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WO2013034805A1 - Peptides de pénétration cellulaire neuroprotecteurs - Google Patents

Peptides de pénétration cellulaire neuroprotecteurs Download PDF

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Publication number
WO2013034805A1
WO2013034805A1 PCT/FI2012/050859 FI2012050859W WO2013034805A1 WO 2013034805 A1 WO2013034805 A1 WO 2013034805A1 FI 2012050859 W FI2012050859 W FI 2012050859W WO 2013034805 A1 WO2013034805 A1 WO 2013034805A1
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disease
peptides
peptide
neurons
seq
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Urmas Arumäe
Mart Saarma
Pia Runeberg-Roos
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • A61P25/14—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser

Definitions

  • the present invention relates to the fields of bioactive peptides and cell-penetrating peptides as well as to the field of neurotrophic factors, i.e. growth factors for neural cells.
  • the present invention provides CXXC peptides with length of 4 to 40 amino acids having the sequence CKGC (SEQ ID NO: l) or CRAC (SEQ ID NO:2).
  • the invention is also directed to a method for promoting survival of dopaminergic neurons.
  • CDNF cerebral dopamine neurotrophic factor
  • MEF mesencephalic astrocyte-derived neurotrophic factor
  • CDNF protects and repairs dopamine neurons also in mouse MPTP model of Parkinson's disease and in a severe 6-OHDA model it is more efficient than glial cell line-derived neurotrophic factor (GDNF) (Voutilainen et al., 2011).
  • GDNF glial cell line-derived neurotrophic factor
  • the mechanism of action of CDNF and MANF is, however, not elucidated. We found that in vitro, MANF and CDNF protect the apoptotic neurons only intracellularly but not in the culture medium (Hellman et al., 2011).
  • CXXC motif (residues 149-152 of human MANF, NCBI Reference Sequence: NP_006001.3) is located in the C-terminal domain (C-MANF) in the loop region outside the helical core of the domain, and the cysteines are connected with the disulfide bond (Hellman et al., 2011).
  • Corresponding motif of CDNF is located at the same position (NCBI Reference Sequence: NP_001025125.2).
  • Figure 1 shows MANF-derived peptides used in this study.
  • MANF-derived peptides protect sympathetic neurons against nerve growth factor (NGF) deprivation-induced death when microinjected into the cytoplasm.
  • NGF nerve growth factor
  • Neurons from the neonatal mouse superior cervical ganglion were grown with NGF for 6 days.
  • the peptides or control substances were microinjected directly into the cytoplasm and NGF was then deprived.
  • the living neurons were counted after three days (72 h) and expressed as percentage of initial number of injected neurons, counted 3-4 hours after injection. The mean + SEM of three independent experiments is shown.
  • C152S one cysteine mutated into serine
  • C149/152S both cysteines mutated into serine
  • w/o S-S peptide without S-S bond.
  • FIG. 3 MANF-derived peptides protect sympathetic neurons against nerve growth factor (NGF) deprivation-induced death when added to the culture medium. Neurons from the neonatal mouse superior cervical ganglion were grown with NGF for 6 days. Then the cultures were deprived of NGF and the peptides added to the culture medium. Living neurons were counted 72 h later and expressed as percentage of initial number of injected neurons, counted 3-4 hours after injection. The mean + SEM of three independent experiments is shown. p ⁇ 0.01 (**) compared to no peptide-control (ANOVA, Dunnett's post hoc test, p ⁇ 0.05 is significant). C149/152S: both cysteines mutated into serine. The NGF+ neurons were maintained in the presence of NGF to show that the neurons did not deteriorate due to poor culture conditions.
  • NGF nerve growth factor
  • FITC-conjugated peptide of MANF spontaneously enters the sympathetic neurons.
  • MANF-derived peptides protect cultured dopaminergic neurons against trophic factor deprivation-induced death when added to the culture medium.
  • Dissociated cultures of the El 3 mouse midbrain floors were cultured with the indicated peptides at 20 mM, with GDNF (100 micro grams/ml), or without factor, for 5 days. The cultures were then fixed and immunostained for tyrosine hydroxylase, a marker of the dopaminergic neurons. The immunopositive neurons were counted and expressed as percent of GDNF-maintained control neurons. The mean + SEM of four independent experiments is shown. p ⁇ 0.05 (*) compared to no factor-control (ANOVA, Dunnett's post hoc test, p ⁇ 0.05 is significant).
  • C149/152S both cysteines mutated into serine
  • w/o S-S peptide without S-S bond.
  • MANF-derived peptide and inactive peptide with two mutated cysteines did not significantly change the number of rat pheochromocytoma PC6 cells.
  • the cells were plated at equal density, treated with the peptides at indicated concentrations for two days, and the number of cells counted by Cell-IQ machine. Shown are the averages of three parallels + standard deviations of one experiment.
  • Figure 8 Combined cumulative rotational behavior measured 2 and 4 weeks after lesion and treatment with MANF peptide.
  • MANF4 peptide i.e. Ac- CKGC-Am
  • 10 ⁇ g and vehicle treated groups p ⁇ 0,01
  • MANF4 peptide 30 ⁇ g and vehicle treated groups p ⁇ 0,05
  • the maximum protective effect was observed with MANF4 peptide dose of 10 ⁇ g.
  • the present invention provides a peptide with the length of 4 - 40 amino acids comprising the sequence CKGC (SEQ ID NO: 1) or CRAC (SEQ ID NO:2).
  • the peptide comprises or consists of the sequence ETCKGCAE (SEQ ID NO:3).
  • the length of the peptide is in the range of 4 - 40, 4 - 35, 4 - 30, 4 - 25, 4 - 20, 4 - 15, or 4 - 10 amino acids.
  • the length of the peptide is in the range of 5 - 40, 6 - 40, 7 -40, or 8 - 40 amino acids. More preferably, the length of the peptide is in the range of 5-35, 5-30, 5-25, 5-20, 5-15, 5-10, 6-35, 6-30, 6-25, 6-20, 6-15, 6-10, 7-35, 7-30, 7-25, 7-20, 7-15, 7-10, 8-35, 8-30, 8-25, 8-20, or 8-15 amino acids.
  • the preferred peptides can consist of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids.
  • the peptides may comprise any of the naturally occurring amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine as well as non-conventional or modified amino acids.
  • the peptide has 100% homology with the sequence of human CDNF or MANF protein.
  • peptide includes native peptides (either degradation products, synthetically synthesized peptides or recombinant peptides) and modified peptides, which may have, for example, modifications rendering the peptides more stable or less immunogenic. Such modifications include, but are not limited to, cyclization, N-terminus modification, C-terminus modification, peptide bond modification, backbone modification and residue modification.
  • a detectable chemical or biochemical moiety means a tag that exhibits an amino acid sequence or a detectable chemical or biochemical moiety for the purpose of facilitating detection of the peptide; such as a detectable molecule selected from among: a visible, fluorescent, chemiluminescent, or other detectable dye; an enzyme that is detectable in the presence of a substrate, e.g., an alkaline phosphatase with NBT plus BCIP or a peroxidase with a suitable substrate; a detectable protein, e.g., a green fluorescent protein.
  • the tag does not prevent or hinder the penetration of the peptide into the target cell.
  • Acetylation - amidation of the termini of the peptide increases the stability and cell permeability of the peptides.
  • Examples of acetylated-amidated peptides are:
  • the present invention is directed to a method for treatment of
  • the peptide according to the present invention is for use in the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, peripheral neuropathy, epilepsy, diabetes or drug addiction, wherein a pharmaceutically effective amount of the peptide with the length of 4 - 40 amino acids comprising the sequence CKGC (SEQ ID NO:l) or CRAC (SEQ ID NO:2) is administered to a patient.
  • the peptide according to the present invention is for use in the treatment of Alzheimer's disease,
  • the peptide is for use in the treatment of Parkinson's disease or diabetes such as type I and type II diabetes.
  • the peptide with the length of 4 - 40 amino acids comprising the sequence CKGC (SEQ ID NO: l) or CRAC (SEQ ID NO:2) can be
  • compositions of the invention are prepared for storage by mixing the peptide having the desired degree of purity with optional physiologically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A., Ed., (1980)), in the form of lyophilized cake or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or
  • immunoglobulins include hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counter-ions such as sodium; and/or non- ionic surfactants such as Tween, Pluronics or polyethylene glycol (PEG).
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, arginine, or lysine
  • monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins include chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counter-ions
  • the peptides may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles, and nanocapsules), or in macroemulsions.
  • coacervation techniques for example, hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacylate) microcapsules, respectively
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano- particles, and nanocapsules
  • the route of peptide administration is in accord with known methods as well as the general routes of injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, or intralesional means, or sustained release systems as noted below.
  • the peptide is administered continuously by infusion or by bolus injection. Generally, where the disorder permits, one should formulate and dose the peptide for site-specific delivery.
  • Administration can be continuous or periodic. Administration can be accomplished by a constant- or programmable-flow implantable pump or by periodic injections.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the peptide, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels as described by Langer et al., J. Biomed. Mater. Res., 15: 167-277 (1981) and Langer, Chem. Tech., 12:98-105 (1982) or polyvinylalcohol, polylactides (U.S. Pat. No. 3,773,919, EP 58,481), or non-degradable ethylene-vinyl acetate (Langer et al., supra).
  • a pharmaceutical composition comprising the peptide of the invention as defined above is for use in the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, peripheral neuropathy, epilepsy, diabetes or drug addiction (e.g., abuse of cocaine, morphine, amphetamine, or alcohol).
  • the present invention provides a method for promoting survival of dopaminergic neurons comprising the step of contacting dopaminergic neurons with the peptide of 4 - 40 amino acids comprising the sequence CKGC (SEQ ID NO: l) or CRAC (SEQ ID NO:2) .
  • the method is performed in vitro as shown below in the
  • Said dopaminergic neurons are preferably cultured non-human neurons, such as mouse or rat sympathetic neurons.
  • the invention is also directed to a peptide with the length of 4 - 40 amino acids comprising the sequence CXXC (SEQ ID NO:5) for use in the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, peripheral neuropathy, epilepsy, diabetes, such as type I and type II diabetes, or drug addiction (e.g., abuse of cocaine, morphine, amphetamine, or alcohol).
  • a peptide with the length of 4 - 40 amino acids comprising the sequence CXXC (SEQ ID NO:5) for use in the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, peripheral neuropathy, epilepsy, diabetes, such as type I and type II diabetes, or drug addiction (e.g., abuse of cocaine, morphine, amphetamine, or alcohol).
  • the peptides (CASLO Laboratory ApS, Lyngby, Denmark) were dissolved in the water according to the manufacturer's instructions, divided into aliquots and stored at -80
  • polyornithine/laminin Sigma-coated 35-mm plastic dishes in the small-size standard microislands in the Neurobasal medium and B27 supplement (Invitrogen/Gibco) in the presence of 30 ng/ml mouse 2.5 S NGF (Promega) for 5-6 days. NGF was deprived by extensive washing and addition of the function-blocking anti-NGF antibodies (Roche). The neurons were pressure-microinjected with our special equipment (Hellman et al., 2011;
  • the midbrain floors were dissected from the ventral mesencephali of 13-d-old NMRI strain mouse embryos. Tissues were incubated with 0.5% trypsin (ICN Biomedical), then mechanically dissociated using a large fire-polished Pasteur pipette.
  • the neurons were grown on the poly-L-ornithine- coated (Sigma) culture dishes on the microislands of the standard size in DMEM/F12 medium (Invitrogen) containing N2 supplement (Invitrogen) in the presence or absence of GDNF (100 ng/ml) or the peptides for three days.
  • the cultures without added neurotrophic factors served as the negative control.
  • the cultures were fixed and immunostained with the antibodies to tyrosine hydroxylase (Millipore), a specific marker for the dopaminergic neurons. All immunopositive neurons were counted from each microisland and expressed as percent of GDNF-maintained neurons. The experiments were repeated 3-5 times on the independent cultures.
  • Rat pheochromocytoma PC6 cells were grown in the DMEM (Invitrogen) containing 10% of horse serum (PAA Laboratories, Pasching, Austria), 5% of fetal bovine serum (HyClone, Thermo Scientific, UK). The number of the neurons was counted in real-time using Cell-IQ machine (Chipman).
  • the 6-OHDA model of Parkinson's disease will be applied in two paradigms: neuroprotective and neurorestorative.
  • the factors MANF, CDNF or the respective peptides are stereotaxically injected into the left striata of the rats 6 h before injection of neurotoxin 6-OHDA.
  • concentrations of the peptides must be determined empirically, taking into account the results of the in vitro titration experiments.
  • amphetamine is injected to the same site and the rotational behavior induced by the amphetamine is measured. The more the neurons are damaged by 6-OHDA, the more the rats rotate.
  • the brains of the rats are fixed, immunostained for the tyrosine hydroxylase, and the dopaminergic neurons and their fibers quantified stereologically.
  • the neurotoxin 6-OHDA is applied first, and the growth factors or the peptides four weeks later.
  • the behavioural tests are carried out 1 week before (that is, 3 weeks after 6-OHDA injection) and 2, 4, 6 and 8 weeks after the growth factor injections.
  • the neurotoxin MPTP is applied systemically to the peritoneum of 2the mice either 20 h before the factors or peptides (neuroprotective model) or one week before the factors or peptides (neurorestorative model) are performed essentially as in the case of 6-OHDA.
  • the behavioural tests will be performed two weeks later and the histological analysis at the end of the experiment.
  • the right middle cerebral artery and bilateral common carotids of the rats are ligated with specific suture for 60 min to cause infarction in one cortical hemisphere.
  • the factors (MANF, CDNF) or the corresponding CXXC-peptides are applied about 20 min before (neuroprotective model).
  • Several behavioural tests will be performed 2, 7 and 14 days after the treatment and the histological analysis will be performed at the end of the
  • mice carrying mutated human APPswe and PSldE genes will be used.
  • the MANF/CDNF proteins or the corresponding CXXC-peptides will be stereotaxically injected into the hippocampi of these mice.
  • a battery of behavioural tests will be performed 3 weeks after the injection.
  • the number of amyloid plaques and the neuroinflammation (microglia, reactive astroglia) around the plaques, as well as the adult neurogenesis (doublecortin immunostaining) will be analysed at the end of the experiment.
  • the mechanism of action of the peptide is currently being studied.
  • the neuroprotective activities seem to depend on the cysteines of the CXXC motif.
  • This motif is known to be critical in the active center of the enzymes of thioredoxin superfamily.
  • the reactive cysteines can also be modified (S-glutathionation, S-sulfenation, S-nitrosation) and participate in the redox-regulation of proteins, in both physiological and pathological (against oxidative or nitrosative stress) situations.
  • the CXXC motif can bind and coordinate metal ions (Zn 2+ , Cd 2+ , Cu 2+ ), thereby controlling metal detoxifixation, metal ion transport etc.
  • CDNF has a similar evolutionarily conserved CXXC-containing sequence EECRACAE in the corresponding position of the C-terminal domain.
  • MANF/CDNF- derived peptides can also protect and repair the degenerating neurons in vivo, just as the full- length proteins (Lindholm et al., 2007; Voutilainen et al., 2009; Voutilainen et al., 2011; Airavaara et al., 2010; Airavaara et al., 2009).
  • such short peptides will certainly diffuse better in the brain parenchyma than the large protein factors. More importantly, such cell-penetrating peptides could also penetrate the brain-blood barrier, such that these could potentially applied systemically via the bloodstream.
  • MANF and CDNF proteins can protect a wide range of cells when expressed intracellularly by transfection of the plasmids (unpublished), we predict that the peptides could be applied also to the non-neuronal pathological conditions.
  • MANF has been related to the alleviation of the endoplasmic reticulum stress (Mizobuchi et al., 2007; tendou et al., 2008).
  • MANF and its CXXC-peptide (but also CDNF and its CXXC- peptide) has potential to be effective on the disease models of the endoplasmic stress-related conditions, in particular the endocrinological disease, and in particular, the type I and type II diabetes.
  • a major cause for the development of diabetes is the endoplasmic reticulum stress in the beta-cells of the Langerhans islands and according to our preliminary results, MANF is related to the development of the conditions for type I diabetes.
  • Rats were operated stereotaxically in two sessions using isoflurane anesthesia.
  • the rats were injected PBS-vehicle, GDNF 10 ⁇ g, MANF peptide CKGC 1, 10 or 30 ⁇ g in 4 ⁇ L ⁇ unilaterally into the left striatum (coordinates relative to bregma and dura: A/P +1,0; L/M +2,7; D/V -4,0).
  • the rats received 6-OHDA-injection (10 ⁇ g in 4 ⁇ ) into the left striatum (the same coordinates as previously).
  • 6-OHDA has two ways of action that act synergistically: 1) it accumulates in the cytosol and forms free radicals causing oxidative stress; 2) it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. Noradrenergic neurons were protected by using a NAT-inhibitor desipramine (15 mg/kg, i.p., 30 mins before 6- OHDA -injection).
  • the size of the unilateral lesion and the effect of the treatments were measured with amphetamine induced rotational behavior 2 and 4 weeks after the lesion.
  • the number of amphetamine-induced (2,5 mg/kg, i.p.) full (360°) ipsi- and contralateral turns were recorded for 120 mins after a 30 mins habituation period.
  • the results are expressed as net ipsilateral turns to the lesion side (see Figure 8).
  • Exclusion criterion was Mean (net rotations) + 2 x STDEV.
  • CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. /. Neurosci. in press .
  • Neuronal apoptosis inhibitory protein Structural requirements for hippocalcin binding and effects on survival of NGF-dependent sympathetic neurons. Biochim.Biophys.Acta.
  • Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature. 448:73-77.
  • Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease. J.Neurosci. 29:9651-9659. doi:
  • mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons.

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Abstract

La présente invention concerne les domaines des peptides bioactifs et des peptides de pénétration cellulaire, ainsi que le domaine des facteurs neurotrophiques, c'est-à-dire les facteurs de croissance pour cellules neuronales. La présente invention concerne des peptides d'une longueur de 4 à 40 acides aminés comprenant la séquence CKGC (SEQ ID NO:1) ou CRAC (SEQ ID NO:2). L'invention concerne également des compositions pharmaceutiques comprenant lesdits peptides, ainsi que les peptides destinés à être utilisés dans le traitement de la maladie d'Alzheimer, la maladie de Parkinson, la sclérose latérale amyotrophique, l'accident vasculaire cérébral, la neuropathie périphérique, l'épilepsie, le diabète ou la toxicomanie. L'invention concerne également un procédé permettant de favoriser la survie des neurones dopaminergiques. De plus, l'invention concerne également les peptides d'une longueur de 4 à 40 acides aminés comprenant la séquence CXXC (SEQ ID NO:5) destinés à être utilisés dans les maladies susmentionnées.
PCT/FI2012/050859 2011-09-05 2012-09-05 Peptides de pénétration cellulaire neuroprotecteurs Ceased WO2013034805A1 (fr)

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FI20115870A FI20115870A0 (fi) 2011-09-05 2011-09-05 Neuroprotektiiviset soluihin tunkeutuvat peptidit

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014191630A3 (fr) * 2013-05-28 2015-03-12 Helsingin Yliopisto Modèle animal non humain codant pour un gène manf non fonctionnel
WO2015134485A1 (fr) * 2014-03-05 2015-09-11 Schwartz Lawrence M Procédés et compositions de protection des cellules sensorielles
WO2015149005A1 (fr) * 2014-03-28 2015-10-01 Buck Institute For Research On Aging Méthodes et compositions pour moduler le système immunitaire
EP2820424A4 (fr) * 2012-01-24 2015-10-21 Univ Massachusetts Manf soluble dans les troubles des cellules bêta pancréatiques
WO2015200469A1 (fr) * 2014-06-24 2015-12-30 University Of Massachusetts Manf en tant que régulateur du fonctionnement du système immunitaire
WO2017085362A1 (fr) 2015-11-18 2017-05-26 Herantis Pharma Plc Compositions comprenant du cdnf ou du manf pour une utilisation dans le traitement par voie intranasale de maladies du système nerveux central
WO2018202957A1 (fr) 2017-05-04 2018-11-08 Helsingin Yliopisto Fragments cdnf et manf c-terminaux, compositions pharmaceutiques les comprenant et leurs utilisations
WO2019185994A1 (fr) 2018-03-29 2019-10-03 Helsingin Yliopisto Fragments cdnf c-terminaux, compositions pharmaceutiques les comprenant et leurs utilisations
EP3838912A1 (fr) 2019-12-20 2021-06-23 Herantis Pharma Oyj Peptides rétro inverses
EP3838345A1 (fr) 2019-12-20 2021-06-23 Herantis Pharma Oyj Peptides macrocycliques

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WO2014191630A3 (fr) * 2013-05-28 2015-03-12 Helsingin Yliopisto Modèle animal non humain codant pour un gène manf non fonctionnel
WO2015134485A1 (fr) * 2014-03-05 2015-09-11 Schwartz Lawrence M Procédés et compositions de protection des cellules sensorielles
US10265380B2 (en) 2014-03-05 2019-04-23 Amarantus Bioscience Holdings, Inc. Method of administering MANF for the protection of sensory cells
WO2015149005A1 (fr) * 2014-03-28 2015-10-01 Buck Institute For Research On Aging Méthodes et compositions pour moduler le système immunitaire
WO2015200469A1 (fr) * 2014-06-24 2015-12-30 University Of Massachusetts Manf en tant que régulateur du fonctionnement du système immunitaire
WO2017085362A1 (fr) 2015-11-18 2017-05-26 Herantis Pharma Plc Compositions comprenant du cdnf ou du manf pour une utilisation dans le traitement par voie intranasale de maladies du système nerveux central
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JP2020518261A (ja) * 2017-05-04 2020-06-25 ヘルシンギン ユリオピストＨｅｌｓｉｎｇｉｎ Ｙｌｉｏｐｉｓｔｏ Ｃ末端ｃｄｎｆ断片及びｃ末端ｍａｎｆ断片、それらを含む医薬組成物、並びにそれらの使用
WO2018202957A1 (fr) 2017-05-04 2018-11-08 Helsingin Yliopisto Fragments cdnf et manf c-terminaux, compositions pharmaceutiques les comprenant et leurs utilisations
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JP7384672B2 (ja) 2017-05-04 2023-11-21 ヘルシンギン ユリオピスト Ｃ末端ｃｄｎｆ断片及びｃ末端ｍａｎｆ断片、それらを含む医薬組成物、並びにそれらの使用
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WO2019185994A1 (fr) 2018-03-29 2019-10-03 Helsingin Yliopisto Fragments cdnf c-terminaux, compositions pharmaceutiques les comprenant et leurs utilisations
US12479895B2 (en) 2018-03-29 2025-11-25 Myneurocure Oy C-terminal CDNF and MANF fragments, pharmaceutical compositions comprising same and uses thereof
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JP2021519578A (ja) * 2018-03-29 2021-08-12 ヘルシンギン ユリオピストＨｅｌｓｉｎｇｉｎ Ｙｌｉｏｐｉｓｔｏ Ｃ末端ｃｄｎｆ断片、それらを含む医薬組成物、並びにそれらの使用
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