissue formation in vitro and/or in vivo.
  • the present disclosure provides an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a medical method such as in therapy, surgery or in diagnostic methods.
  • the present disclosure provides a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation, the method comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein.
  • the present invention discloses an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation
  • the present disclosure provides a method of inducing or promoting or enhancing or controlling or regulating tissue regeneration/formation, the method comprising administering to a mesenchymal stem cell or to a progenitor cell at any stage of differentiation or to a mature cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein.
  • the present invention discloses an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing or promoting or enhancing or controlling or regulating tissue regeneration/formation.
  • the present disclosure provides a method of inducing and/or promoting and/or enhancing cell motility or single/collective cell migration, the method comprising administering to a mesenchymal stem cell or to a progenitor cell at any stage of differentiation or to a mature cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein.
  • the present invention discloses an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing and/or promoting and/or enhancing cell motility or single/collective cell migration.
  • the present invention discloses a method of inducing and/or promoting and/or enhancing cell maturation, the method comprising administering to a differentiated cell or to a mature cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein.
  • the present invention discloses an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing and/or promoting and/or enhancing cell maturation.
  • the (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be combined/mixed with adult stem cells and/or multipotent progenitor cells prior to be administered or implanted into a mammal (preferably a human) to promote tissue regeneration.
  • the (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be administered as such and may be combined/mixed with adult stem cells and/or multipotent progenitor cells prior to administration to a mammal (preferably a human) to promote tissue regeneration.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of osteogenesis, inducing bone formation, inducing osteocyte maturation, and/or treating and/or preventing osteoporosis.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may thus be an osteoinductive compound, bioactive carrier or composition which has demonstrated an ability to induce bone formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor osteoblast (at any stage of differentiation of the Osteoblast cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating bone tissue regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor osteoblast at any stage of differentiation of the osteoblast cell lineage or to a mature osteoblast, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing osteocyte maturation comprising administering to a differentiated osteoblast or to a mature osteoblast (e.g. an osteocyte) an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor osteoblast (at any stage of differentiation of the osteoblast cell lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing osteoblast maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of chondrogenesis and/or inducing cartilage formation, and/or inducing chondrocyte maturation and/or treating and/or preventing at least one of osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a chondroinductive compound, bioactive carrier or composition which has demonstrated the ability to induce cartilage formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor chondroblast (at any stage of differentiation of the chondrocytic cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating cartilage tissue regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor chondroblast (at any stage of differentiation of the chondrocytic cell lineage) or to a mature chondroblast, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing chondrocyte maturation comprising administering to a differentiated chondroblast or to a mature osteoblast (e.g. a chondrocyte) an effective amount of at least one cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing chondroblast maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of endothelization and/or vascularization/angiogenesis and/or treating and/or preventing at least one of coronary artery disease (also known as coronary heart disease and ischemic heart disease), cardiomyopathy, hypertensive heart disease, heart failure, cor pulmonale, cardiac dysrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, or rheumatic heart disease.
  • coronary artery disease also known as coronary heart disease and ischemic heart disease
  • cardiomyopathy hypertensive heart disease
  • heart failure also known as coronary heart disease and ischemic heart disease
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be an endothelization/vascularization/angiogenesis -promoting compound, bioactive carrier or composition which has demonstrated the ability to induce vascular tissue formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor endothelial cell (at any stage of differentiation of the vascular cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating vascular tissue regeneration/formation and/or tubular formation comprising administering to a mesenchymal stem cell or to a progenitor endothelial cell at any stage of differentiation of the vascular cell lineage or to a mature endothelial cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing cell motility or single/collective endothelial cell migration and/or angiogenesis comprising administering to a mesenchymal stem cell or to a progenitor endothelial cell at any stage of differentiation of the vascular cell lineage or to a mature endothelial cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein.
  • a method of inducing and/or promoting and/or enhancing endothelial cell maturation comprising administering to a differentiated endothelial cell or to a mature endothelial cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor endothelial cell (at any stage of differentiation of the vascular cell lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating vascular tissue regeneration/formation and/or tubular formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing cell motility or single/collective endothelial cell migration and/or angiogenesis,
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing endothelial cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing axonal dendritic neuron growth thus promoting neuron-regeneration and/or treating and/or preventing and/or decreasing or suppressing neuron degeneration-related conditions and diseases.
  • neuroneuron-regeneration or “neuroregeneration” means the regrowth or repair of nervous tissues, cells or cell products involving the participation of stem cells. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses.
  • Neurological disorders in which the present invention may thus be useful include, but are not limited to, ALS, Agraphia Alzheimer's disease, Amyotrophic lateral sclerosis, Angle man syndrome, Aphasia Apraxia, Arachnoiditis, Ataxia Telangiectasia, Attention deficit hyperactivity disorder, Auditory processing disorder, Autism, Alcoholism , asperger's syndrome, Bipolar disorder, Bell's palsy, Brachial plexus injury, Brain damage, Brain injury, Canavan disease, Capgras delusion, Causalgia, Central pain syndrome, Central pontine myelolysis, Centronuclear myopathy, Cephalic disorder, Cerebral aneurysm , Cerebral arteriosclerosis, Cerebral atrophy, Cerebral gigantism , Cerebral palsy, Cerebral vasculitis, Cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, Chorea, Chronic fatigue syndrome, Chronic inflammatory dem
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a neuroregenerative or neurodegeneration regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to induce neuroregeneration and/or prevention, decrease or suppression of neuron degeneration in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides : a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor neuronal cell (at any stage of differentiation of the neuronal cell lineage) differentiation, the method comprising administering to the cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating neuron regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor neuronal cell at any stage of differentiation of the neuronal cell lineage or to a mature neuron, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing neuronal cell maturation comprising administering to a differentiated neuronal cell or to a mature neuronal cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor neuronal cell (at any stage of differentiation of the neuronal cell lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating neuron regeneration/formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing neuronal cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting eye retina cell regeneration and/or treating and/or preventing and/or decreasing or suppressing eye retina cell degeneration-related conditions or diseases.
  • Eye-related diseases or disorders in which the present invention may thus be useful include, but are not limited to, Focal chorioretinal inflammation
  • Focal such chorioretinitis, choroiditis, retinitis and retinochoroiditis, Disseminated chorioretinal inflammation, Posterior cyclitis, Harada's disease, Chorioretinal scars such as Macula scars of posterior pole and Solar retinopathy, Choroidal degeneration such as Atrophy and Sclerosis, Hereditary choroidal dystrophy such as Choroideremia, Gyrate atrophy, Choroidal haemorrhage, Choroidal detachment, Chorioretinitis, Retinal detachment, Retinoschisis, Retinal vascular occlusions, Hypertensive retinopathy, Diabetic retinopathy, Retinopathy, Retinopathy of prematurity, Age-related macular degeneration, Macular degeneration, Epiretinal
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be an eye tissue-regenerative or eye tissue-degeneration regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to induce eye retina cell regeneration and/or prevent and/or decrease or suppress eye retina cell degeneration in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor eye retina cell (at any stage of differentiation of the retinal cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating eye retina cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor eye retina cell at any stage of differentiation of the retinal cell lineage or to a mature eye retina cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing eye retina cell maturation comprising administering to a differentiated eye retina cell or to a mature eye retina cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor eye retina cell (at any stage of differentiation of the retinal cell lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating eye retina cell regeneration/formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing eye retina cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting renal functions such as enhancing/improving waste removal, body's fluid balance control and electrolytes balance control and/or preventing/treating kidneys failure and/or chronic kidney disease (CKD) and/or renal fibrosis.
  • CKD chronic kidney disease
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a kidneys-function enhancing compound, bioactive carrier or composition which has demonstrated the ability to promote/improve kidneys functions and/or preventing/treating kidneys failure and/or chronic kidney disease (CKD) and/or renal fibrosis in vitro and/or ex-vivo and/or in vivo.
  • CKD chronic kidney disease
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor renal cell (at any stage of differentiation of the renal cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating renal cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor renal cell at any stage of differentiation of the renal cell lineage or to a mature renal cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing renal cell maturation comprising administering to a differentiated renal cell or to a mature renal cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor renal cell (at any stage of differentiation of the renal cell lineage) differentiation; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating renal cell regeneration/formation;
  • medical applications which may result from the mediation of type I and I I growth factor receptors by a cyclic G FR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein , include, but are not limited to, enhancing/promoting fibrous tissue formation and tendon and ligament regeneration and/or preventing and/or decreasing or suppressing tendon/ligament cell degeneration.
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a fibrous tissue formation promoting compound, bioactive carrier or composition which has demonstrated the ability to induce fibrous tissue formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides :
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor tendon/ligament cell (at any stage of differentiation of the T/L cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic G FR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein ;
  • a method of inducing or promoting or enhancing or controlling or regulating tendon/ligament cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor tendon/ligament cell at any stage of differentiation of the T/L cell lineage or to a mature tendon/ligament cell, an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein ;
  • a method of inducing and/or promoting and/or enhancing tendon/ligament cell maturation comprising administering to a differentiated tendon/ligament cell or to a mature tendon/ligament cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein ;
  • At least one (modified) cyclic G FR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor tendon/ligament cell (at any stage of differentiation of the T/L cell lineage) differentiation ;
  • At least one (modified) cyclic G FR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing tendon/ligament cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, hair follicle tissue regeneration and formation (hair growth), hair follicle stem cell activation (loss of quiescence state) and/or preventing/treating alopecia areata, alopecia totalis, alopecia universalis, androgenic alopecia (male pattern baldness), telogen effluvium, anagen effluvium or chemotherapy-induced alopecia.
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a hair follicle growth activation promoting compound, bioactive carrier or composition which has demonstrated the ability to induce hair follicle formation and/or hair follicle stem cell activation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor hair follicle cell (at any stage of differentiation of the hair follicle cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating hair follicle cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor hair follicle cell at any stage of differentiation of the hair follicle cell lineage or to a mature hair follicle cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing hair follicle cell maturation comprising administering to a differentiated hair follicle cell or to a mature hair follicle cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of activating hair follicle stem cells comprising administering to a quiescent hair follicle stem cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor hair follicle cell (at any stage of differentiation of the hair follicle cell lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating hair follicle cell regeneration/formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing tendon/ligament cell maturation;
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing tissue closure.
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a tissue-closure-promoting compound or biomaterial which has demonstrated the ability to induce tissue closure in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing tissue closure comprising administering to an incised/opened tissue an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • medical applications which may result from the mediation of type I and II growth factor receptors by a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting female fertility and/or preventing and/or decreasing or suppressing female infertility.
  • a cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a female fertility enhancing or a female infertility regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to enhance/promote female fertility and/or prevent and/or decrease or suppress female infertility in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides: a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor ovarian cell (at any stage of differentiation of the reproduction system lineage) differentiation, the method comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating ovarian cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor ovarian cell at any stage of differentiation of the reproduction system lineage or to a mature ovarian cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing ovarian cell maturation comprising administering to a differentiated ovarian cell or to a mature ovarian cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor ovarian cell (at any stage of differentiation of the reproduction system lineage) differentiation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating ovarian cell regeneration/formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing ovarian cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of myogenesis, inducing muscle tissue formation, reinforcing muscle tissues, inducing myocyte maturation, repairing damaged muscles, preventing muscle tissue degeneration or damages, and/or protecting a subject from one or more muscle tissue-related diseases, disorders, conditions or pathologies.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may thus be an myoinductive compound, bioactive carrier or composition which has demonstrated an ability to induce muscle tissue formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor myoblast (at any stage of differentiation of the muscle cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating muscle tissue regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor myoblast at any stage of differentiation of the muscle cell lineage or to a mature myoblast, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing myocyte maturation comprising administering to a differentiated myoblast or to a mature myoblast (e.g. an myocyte) an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing myoblast maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing blood tissue regeneration, inducing blood cell differentiation, or protecting a patient from a blood cell degeneration-related disease, condition, disorder, or pathology.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may thus be a blood cell degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce blood cell formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor blood cell (at any stage of differentiation of the Osteoblast cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating blood cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor blood cell at any stage of differentiation of the blood cell lineage or to a mature blood cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing blood cell maturation comprising administering to a differentiated blood cell or to a mature blood cell (e.g. a mature red blood cell) an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing blood cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of lung tissue regeneration, inducing lung cell differentiation, or protecting a patient from a lung cell degeneration-related disease, condition, disorder, or pathology.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may thus be a lung cell degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce lung cell formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor lung cell (at any stage of differentiation of the Osteoblast cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR- binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating lung cell regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor lung cell at any stage of differentiation of the lung cell lineage or to a mature lung cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing lung cell maturation comprising administering to a differentiated lung cell or to a mature lung cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor lung cell (at any stage of differentiation of the lung cell lineage) differentiation; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating lung cell regeneration/formation;
  • At least one (modified) cyclic GFR-binding compound at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing and/or promoting and/or enhancing lung cell maturation.
  • medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing adipose tissue regeneration, inducing adipocyte differentiation, or protecting a patient from a adipose tissue degeneration-related disease, condition, disorder, or pathology.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may thus be an adipose tissue degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce adipose tissue formation in vitro and/or ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor adipocyte (at any stage of differentiation of the Osteoblast cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing or promoting or enhancing or controlling or regulating adipose tissue regeneration/formation comprising administering to a mesenchymal stem cell or to a progenitor adipocyte at any stage of differentiation of the adipocyte lineage or to a mature adipocyte, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein;
  • a method of inducing and/or promoting and/or enhancing adipocyte maturation comprising administering to a differentiated adipocyte or to a mature adipocyte an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor adipocyte (at any stage of differentiation of the adipocyte lineage) differentiation; an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition, all as defined herein for use in a method of inducing or promoting or enhancing or controlling or regulating adipose tissue regeneration/formation
  • Protected from a disease, condition, disorder or pathology refers to the treatment of the underlying cause of the disease, condition, disorder or pathology as well as reducing the symptoms of the disease, condition, disorder or pathology; and/or reducing the occurrence of the disease, condition, disorder or pathology; and/or reducing the severity of the disease, condition, disorder or pathology.
  • Protecting a patient can refer to the ability of a therapeutic composition of the present invention, when administered to a patient, to prevent a disease, condition, disorder or pathology from occurring and/or to cure or to alleviate disease, condition, disorder or pathology symptoms, signs or causes.
  • to protect a patient from a disease, condition, disorder or pathology includes both preventing disease, condition, disorder or pathology occurrence (prophylactic treatment) and treating a patient that has a disease, condition, disorder or pathology or that is experiencing initial symptoms or later stage symptoms of a disease, condition, disorder or pathology (therapeutic treatment).
  • Treating refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, pathology and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, pathology and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • the term "preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.
  • disease refers to any deviation from the normal health of a patient and includes a state when disease symptoms are present, as well as conditions in which a deviation has occurred, but symptoms are not yet manifested. The same applies to "condition”, “disorder” and "pathology”.
  • the present disclosure provides methods of determining the effectiveness of a (modified) cyclic GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition as defined herein for inducing cell differentiation, or inducing, promoting, enhancing, controlling or regulating tissue regeneration/formation in-vitro, ex-vivo and in-vivo comprising the administration of said (modified) cyclic GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition to a cell; the measurement of the expression of specific differentiation markers as defined herein in the cell; the comparison of the expression of said specific differentiation markers in the cell to the expression of said specific differentiation markers in a cell treated with a reference (or control) functionalised bioactive carrier, compound or solvent; and determining the effectiveness of the (modified) cyclic GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition relative to the reference pharmaceutical association or compound.
  • the present disclosure provides methods to activate, promote, support, improve, or increase the activity of a growth factor receptor present in, on the surface of a mesenchymal stem cell or progenitor cell (at any stage of differentiation thereof) such that said cell may undergo efficient cell differentiation.
  • the present disclosure provides methods of identifying, diagnosing, and optionally classifying subjects on these bases, which may include clinical diagnosis, biomarker levels, and other methods known in the art.
  • dermatological applications which may result from the mediation of type I and II growth factor receptors by a compound, functionalised bioactive carrier, or composition of the invention include, but are not limited to, enhancing wound healing, skin repair and cellular migration.
  • Skin repair means dermal and epidermal cells regeneration, collagen and other skin protein synthesis by epithelial cells.
  • cellular migration means a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations.
  • the cells involved in cellular migration include the cells of the epithelial and dermal cell lineages forming the connective tissue i.e. the fibroblasts, fibrocytes, myofibroblasts, adipocytes, synoviocytes, macrophages, histiocytes, granulocytes, plasmocytes and mastocytes.
  • a (modified) cyclic GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition may be a wound-healing-promoting compound, bioactive carrier, or composition which has demonstrated the ability to induce wound healing, skin repair and/or cellular migration in vitro, ex-vivo and/or in vivo.
  • the present disclosure thus provides:
  • a method of inducing or promoting or enhancing mesenchymal stem cell, progenitor epithelial cell (at any stage of differentiation of the epithelial and dermal cell lineage) differentiation comprising administering to the cell an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition of the invention;
  • a method of inducing or promoting or enhancing or controlling or regulating skin tissue regeneration/formation and/or tubular formation comprising administering to a mesenchymal stem cell or to a progenitor epithelial cell at any stage of differentiation of the epithelial and dermal cell lineage or to a mature epithelial cell, an effective amount of at least one (modified) cyclic GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical composition of the invention;

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Abstract

La présente invention concerne un peptide cyclique, ou un variant ou un analogue de celui-ci, ou un peptidomimétique cyclique, présentant entre 10 et 35 acides aminés, ayant une capacité de liaison au récepteur du facteur de croissance et comprenant un peptide présentant cinq acides aminés PEP2 ; PEP2 étant choisi dans le groupe constitué de LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV et KKATV.
PCT/EP2016/070136 2015-08-25 2016-08-25 Composés pour induire la formation tissulaire et leurs utilisations WO2017032859A2 (fr)

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WO2021054449A1 (fr) * 2019-09-18 2021-03-25 国立大学法人 岡山大学 Production de lbm, cpc, opc, et procédés de contrôle de qualité correspondants, kit, matériau de greffe et modèle de maladie

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US20020068301A1 (en) * 1997-05-28 2002-06-06 Hung-Sen Lai Cyclic peptide libraries and methods of use thereof to identify binding motifs
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FR3003173B1 (fr) * 2013-03-14 2016-08-19 Teknimed Substituts osseux greffes par des peptides mimetiques de la proteine humaine bmp-2.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021054449A1 (fr) * 2019-09-18 2021-03-25 国立大学法人 岡山大学 Production de lbm, cpc, opc, et procédés de contrôle de qualité correspondants, kit, matériau de greffe et modèle de maladie

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