[go: up one dir, main page]

US20070009575A1 - Novel use of antisecretory factor - Google Patents

Novel use of antisecretory factor Download PDF

Info

Publication number
US20070009575A1
US20070009575A1 US10/573,601 US57360106A US2007009575A1 US 20070009575 A1 US20070009575 A1 US 20070009575A1 US 57360106 A US57360106 A US 57360106A US 2007009575 A1 US2007009575 A1 US 2007009575A1
Authority
US
United States
Prior art keywords
cells
seq
cell
condition
amino acids
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/573,601
Other languages
English (en)
Inventor
Hans-Arne Hansson
Eva Jennische
Stefan Lange
Ivar Lonnroth
Peter Eriksson
Anders Persson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AS FAKTOR AB
Original Assignee
AS FAKTOR AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AS FAKTOR AB filed Critical AS FAKTOR AB
Assigned to AS FAKTOR AB reassignment AS FAKTOR AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PERSSON, ANDERS, ERIKSSON, PETER, HANSSON, HANS-ARNE, JENNISCHE, EVA, LANGE, STEFAN, LONNROTH, IVAR
Publication of US20070009575A1 publication Critical patent/US20070009575A1/en
Priority to US12/659,142 priority Critical patent/US8748367B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of peptides, polypeptides and proteins, comprising certain elements of the group of proteins called Antisecretory Factor (AF) in the manufacture of a medicament for treating and/or preventing a condition that is characterised by or associated with the pathological loss and/or gain of cells or hyperproduction or abnormal degradation rate of proteins, expressed in the cell, such as at pathological degeneration, or loss of control of repair, recovery and/or regeneration of differentiated cells and/or tissues, including stem cells or progenitor cells, or medical conditions characterised by or associated with such conditions including damage to the brain and other parts of the nervous system by trauma, asphyxia, toxins, hypoxia, ischemia, infections or degenerative or metabolic insults, resulting in defect, hampered or otherwise abnormal structure and function.
  • AF Antisecretory Factor
  • the present invention relates to a method of propagating, inducing, reducing and/or maintaining the genesis of an isolated stem cell, and a method of treatment.
  • Examples on a degenerative condition in the CNS are Parkinson and Alzheimer desease, either of which often causes loss of specific populations of cells. The former is in particular associated with the specific loss of dopaminergic neurons in the substantia nigra.
  • multiple sclerosis is associated with structural and functional affection of axons as well as loss of myelin and oligodendrocytes.
  • Another illustration of a degenerative disorder caused by a loss of neurons is Alzheimer's disease.
  • CNS, PNS and ANS injuries or diseases are associated with damage to oligodendroglia, astroglia, satellite cells, Schwann cells, microglia, vascular cells and neurons.
  • progenitor cells there exists an omnipotent cell population in the brain, named the progenitor cells, as in other tissues in the body of adult mammals, including humans.
  • Neuronal progenitor cells are stem cells and reside in the subventricular zone (SVZ) at the lateral ventricles of the brain and in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, where such cells continuously proliferate, and migrate into the adjacent brain structures, and eventually either degenerate or survive and differentiate.
  • SVZ subventricular zone
  • SGZ subgranular zone
  • the new-born neurons preferentially in e.g.
  • the SGZ migrate into the granule cell layer of the hippocampus and eventually express markers of differentiated neurons and have morphological characteristics corresponding to differentiated granular cells, establish axonal processes into the mossy fibre pathway and form synaptic connections with their targets in the hippocampus. (Ref. 5) It ought to be stressed that a considerable proportion of such newly formed cells may degenerate if not adequately stimulated, while others gain glial cell characteristics (Ref. 3, 4, 5).
  • the neurogenesis in the dentate gyrus is in itself especially interesting as the hippocampus is intimately associated with spatial learning and memory (Ref. 6).
  • the neurogenesis in the SVZ is via the rostral migratory stream supplying the olfactory lobe with new nerve cells, but at e.g. stroke and neurotrauma may the migrating primitive neuronal progenitor cells deviate to the injured or diseased site, if situated in reasonable vicinity to the migrating precursor cells.
  • the proliferation of progenitor cells in the SVZ and in the SGZ are influenced by e.g. the administration of growth factors, interleukines, N-methyl-d-aspartate (NMDA) receptor antagonist or by the removal of the adrenal glands, which latter results in reduced levels of or absence of corticosteroid hormones (Ref. 7, 8). Additionally, the exposure to an enriched environment is accompanied by an increased number of surviving, newly formed granule cells as well as by increased total number of surviving neurons in e.g. the dentate gyrus (Ref.9). The formation of new nerve cells turns reduced with age (Ref. 3).
  • NMDA N-methyl-d-aspartate
  • Diminishing the inflammatory reaction in a nervous tissue after an injury or a disease is beneficiary and results in an increased number of surviving neurons, improved and extended formation of synapses and reduced astrocytosis, concomitant with less hampering effects on the blood vessels and associated structures and thereby the circulation.
  • a weak to moderate inflammation is beneficial with regard to the repair and to restorative events as well as to the neurogenesis, while a strong inflammation is detrimental and may result in an accentuated loss of cells and tissue, that otherwise might have recovered.
  • the antisecretory factor is a class of proteins occurring naturally in the body.
  • the common knowledge of the Antisecretory Factor is summarised by Lange & Lönnroth (Ref. 1.). Its structure and some effects exerted by AF in the body of animals, including in man, is described in patent No WO97/08202 (Ref. 10).
  • the human AF protein is a 41 kD protein, when isolated from the pituitary gland, comprising 382 amino acids.
  • the active site with regard to anti-inflammatory and antisecretory effects in AF is seemingly localized to the protein in a region close to the N-terminal parts of the AF, localized to no 1-163, or more preferably 36-52 or 36-44, or modifications thereof.
  • AF proteins are to some extent homologous with the protein S5a, also named Rpn 10, which constitute a subunit of a constituent prevailing in all cells, the 26 S proteasome, more specifically in the 19 S/PA 700 cap.
  • AF proteins are defined as a class of homologous proteins having the same functional properties.
  • the proteasomes have a multitude of functions related to the degradation of surplus proteins as well as short-lived, unwanted, denatured, misfolded and otherwise abnormal proteins.
  • the AF/S5a/Rpn10 is involved in the distribution and transportation of cell constituents, most evidently proteins.
  • AF's and fragments thereof are capable of improving the repair of nervous tissues, as well as mediating and/or reducing the effects of trauma, inflammations and at progressive degenerations, as determined by reduced loss of nervous tissue, and by inhibiting the formation of, or improving the break-down of, ⁇ -amyloid and other tissue constituents otherwise accumulating, thereby rescuing the tissue.
  • Beneficial effects have been documented for e.g. vascular constituents as well.
  • AF and fragments thereof are further capable of rescuing nervous tissue constituents and support proliferation of progenitor cells prevailing in the adult CNS. This suggests a new and exiting mode of action in that AF and its fragments could mediate the rescuing and survival of affected cells, as well as facilitating proliferation and migration of stem and progenitor cells in the SVZ and SGZ.
  • AF and certain fragments thereof can modulate the destruction, repair, regeneration of nervous tissue constituents, migration and differentiation of progenitor cells and the formation of synapses between existing cells and new cells, facilitating synapse formation and functional recovery as well as decreasing the rate and extent of degeneration and tissue destruction.
  • the present invention thus provides a new and improved means to treat injuries to, dysfunctions of, diseases in or disorders of the CNS, PNS and/or ANS, inter alia, and thereby provides possibilities for beneficial influence on the function of the tissue.
  • New neurons, glial cells and tentatively also vascular cells are generated by the proliferation of stem or progenitor cells.
  • certain AF fragments rescue nervous tissue, and induced an increased formation of new cells, including processes and synapses between cells.
  • amino acids are named according to the in biochemistry commonly used abbreviations based on the use of a single letter to identify each amino acid.
  • the present invention relates to the use of
  • X1 is I, amino acids nos. 1-35 of SEQ ID NO:1, or is absent
  • X2 is H, R or K
  • X3 is S or L
  • X4 is T or A
  • X5 is amino acids nos. 43-46, 43-51, 43-80 or 43-163 of SEQ ID NO:1, or is absent;
  • SEQ ID NO: 1 is the amino acid sequence of the anti-secretory factor polypeptide or protein as given in Johansson, E. et al. (Ref. 13) or Lange, S et al. (Ref. 10, 14)
  • the present invention relates to the use of an antisecretory protein inducing food in the manufacture of a food or medical food for the treatment and/or prevention of a condition associated with or characterised by rescue or by a pathological loss and/or gain of cells and/or brain oedema.
  • the present invention relates to the use of an egg yolk with a high level, preferably at least 1000 FIL units/ml, of antisecretory protein or homologues thereof having the same functional properties, in the manufacture of a food or a medical food for the treatment and/or prevention of a condition associated with or characterised by rescue or by a pathological loss and/or gain of cells and/or brain oedema.
  • the condition is characterised by displaying a pathological degeneration of, loss of ability and/or loss of control of regeneration of and/or loss of control of regeneration of a differentiated cell and/or tissue, an embryonic stem cell, an adult stem cell, a progenitor cell and/or a cell derived from a stem cell or progenitor cell.
  • the condition is associated with or characterised by a pathological loss and/or gain of cells in the peripheral nervous system, autonomic nervous system and/or central nervous system, and in yet another embodiment the condition is associated with or characterised by rescue or by a pathological loss and/or gain of neural stem cells or neural progenitor cells.
  • the condition is associated with or characterised by a pathological loss and/or gain of oligodendroglia, astroglia, Schwann cells, and/or neuronal cells and/or cell populations, and in another the condition is associated with or characterised by a pathological loss and/or gain of non-cholinergic neuronal cells, cholinergic neuronal cells and/or glial cells, and/or cell populations.
  • condition is caused by damage to the central nervous system or a defect in the central nervous system, and in yet another one the condition is caused by a traumatic, malignant, inflammatory, auto-immune or degenerative disorder.
  • condition is caused by axonal damage caused by concussion, contusion, axonal damage caused by head trauma, axonal damage caused by small vessel disease in the CNS and/or damage to the spinal cord after disease and/or trauma, in another embodiment said condition is characterised by memory loss, and finally in a last embodiment of the new uses the condition is brain oedema, multiple sclerosis, asphyxia, hypoxic injury,.ischemic injury, traumatic injury, Parkinson's disease, Alzheimer's disease, stroke, Mérier's disease or demyelinating disorder.
  • the present invention relates to The use of an egg yolk with a high level of antisecretory proteins or homologues thereof having the same functional properties according to any one of new uses as described above.
  • the present invention relates to the use of a food and/or drinking solution inducing the formation of antisecretory proteins or homologues thereof having the same functional properties according to any one of new uses as described above.
  • the medicament is formulated for intravenous infusion, intramuscular injection and/or subcutaneous injection
  • the medicament is formulated-so that the active substance will pass into the ventricles and/or other cavities at or in a patient's brain when it is administered to said patient
  • the medicament is formulated so that the active substance will pass into the cerebrospinal fluid of a patient when it is administered to said patient.
  • the present invention relates to a method of propagating, inducing, reducing and/or maintaining the genesis of an isolated stem cell and/or stem cell progeny from any germinal layer in vitro, characterised by treating the isolated cell with an antisecretory protein or homologues thereof having the same functional properties, or an oligo- or polypeptide or derivatives thereof comprising an amino acid sequence of Formula I: X1-V-C-X2-X3-K-X4-R-X5 (Formula I) wherein
  • X1 is I, amino acids nos. 1-35 of SEQ ID NO:1, or is absent
  • X2 is H, R or K
  • X3 is S or L
  • X4 is T or A
  • X5 is amino acids nos. 43-46, 43-51, 43-80 or 43-163 of SEQ ID NO:1, or is absent,
  • said isolated cell is chosen from the group comprising epithelial cells, fibroblasts, osteogenic cells, macrophages and microglial cells, vascular cells, bone cells, chondrocytes, myocardial cells, blood cells, neurons, oligodendrocytes, astroglial cells, progenitor cells, stem cells and/or cells derived from progenitor cells or stem cells.
  • the present invention relates to a method of treatment and/or prevention of a condition associated with or characterised by a pathological loss and/or gain of cells, comprising administering to a patient in need thereof an effective amount of an antisecretory protein, or an oligo- or polypeptide or derivatives thereof comprising an amino acid sequence of Formula I: X1-V-C-X2-X3-K-X4-R-X5 (Formula I) wherein
  • X1 is I, amino acids nos. 1-35 of SEQ ID NO:1, or is absent
  • X2 is H, R or K
  • X3 is S or L
  • X4 is T or A
  • X5 is amino acids nos. 43-46, 43-51, 43-80 or 43-163 of SEQ ID NO:1, or is absent,
  • the Formula I has a sequence chosen from one of:
  • the condition is characterised by displaying a pathological degeneration of, loss of ability and/or loss of control of regeneration of and/or loss of control of regeneration of a differentiated cell and/or tissue, an embryonic stem cell, an adult stem cell, a progenitor cell and/or a cell derived from a stem cell or progenitor cell, and in still another one the condition is associated with or characterised by a pathological loss and/or gain of cells in the peripheral, autonomic or central nervous system.
  • condition is associated with or characterised by a pathological loss and/or gain of neural stem cells or neural progenitor cells, and in still another one the condition is associated with or characterised by a pathological loss and/or gain of oligodendroglial, astroglial, Schwann cells, and/or neuronal cells and/or cell populations.
  • condition is associated with or characterised by a pathological loss and/or gain of non-cholinergic neuronal cells, cholinergic neuronal cells and/or glial cells, and/or cell populations, and in still another one the condition is caused by damage to the central nervous system or a defect in the central nervous system.
  • condition is caused by a traumatic, malignant, inflammatory, auto-immune or degenerative disorder
  • condition is caused by axonal damage caused by concussion, contusion, axonal damage caused by head trauma, axonal damage caused by small vessel disease in the CNS and/or damage to the spinal cord after disease and/or trauma
  • condition is characterised by memory loss
  • the condition is brain oedema, multiple sclerosis, asphyxia, hypoxic injury, ischemic injury, traumatic injury, Parkinson's disease, Alzheimer's disease, stroke, Mérier's disease or demyelinating disorder.
  • the antisecretory protein or homologues thereof having the same functional properties, or the oligo- or polypeptide or derivatives thereof is formulated into a medicament for intravenous infusion, intramuscular injection and/or subcutaneous injection, in yet another one the antisecretory protein or homologues thereof having the same functional properties, or the oligo- or polypeptide or derivatives thereof is formulated into a medicament so that the active substance will pass into the ventricles and/or other cavities in and/or at a patient's brain when it is administered to said patient, and in a final one the antisecretory protein or homologues thereof having the same functional properties, or the oligo- or polypeptide or derivatives thereof is formulated into a medicament so that the active substance will pass into the cerebrospinal fluid of a patient when it is administered to said patient.
  • the present invention relates to a method of propagating, inducing, reducing and/or maintaining the genesis of an isolated stem cell and/or stem cell progeny from any germinal layer from a patient, characterised by:
  • the present invention relates to a method of propagating, inducing, reducing and/or maintaining the genesis of an isolated stem cell and/or stem cell progeny from any germinal layer from a patient, characterised by:
  • said isolated cell is selected from the group consisting of fibroblasts, macrophages, vascular cells, bone cells, chondrocytes, myocardial cells, blood cells, neurons, oligodendrocytes, astroglial cells, Schwann cells, progenitor cells, stem cells and/or cells derived from progenitor cells or stem cells.
  • the polypeptides of Formula I may additionally comprise protecting groups.
  • N-terminal protecting groups include acetyl.
  • C-terminal protecting groups include amide.
  • Another embodiment of the invention is to treat conditions associated with insufficient formation of AF:s and related compounds or deficiency of AF receptor function by supplying the individual in an appropriate manner with the required AF, as described above.
  • Another embodiment of the invention utilizes the administration of egg yolks containing high levels of AF:s, also previously described in a patent (Ref. 16).
  • pathological loss and/or gain of cells are in the present context used to describe the common technical feature of a number of medical conditions and disorders.
  • the conditions and disorders are characterised by displaying pathological degeneration of, loss of ability of regeneration of and/or loss of control of regeneration-of a differentiated cell and/or tissue, an embryonic cell, an adult stem cell, a progenitor cell and/or a cell derived from a stem cell or a progenitor cell. Additionally, the term further does include improved survival and rescue of nervous tissue cells and reduced or abolished secondary degenerative effects.
  • the condition to be treated may be caused, inter alia, by one or more of traumatic asphyxia, neuropathic pain, hypoxic, ischemic, toxic, infectious, degenerative or metabolic insults to the nervous system. These often result in damage to several different cell types. Thus damage to brain due to any of the mentioned reasons, frequently causes neurological, cognitive defects and additional psychiatric symptoms.
  • the conditions may be caused by a traumatic, malignant, inflammatory, autoimmune or degenerative disorder or by treatment with drugs or x-ray.
  • the condition may be caused by genetic factors or the cause may be unknown.
  • condition may be caused by axonal damage caused by concussion, axonal damage caused by head or body trauma, axonal damage caused by small vessel disease in the CNS and/or damage to the spinal cord after disease and/or trauma or by the effects of oedema at such an injury.
  • the condition to be treated is a condition that is associated with or characterised by a pathological loss and/or gain of cells in the CNS as well as PNS and/or ANS.
  • Cells that may be affected by a polypeptide comprising a fragment of an amino acid sequence according to SEQ ID NO: 1 are, for example, stem cells, progenitor cells and or even differentiated cells gaining improved survival and regaining transiently lost function. They can belong to any of the three germ layers. Once stimulated the cells will differentiate, gain function and form synapses to replace malfunctioning, dying or lost cells or cell populations, such as in a in pathological CNS, PNS and/or ANS conditions, characterised by abnormal loss of cells, such as glia, and/or neuronal cell or cell populations, such as neuronal cells, and/ or glial cell and/or cell population as well as vascular and inflammatory cells.
  • the invention particularly relates to the treatment of conditions associated with or characterised by a loss of stem cells, preferably neural stem cells, or conditions characterised by or associated with a loss and/or gain of progenitor cells. Additionally, the invention relates to improved survival of stem or progenitor cells transplanted to nervous tissue.
  • the invention also relates particularly to the treatment of conditions associated with a loss and/or a gain of differentiated cells.
  • the differentiated cells are bone cells, cartilage cells, cardiomyocytes, oligodendroglia, astroglia, neuronal cells, epithelial cells endothelium, skin, blood, liver, kidney, bone, connective tissue, lung tissue, exocrine gland tissue, and/or endocrine gland tissue or muscle cells.
  • the differentiated cells are neuronal cells, neurons, astrocytes, oligodendrocytes, Schwann cells, or other glial cells.
  • the invention also provides the use of a polypeptide comprising an amino acid sequence of formula 1, in the manufacture of a medicament for rescuing and normalising the cells in the nervous tissue as well as modulating the development of stem cells/progenitor cells, and/or synapses between cells in the CNS, PNS and/or ANS.
  • a further embodiment of the invention provides a method of modulating the development of stem cells and the synapses between cells in the CNS comprising contacting the stem cells ex vivo or in vivo with an amount of a polypeptide comprising an amino acid sequence of formula 1.
  • the uses and methods of the invention are preferably suited for the treatment for the treatment of abnormal and/or medical conditions affecting pathological loss or gain of progenitor cells and synapses between neural cells and/or cells derived from neuronal stem cells.
  • the methods may thus be used to prevent, treat or ameliorate damages, diseases or deficits of the CNS, PNS and/or the ANS.
  • the pharmaceutical active substance used according to the invention is especially suitable for the treatment of conditions affecting the Schwann cells, satellite cells, oligodendroglia, astroglia and/or neuronal cells. Such conditions may, e.g. be due to due to CNS damage or deficits, neuronal cell loss or memory loss. Such conditions may, e.g.
  • the effect of the pharmaceutically active substance used to this preferred embodiment of the invention is due to their ability to improve cell survival, induce cell formation, synapses generation or the breakdown of neuronal plaque and/or ⁇ -APP, ⁇ -amyloid and other compounds accumulated in named cells.
  • the present invention is not restricted to the uses and methods for treating neuronal diseases and conditions, but said uses and methods may also be used for treating a large variety of mammalian conditions that are characterised by pathological cell loss and/or gain, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, asphyxia or hypoxia heart failure, heart infarction, diabetes, artrosis or arthritis, skin disease and burn injuries, chronic wounds, liver diseases or failure, muscle diseases or damages, cancer (tissues affected by cancer), pancreatic dysfunction and inflammatory bowel disease.
  • pathological cell loss and/or gain such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, asphyxia or hypoxia heart failure, heart infarction, diabetes, artrosis or arthritis, skin disease and burn injuries, chronic wounds, liver diseases or failure, muscle diseases or damages, cancer (tissues affected by cancer), pancreatic dysfunction and inflammatory bowel disease.
  • composition or medicament of the invention may additionally comprise one or more pharmacologically acceptable carriers, recipients or diluents, such as those known in the art.
  • compositions or medicaments may be in form of, for example, fluid, semi-fluid, semi-solid or solid compositions such as, but not limited to, dissolved transfusion liquids, such as sterile saline, various salt solution, glucose solutions, phosphate buffer saline, blood, plasma or water, powders, microcapsules, micro spheres, nanoparticles, sprays, aerosols, inhalation devices, solutions, dispersions, suspensions, emulsions and mixtures thereof.
  • dissolved transfusion liquids such as sterile saline, various salt solution, glucose solutions, phosphate buffer saline, blood, plasma or water, powders, microcapsules, micro spheres, nanoparticles, sprays, aerosols, inhalation devices, solutions, dispersions, suspensions, emulsions and mixtures thereof.
  • compositions may be formulated according to conventional pharmaceutical practice, taking into consideration the stability and reactivity of oligo- or polypeptides or of the protein.
  • compositions can include AF inducing food or egg yolks, which contain high levels of AF:s.
  • AF inducing foods are preferably administered orally or perorally in compositions adapted for such a purpose.
  • Egg yolks with levels of AF:s are preferably administered orally or perorally.
  • AF and its derivates may as well be administrated by injections and with the aid of an aerosol or by superficial deposition.
  • compositions or medicaments may be formulated according to conventional pharmaceutical practice, see, e.g., “Remington: The science and practice of pharmacy” 20 th ed. Mack Publishing, Easton Pa., 2000 ISBN 0-912734-04-3 and “Encyclopedia of Pharmaceutical Technology”, edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9.
  • compositions or medicament for use according to the invention may readily be determined by experimentation. Also whether a pharmaceutically acceptable excipient is suitable for use in a pharmaceutical composition is generally dependent on which kind of dosage form is chosen. However, a person skilled in the art of pharmaceutical formulation can find guidance in e.g., “Remington: The science and practice of pharmacy” 20 th ed. Mack Publishing, Easton Pa., 2000 ISBN 0-912734-04-3.
  • compositions or medicament for use according to the invention may readily be determined by experimentation. Also whether a pharmaceutically acceptable excipient is suitable for use in a pharmaceutical composition is generally dependent on which kind of dosage form is chosen. However, a person skilled in the art of pharmaceutical formulation can find guidance in e.g., “Remington: The science and practice of pharmacy” 20 th ed. Mack Publishing, Easton Pa., 2000 ISBN 0-912734-04-3.
  • a pharmaceutically acceptable excipient is a substance, which is substantially harmless to the individual to which the composition will be administered. Such an excipient normally fulfils the requirements given by the national drug agencies. Official pharmacopoeias such as the United States of America Pharmacopoeia and the European Pharmacopoeia set standards for well-known pharmaceutically acceptable excipients.
  • compositions for use according to the invention are based on the particular route of administration. However, it is appreciated that in those cases where a pharmaceutically acceptable excipient may be employed in different dosage forms or compositions, the application of a particular pharmaceutically acceptable excipient is not limited to a particular dosage form or of a particular function of the excipient.
  • compositions according to the invention may contain conventional non-toxic pharmaceutically acceptable carriers and excipients, including microspheres and liposomes.
  • compositions for use according to the invention may include all kinds of solid, semi-solid and fluid compositions.
  • Compositions of particular relevance are e.g. solutions, suspensions and emulsions.
  • the pharmaceutically acceptable excipients may include solvents, buffering agents, preservatives, chelating agents, antioxidants, stabilisers, emulsifying agents, suspending agents and/or diluents. Examples of the different agents are given below.
  • solvents include but are not limited to water, alcohols, blood, plasma, spinal fluid, ascites fluid and lymph fluid.
  • buffering agents include but are not limited to citric acid, acetic acid, tartaric acid, lactic acid, hydrogenphosphoric acid, bicarbonates, phosphates, diethylamine, etc.
  • chelating agents include but are not limited to sodium EDTA and citric acid.
  • antioxidants include but are not limited to butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, cysteine, and mixtures thereof.
  • BHA butylated hydroxy anisole
  • diluents and disintegrating agents include but are not limited to lactose, saccharose, emdex, calcium phosphates, calcium carbonate, calcium sulphate, mannitol, starches and microcrystaline cellulose.
  • binding agents include but are not limited to saccharose, sorbitol, gum acacia, sodium alginate, gelatine, starches, cellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyethyleneglycol.
  • the pharmaceutical composition or the substance used according to the invention is preferably administered via intravenous peripheral infusion or via intramuscular or subcutaneous injection into the patient or via buccal, pulmonary, nasal or oral routes. Furthermore, it is also possible to administer the pharmaceutical composition or the pharmaceutically active substance through a surgically inserted shunt into a cerebral ventricle of the patient.
  • said pharmaceutical composition is formulated so that the active substance will pass into the ventricles of a patient's brain
  • said pharmaceutical composition is formulated so that the active substance will pass into the ventricles of a patient's brain or into the cerebrospinal fluid of said patient, when it is administered to said patient.
  • This may e.g. be achieved by mechanical devices, vectors, liposomes, lipospheres, or biological or synthetical carriers.
  • the administered dosage range is about 0.001-100 mg of a polypeptide comprising the amino acid sequence of Formula I per 100 g body weight, comprising a range of 0.001-100 mg/1 g, 0.001-100 mg/10 g and 0.001-100 mg/50 g body weight.
  • the administered dosage range is about 0.001-100 mg of a polypeptide comprising the amino acid sequence of Formula I per 1 kg body weight.
  • the administered dosage correspond to 0.2-5 g of malted cereals per kg of bodyweight.
  • egg yolks with high levels, i e at least 1000 FIL units/ml, of AF:s are administered a dosage of 0.05-0.5 g per kg of bodyweight are used.
  • the response of the individual should be controlled.
  • the invention may be used to treat humans or non-human mammals.
  • treatment or “treating” as used herein relate to both therapeutic treatment in order to cure or alleviate a disease or a medical condition, characterised by abnormal loss and/or gain of cells, and to prophylactic treatment in order to prevent the development of a disease or a medical condition, characterised by pathological loss and/or gain of cells and cell constituents, e.g., synpapses.
  • prophylactic and therapeutic treatments are included in the scope of the present invention.
  • treatment or “treating” also refer to the effecting of cell genesis from stem cells or progenitor cells by inducing the genesis of differentiated cells, such as e.g.
  • the treatment may either be performed in an acute or in a chronic way.
  • AF-expanded stem and/or progenitor cells may be propagated and either pre-differentiated prior to grafting or allowed to differentiate as a result of interactions between the transplanted cells and the host.
  • AF-expanded stem cells and/or progenitor cells may be administered and/or grafted at a single time, or delivered repeatedly over a prolonged period. This will be especially useful if stem cells and/or progenitor cells are administered to enter the target organ via the bloodstream.
  • a polypeptide comprising the amino acid sequence of Formula I may thereafter be used for cell transplantation into a patient suffering from e.g. neuronal cell loss or a condition due to lack of endogenous cells of another type.
  • the cells used to start the culture may either originate from the patient or from another human or animal donor, and may be used in the treatment of a broad variety of diseases and disorders comprising heart diseases such as infarct, diabetes, or in an assortment of neurological diseases and disorders, such as those referred to above.
  • the invention also provides a method of propagating, inducing, reducing and/or maintaining the genesis of an isolated stem cell and/or stem cell progeny in vitro, characterised by treating the isolated cell with a polypeptide comprising the amino acid sequence of Formula I.
  • the isolated cell is selected from the group comprising epithelial cells, fibroblasts, osteogenic cells, macrophages and microglial cells, chondrocytes, myocardial cells, blood cells, neurons, oligodendrocytes, astroglial cells, progenitor cells, stem cells and/or cells derived from said cells.
  • the isolated cell will be treated under appropriate conditions and for a time, which is sufficient to achieve the desired propagation, induction, reduction and/or maintenance.
  • progenitor cells When cells are to be removed from a patient for in vitro propagation, it may be advantageous first to increase the number of progenitor cells in the patient. This will better facilitate the subsequent isolation of said cells from patients.
  • the number of progenitor cells is increased by use of the method or pharmaceutical composition according to the invention.
  • a polypeptide comprising the amino acid 'sequence of Formula I may be used alone or conjunction with other medicaments, interleukins or e.g. growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF) or insulin-like growth factor (IGF), designed to induce cell genesis or proliferation e.g. in the CNS, PNS or ANS.
  • growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF) or insulin-like growth factor (IGF)
  • EGF epidermal growth factor
  • TGF transforming growth factor
  • PDGF platelet derived growth factor
  • FGF fibroblast growth factor
  • IGF insulin-like growth factor
  • a polypeptide comprising the amino acid sequence of Formula I, alone or in conjunction with other medicaments, peptides, growth-factors, steroids, lipids, glycosylated proteins or peptides, used either simultaneously or in sequence, may be used in order to facilitate cell genesis or the generation of specific cell types in vivo or in vitro. It may also be used to induce immature or multipotent cells to activate specific developmental programs as well as specific genes in the aforementioned cells.
  • cell genesis is meant the generation of new cells such as neurons, oligodendrocytes, Schwann cells, satellite cells and astroglial cells from multipotent cells, progenitor cells or stem cells within the adult CNS or PNS or other organs of the body, in situ or in isolation.
  • the invention also relates to the therapeutic use of substances that decrease the amount of active AF or naturally occurring analogous of AF in the patient and thus decrease the genesis of new cells, e.g. of oligodendrocytes in patients with axonal or spinal cord injury, such as axonal damage caused by concussion, axonal damage caused by head trauma, axonal damage caused by small vessel disease in the CNS, and/or damage to the spinal cord after disease and/or trauma.
  • substances are drugs, antibodies, compounds, peptides and/or inhibitor of endogenous AF release.
  • a polypeptide comprising the amino acid sequence of Formula I may be used in order to facilitate learning and memory by the genesis of said cells.
  • the present invention relates primarily to a method for treating abnormal conditions in-the CNS or PNS that are characterised by pathological loss and/or gain of cells, by affecting neural stem cells or progenitor cells
  • the uses and methods of the invention may be equally useful for treating and/or preventing medical conditions in other organs of the body, provided that said medical conditions characterised by pathological loss and/or gain of cells.
  • polypeptides comprising an amino acid sequence of Formula I
  • the invention relates, mutatis mutandis, also to polypeptides consisting essentially of an amino acid sequence of Formula I, and to polypeptides consisting of an amino acid sequence of Formula I.
  • polypeptides comprising an amino acid sequence of Formula I may be produced by standard means, including recombinant and synthetic routes.
  • FIG. 1 Confocal immunofluorescence micrographs of dentate gyrus from a sham treated control brain (A) and after seizures induced by intraabdominal injection of kainic acid (10 mg/ml) in buffered saline (B-7 d; C-28 d), disclosing the distribution of proliferating cell clusters. The newly formed cells are stained dark. The number of ribonucleotide reductase (RNR) positive cells, i.e. mitotic, in the SGZ is significantly increased at 7 d (B), and at 28 d (C) after seizures.
  • FIG. 2 Photo of brains from rats 2 days after that a freezing probe had been positioned for 40 seconds on the outside of their skull bone.
  • the two brains in the upper row had had free access to standard pellets and tap water prior to and after the brain injury. Note the bleedings and the discoloured brain tissue.
  • the two brains in the lower row had had unlimited access to SPC food and drinking solution for 12 days prior to the exposure of the outside of the skull bone to a freezing probe and then for the next two days, prior to sacrifice. Note the absence of macroscopic bleeding and the less extensive brain damage.
  • the high AF levels in the rats fed on SPC reduced the brain damage, as further confirmed by light microscopy of stained sections.
  • FIG. 3 Photo of brains from rats 6 days after that a freezing probe had been positioned for 40 seconds on the outside of their skull bone.
  • the three brains in the upper row are from adult rats that had had free access to standard pellets and tap water prior to and after the brain injury. Note the minor bleedings and the shallow defect in the brain tissue.
  • the three brains in the lower row had had unlimited access to SPC food and drinking solution for 5 days prior to the exposure of the outside of the skull bone to a freezing probe and then for the next six days, prior to sacrifice. Note the less extensive brain damage, as compared to the rat brains in the upper panel.
  • the AF levels in the rats fed on SPC for days prior to the freezing injury reduced the brain damage, as further confirmed by light microscopy of stained sections.
  • the following experiment was performed to assess whether administration of AF influenced the neurogenesis in the brain of a normal adult mammal, the rat.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were purchased from B & K AB, Sweden. The animals were kept in cages of approved type and size, and the light was on from 06 to 18. The regional animal experiments ethical committee granted permission for the experiments. Measures were taken to reduce discomfort and pain.
  • the test rats were fed on SPC pelleted food and drinking an extract of SPC for at least 10 days prior to sacrifice. The animals were not exposed to any surgery or otherwise manipulated.
  • the rats were anaesthetized by either an intraabdominal injection of an overdose of pentobarbital sodium in saline or by the inhalation of isofluorane.
  • the thoracic cavity was opened, the left ventricle of the heart canulated and a tempered balanced buffered salt solution, with heparin added, infused to rinse the vascular system from blood. Thereafter, a buffered formaldehyde solution in saline was infused to fix the tissue.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were purchased from B & K AB, Sweden. The animals were kept in cages of approved type and size, and the light was on from 06 to 18. The regional animal experiments ethical committee granted permission for the experiments. Measures were taken to reduce discomfort and pain.
  • the rats were anaesthetized by the inhalation of isofluorane, and had their heads shaved.
  • the skin was cut open in the mid sagittal plane on the skull.
  • the calvarium was exposed on the left side between the bregma and the lambda.
  • the periostium was detached from the bone, which then was rinsed. Thereafter, great care was taken to remove blood and any fluid from the calvarium as that may impair the subsequent procedure.
  • the cooled probe was thereafter applied for 40 s on the calvarium in between the lambda and bregma, 4 mm lateral to the sagittal mid line.
  • the probe was then removed and the skin wound sutured.
  • the application of the freezing probe resulted transiently in that the brain tissue underlying the exposure site turn frozen. It ought to be stressed that the skull was not opened and no fractures or other signs of gross damage induced.
  • the left cerebral cortex showed discoloration and bleeding in an area with a diameter of 3-5 mm, immediately underneath the part of the skull bone exposed to the cooling ( FIG. 2 ).
  • a shallow depression indicated that there was a loss of nervous tissue.
  • the primary damage is the one taking place during the first few seconds after the application of the freezing probe.
  • the secondary brain damage comprises changes taking place after a minute or more, the exact time being defined depending on the type of injury.
  • the secondary changes may turn out to become more severe with time, especially if there is a brain oedema, which tend to be deleterious.
  • the blood vessels were also damaged but rapidly rebuilt. However, the necrotic, central part of the injured tissue was not revascularised until after days or even weeks.
  • any injury to the brain inducing an inflammation causes a transient elevation of the stem and progenitor cell proliferation in the SGZ and in the SVZ, if those areas are not badly impaired. Further, the new neural stem and progenitor cells must be stimulated in order to survive, migrate, and differentiate; otherwise the cell proliferation may result in a net loss of neuronal cells.
  • beta amyloid precursor proteins ⁇ -APP
  • beta-amyloid A ⁇
  • ⁇ -APP and A ⁇ are both toxic to nerve cells and start to accumulate within a few hours after a neurotrauma.
  • these two proteins dissolve and thus disappear, the possibility for the affected nerve cells to survive, recover, and reintegrate structurally and functionally must be considered as highly beneficial.
  • cytoskeletal constituents such as neurofilaments and microtubules, are suffering at a neurotrauma and accumulate, forming aggregates and tangles, which make the primary injury worse and even deleterious.
  • Axons and dendrites appear as being irregularly beaded, swollen and distorted due to the focal accumulation of cytoskeletal constituents, cell organelles and amyloid. Due to the disorganisation of nerve cells after a trauma, such as that due to freezing, the normal very precise and regular organisation of the cell machinery is lost in parts and normal cell constituents may accumulate or appear in abnormal concentrations, such as ubiquitin. Nerve cells do normally not divide, with the exception of those in the SGZ and SVZ, but may after a neurotrauma start to form proteins and other compounds in abnormally high amounts, such as i.e. cyclins and related constituents, normally only prevalent in dividing cells.
  • the glial cells, the astrocytes and the microglial cells proliferated and turned hypertrofic. There was further a rebuilding of the residuing blood vessels and angiogenesis in the injured tissue.
  • the following experiment was performed to assess if increased occurrence of AF in a body affected the extent and severity of a brain injury caused on the rodent brain by the application of a freezing probe on the outside of the skull bone, exerted neuroprotection.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were supplied with SPC food and drinking fluid for at least 10 days prior to the brain injury. At the day of injury, the rat were anaesthetized and prepared as described in experiment 2. The freezing probe was applied once for 40 seconds. After suturing the skin wound in the skull and recovered from the anaesthesia, the rats were allowed to move freely and had access to SPC food and drinking fluid.
  • the following experiment was performed to assess if increased occurrence of AF in a body affected the extent and severity of a brain injury caused on the rodent brain by the application of a freezing probe on the outside of the skull bone, exerting neuroprotection.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were supplied with SPC food and drinking fluid for at least 10 days prior to the brain injury. At the day of injury, the rat were anaesthetized and prepared as described in experiment 2. The freezing probe was applied once for 40 seconds. After suturing the skin wound in the skull and recovered from the anaesthesia, the rats were allowed to move freely and had access to SPC food and drinking fluid.
  • the following experiment was performed to assess if increased occurrence of AF in a body affected the extent and severity of a brain injury caused on the rodent brain by the application of a freezing probe on the outside of the skull bone, exerted neuroprotection.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were supplied with standard pelleted food and tap water prior to and after the brain injury. At the day of injury, the rat were anaesthetized and prepared as described in experiment 2. The freezing probe was applied once for 40 seconds. After suturing the skin wound in the skull and recovered from the anaesthesia, the rats were allowed to move freely.
  • the following experiment was performed to assess if increased occurrence of AF in a body affected the extent and severity of a brain injury, caused on the rodent brain by the intraperitoneal injection of the excitotoxic compound kainic acid, exerted neuroprotection.
  • Rats (body weight 180-350 g at the start of the experiments), male and female, were supplied with SPC food and drinking fluid for at least 10 days prior to the brain injury. The same number of rats got in parallel standard pelleted food and tap water, for comparison.
  • the following experiment is to be performed to assess if increased occurrence of AF or AF fragments in a body affected the extent and severity of a diffuse brain injury, caused by a rotational acceleration trauma to a rabbits head.
  • brain concussion The most common brain injury is that named brain concussion. It affects 80.000-90.000 Swedes annually and of those about every fourth had to stay in a hospital for at least a day for clinical examination and observation.
  • the corresponding figures for the USA is that about 2 million individuals suffer from brain concussion and of those roughly half a million stay in a hospital for a day or more. A large number of those affected are investigated by x-ray, and/or MRI.
  • Anaesthetized rabbits will have their skull bone freed from soft tissue.
  • a helmet made of plastic and reinforced with glass fibres, will be glued to the skull bone.
  • the helmet is connected to a exposure equipment, that transmit a rotational acceleration trauma to the head, either anterior-posterior or the reverse.
  • the rabbits will be treated by administration of AF or synthetic peptides corresponding to selected sequences of AF.
  • Additional rabbits will be fed SPC food and drinking solution or alternatively compositions based on egg yolk.
  • the exposure parameters will be closely monitored by a computerised recording system.
  • the brains will be removed from'sacrificed rabbits and carefully investigated for presumed neuroprotective effects by the AF and its derivates as well as egg yolk.
  • the advantage of the planned experiments is that the brain injury is standardized and correspond to that most frequent for human beings, a brain concussion.
  • the formation of brain oedema will be closely monitored by the intracerebral implantation of fibre optic sensors, connected to a computer. Thereby, the effects of AF and its derivates on the oedema formation and histopathological abnormalities can be closely followed and documented. Long-term studies will as well be performed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Reproductive Health (AREA)
  • Developmental Biology & Embryology (AREA)
  • Cell Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Biotechnology (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Virology (AREA)
US10/573,601 2003-09-26 2004-09-24 Novel use of antisecretory factor Abandoned US20070009575A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/659,142 US8748367B2 (en) 2003-09-26 2010-02-26 Use of antisecretory factor

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0322645.3 2003-09-26
GBGB0322645.3A GB0322645D0 (en) 2003-09-26 2003-09-26 Use of antisecretory factor peptides
PCT/SE2004/001369 WO2005030246A1 (en) 2003-09-26 2004-09-24 Novel use of antisecretory factor

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/659,142 Continuation US8748367B2 (en) 2003-09-26 2010-02-26 Use of antisecretory factor

Publications (1)

Publication Number Publication Date
US20070009575A1 true US20070009575A1 (en) 2007-01-11

Family

ID=29286947

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/573,601 Abandoned US20070009575A1 (en) 2003-09-26 2004-09-24 Novel use of antisecretory factor
US12/659,142 Active 2027-02-14 US8748367B2 (en) 2003-09-26 2010-02-26 Use of antisecretory factor

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/659,142 Active 2027-02-14 US8748367B2 (en) 2003-09-26 2010-02-26 Use of antisecretory factor

Country Status (18)

Country Link
US (2) US20070009575A1 (ru)
EP (1) EP1734989B1 (ru)
JP (1) JP4943847B2 (ru)
KR (1) KR101159858B1 (ru)
CN (2) CN103028110B (ru)
AT (1) ATE550030T1 (ru)
AU (1) AU2004275682B2 (ru)
BR (1) BRPI0414793A (ru)
CA (1) CA2537335C (ru)
DK (1) DK1734989T3 (ru)
ES (1) ES2384385T3 (ru)
GB (1) GB0322645D0 (ru)
IL (1) IL174464A (ru)
NO (1) NO340187B1 (ru)
NZ (1) NZ545661A (ru)
RU (1) RU2416426C2 (ru)
WO (1) WO2005030246A1 (ru)
ZA (1) ZA200601807B (ru)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090149382A1 (en) * 2006-04-27 2009-06-11 Hans-Arne Hansson Modulation of lipid rafts
WO2014096384A1 (en) * 2012-12-20 2014-06-26 Lantmännen As-Faktor Ab Use of antisecretory factor (af) in glioblastoma treatment
US20170334758A1 (en) * 2012-03-16 2017-11-23 Aquatech International, Llc Process for purification of produced water
WO2021191431A1 (en) * 2020-03-26 2021-09-30 Lantmännen Functional Foods Ab A consumable product comprising malted cereals for promoting recovery at physical activity

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2015767B1 (en) 2006-04-27 2016-01-06 Lantmännen AS-Faktor AB Use of antisecretory factor for treating intraocular hypertension
CN101437533B (zh) * 2006-04-27 2016-10-12 兰特门内阿斯-法克托尔公司 抗分泌蛋白对于治疗间室综合症的应用
AU2012201165B2 (en) * 2006-04-27 2013-12-19 Lantmannen As-Faktor Ab New approach to treat intraocular hypertension
US9962424B2 (en) 2007-04-27 2018-05-08 Lantmännen As-Faktor Ab Use of antisecretory factors (AF) for optimizing cellular uptake
JP5820277B2 (ja) 2009-02-11 2015-11-24 ラントメネン・アーエス−ファクトール・アーベー 細胞取込を最適化するための抗分泌性因子（ａｆ）の使用
ITMI20120008A1 (it) * 2012-01-04 2013-07-05 Biava Maura Composizioni ad attività anti-neurodegenerativa
RU2673484C2 (ru) * 2012-05-18 2018-11-27 Юниверсити Оф Айова Рисерч Фаундейшн Способы и композиции для лечения амилоидных отложений
ES2887086T3 (es) 2015-07-10 2021-12-21 Lantmaennen Functional Foods Ab Procedimiento para producir yema de huevo con alto contenido de af-16
CA3030316C (en) * 2016-07-18 2023-10-10 Lantmannen As-Faktor Ab Antisecretory factor 17
US20250177480A1 (en) 2018-06-28 2025-06-05 Lantmännen Medical Ab Antisecretory Factor for Use in Treatment and/or Prevention of Acute Respiratory Failure
EP3855934A2 (en) 2018-09-28 2021-08-04 Lantmännen Functional Foods AB A consumable product comprising malted dehulled oat
CN112770644A (zh) 2018-09-28 2021-05-07 兰特门内保健食品公司 包含麦芽化小麦的可消耗产品
CN112006035B (zh) * 2020-07-24 2021-07-30 江西新龙生物科技股份有限公司 用于防治植物病害的微生物源杀菌剂及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6344440B1 (en) * 1995-08-24 2002-02-05 Rural Patent Svenska Ab Antisecretory factor peptides regulating pathological permeability changes

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7566455B1 (en) * 1995-06-07 2009-07-28 Gpc Biotech, Inc. E6AP-binding proteins
AU732508B2 (en) * 1996-01-26 2001-04-26 Governing Council Of The University Of Toronto, The Nucleic acids and proteins related to Alzheimer's disease, and uses therefor
SE513496C2 (sv) * 1998-12-17 2000-09-18 Rural Patent Svenska Ab NASP-berikad äggula samt dess användning
EA200100264A1 (ru) * 1999-06-21 2001-10-22 Филадельфия Хеалс Энд Эдьюкейшн Корпорейшн Ангиоцидин: адгезионный рецептор опухолей клетки, специфический для cys-ser-val-thr-cys-gly
EP1350847A4 (en) * 2001-01-09 2005-12-28 Inst Of Gene And Brain Science HUMAN GLIOMANTIGEN AND METHOD FOR THE PRODUCTION THEREOF
WO2003063688A2 (en) * 2002-01-25 2003-08-07 Incyte Corporation Protein modification and maintenance molecules

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6344440B1 (en) * 1995-08-24 2002-02-05 Rural Patent Svenska Ab Antisecretory factor peptides regulating pathological permeability changes

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090149382A1 (en) * 2006-04-27 2009-06-11 Hans-Arne Hansson Modulation of lipid rafts
US8487074B2 (en) * 2006-04-27 2013-07-16 Lantmannen As-Faktor Ab Modulation of lipid rafts
US20170334758A1 (en) * 2012-03-16 2017-11-23 Aquatech International, Llc Process for purification of produced water
WO2014096384A1 (en) * 2012-12-20 2014-06-26 Lantmännen As-Faktor Ab Use of antisecretory factor (af) in glioblastoma treatment
AU2013366509B2 (en) * 2012-12-20 2016-11-03 Lantmannen As-Faktor Ab Use of antisecretory factor (AF) in glioblastoma treatment
WO2021191431A1 (en) * 2020-03-26 2021-09-30 Lantmännen Functional Foods Ab A consumable product comprising malted cereals for promoting recovery at physical activity
CN115605214A (zh) * 2020-03-26 2023-01-13 兰特门内保健食品公司（Se） 用于促进身体活动恢复的包含麦芽化谷物的可消耗产品
US20230096303A1 (en) * 2020-03-26 2023-03-30 Lantmännen Functional Foods Ab A Consumable Product Comprising Malted Cereals for Promoting Recovery at Physical Activity

Also Published As

Publication number Publication date
US8748367B2 (en) 2014-06-10
US20100286052A1 (en) 2010-11-11
BRPI0414793A (pt) 2006-11-21
IL174464A0 (en) 2006-08-01
RU2416426C2 (ru) 2011-04-20
EP1734989B1 (en) 2012-03-21
CN103028110B (zh) 2016-02-17
NZ545661A (en) 2009-10-30
CA2537335C (en) 2017-12-05
ZA200601807B (en) 2007-06-27
CA2537335A1 (en) 2005-04-07
DK1734989T3 (da) 2012-07-09
CN1856320A (zh) 2006-11-01
IL174464A (en) 2015-08-31
JP4943847B2 (ja) 2012-05-30
GB0322645D0 (en) 2003-10-29
CN103028110A (zh) 2013-04-10
AU2004275682B2 (en) 2010-01-28
KR20060097718A (ko) 2006-09-14
ES2384385T3 (es) 2012-07-04
KR101159858B1 (ko) 2012-06-25
WO2005030246A1 (en) 2005-04-07
JP2007506735A (ja) 2007-03-22
AU2004275682A1 (en) 2005-04-07
EP1734989A1 (en) 2006-12-27
RU2006114030A (ru) 2007-11-20
NO20060901L (no) 2006-06-20
ATE550030T1 (de) 2012-04-15
NO340187B1 (no) 2017-03-20

Similar Documents

Publication Publication Date Title
US8748367B2 (en) Use of antisecretory factor
JP4861177B2 (ja) 神経系の障害の処置
Martini et al. The L2/HNK‐1 carbohydrate epitope is involved in the preferential outgrowth of motor neurons on ventral roots and motor nerves
US9480658B2 (en) Modulation of synaptic maintenance
EP3372613A1 (en) Peptide having neuronal loss prevention and regeneration effects, and composition containing same
EP3209306B1 (en) Stable neural stem cells comprising an exogenous polynucleotide coding for a growth factor and methods of use thereof
Barami et al. Cellular transplantation and spinal cord injury
CN105377273A (zh) 用于治疗眼睛疾病或病症的人类单核细胞亚群
AU748143B2 (en) Immunological compositions and methods of use to transiently alter mammalian central nervous system myelin to promote neuronal regeneration
US20240100076A1 (en) Methods and compositions for treating neurodegenerative diseases
Brandis et al. Time-dependent expression of donor-and host-specific major histocompatibility complex class I and II antigens in allogeneic dopamine-rich macro-and micrografts: comparison of two different grafting protocols
US7427597B2 (en) Method of treating brain tissue damages
HK1183803A (en) Novel use of antisecretory factor
Culley et al. Amyloid-beta peptide toxicity in the aged brain is a one-way journey into Alzheimer’s disease
JP2008545705A (ja) 軸索再生を促進する組成物及び方法
US20110178025A1 (en) Amidated Dopamine Neuron Stimulating Peptides for CNS Dopaminergic Upregulation
US20050008641A1 (en) Composition for neuronal regeneration comprising myelin-specific antibodies and complement proteins
US20090291887A1 (en) Proteins of the SDF-1-Family for the Manufacturing of a Medicament
Leo et al. Hyper-homocysteinemia alters amyloid peptide-clusterin interactions and neuroglial network morphology and function in the caudate after intrastriatal injection of amyloid peptides
Dimas The essential role of de novo fatty acid synthesis in CNS myelin regeneration
da Silva Janota Vascular and Glial Alterations During Aging in Wild-Type Mice and Along Alzheimer's Disease Progression in APP/PS1 Mice
JPWO2000062796A1 (ja) 膵臓機能障害改善剤

Legal Events

Date Code Title Description
AS Assignment

Owner name: AS FAKTOR AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HANSSON, HANS-ARNE;JENNISCHE, EVA;LANGE, STEFAN;AND OTHERS;REEL/FRAME:018105/0490;SIGNING DATES FROM 20060418 TO 20060531

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION