WO2020109546A1 - Traitement de maladies cardiovasculaires - Google Patents

Traitement de maladies cardiovasculaires Download PDF

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Publication number
WO2020109546A1
WO2020109546A1 PCT/EP2019/083077 EP2019083077W WO2020109546A1 WO 2020109546 A1 WO2020109546 A1 WO 2020109546A1 EP 2019083077 W EP2019083077 W EP 2019083077W WO 2020109546 A1 WO2020109546 A1 WO 2020109546A1
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seq
amino acid
peptide
acid substitutions
sequence
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PCT/EP2019/083077
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David Paul Drucker Woldbye
Morten Schak Nielsen
Christa Funch JENSEN
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University Of Copenhagen
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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
    • A61K38/16—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
    • A61K38/22—Hormones
    • A61K38/2271—Neuropeptide Y
    • 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
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to compounds that bind to Neural Cell Adhesion Molecule (NCAM), in particular neuropeptide Y (NPY)-derived peptide fragments, for use in the treatment of cardiovascular diseases, such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • NCAM Neural Cell Adhesion Molecule
  • NPY neuropeptide Y
  • Cardiovascular disease is a general term for conditions affecting the heart or blood vessels. According to the World Health Organization (WHO), more people die from cardiovascular diseases than from any other cause. In 2016, approximately 17.9 million people died from cardiovascular diseases, representing 31 % of all global deaths.
  • WHO World Health Organization
  • Cardiac arrest which is a sudden loss of blood flow resulting from the failure of the heart to pump effectively, is the cause of about half of deaths due to cardiovascular disease. About 80% of sudden cardiac death is the result of ventricular arrhythmias.
  • antiarrhythmic drugs on the market today, which mainly target ion channels and changes in action potential morphology. These antiarrhythmic drugs are often associated with pro-arrhythmias or severe side effects, and hence, there is a need for more safe anti-arrhythmic drugs, such as drugs that target cardiac conduction velocity rather than the action potential.
  • Neuropeptide Y is a 36 amino acid-long polypeptide (NPY1-36; SEQ ID NO: 1 ) widely distributed in the central and peripheral nervous system of mammals. NPY is the most abundant neuropeptide in the brain and is known to induce vasoconstriction, to inhibit noradrenaline release at a pre-synaptic level, and to regulate diverse functions including blood pressure, stress, pain, hormone secretion, reproduction, circadian rhythm and food intake. NPY has been implicated in feeding disorders, epilepsy, hypertension, pain disorders, depression and anxiety.
  • NPY is known to bind and stimulate receptors belonging to the GPCR family, also known as seven-transmembrane receptors (7TM); including NPY receptors Y1 , Y2, Y3, Y4, Y5 and Y6 (aka y6). In the central nervous system, NPY predominantly acts via Y1 , Y2 and Y5. These 7TM receptors display different affinities for full-length NPY and N- terminally truncated fragments thereof such as NPY3-36; a physiological cleavage product which loses affinity for the Y1 receptor to become an Y2/Y5 receptor agonist. NPY is known to exert neuroprotective and neurogenic effects reported to occur via activation of the GPCR NPY-receptors.
  • 7TM seven-transmembrane receptors
  • NPY fragments have been disclosed that retain activity at the native NPY receptors, including some of 8 to 18 amino acids in length with a D-Thr amino acid substitution of the Thr32 position, such as NPY27-36, for inducing satiety and lowering blood pressure (Nyce et al. US 6,426,330); expression vectors comprising a nucleic acid encoding NPY or a functional fragment thereof, such as NPY2-36, NPY13-36, NPY16-36 and NPY18-36, for treating neurological diseases (During et al.
  • NPY Native NPY is known to bind to and exert its various biological effects through NPY receptors Y1-Y6.
  • NPY as an Y1-Y6 ligand or agonist is dependent on amino acid residue 36 (Tyr36), which position is amidated. It has previously been shown that NPY not comprising Tyr36 lacks the classical NPY effects such as on food intake which is mediated through the classical or cognate NPY-receptors (Y1-Y6).
  • NPY3-35 is known in the art as a degradation product with no biological effects through the known NPY-receptors (Abid et al. J Biol Chem Vol 284, No 37, pp. 24715-24724, 2009).
  • NPY as well as fragments thereof lacking Tyr36 bind predominantly to the Ig1 module of NCAM, in the area where two NCAM molecules would otherwise interact. Without residue Tyr36, the NPY fragments do not bind to and activate the cognate NPY-receptors and thus effectively avoids the risk of adverse effects through general activation of Y1-Y6 receptors.
  • the NPY peptides have several neuronal effects and are known to be useful in treating disorders of the central nervous system and the eye.
  • NPY attenuates vagal bradycardia via a pre-synaptic decrease in
  • NPY Y2 receptor pathway a Y2 receptor pathway
  • US 2012/040885 discloses NPY peptide variants having at least one unnatural amino acid substitution for treating diseases mediated by neuropeptide-Y-receptor binding such as arrhythmia.
  • the present disclosure concerns a compound that binds to NCAM for use in the treatment of cardiovascular diseases; such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • Said compound binding to NCAM are in preferred embodiments a peptide.
  • the present disclosure concerns a peptide, said peptide consisting of from 15 to 35 contiguous amino acid residues derived from NPY (SEQ ID NO: 1 ), wherein said peptide comprises at least the sequence YSALRHYINLITRQR (NPY21- 35; SEQ ID NO: 22), or a functional variant having at least 60% sequence identity to
  • SEQ ID NO: 22 wherein said peptide does not comprise the Tyr amino acid of position 36 of SEQ ID NO: 1 , for use in a method of treating cardiovascular diseases; such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • FIG. 1A Treatment protocol for Langendorff perfused hearts, and representative electrical and mechanical traces. An overview of the protocol is depicted in Figure 1A.
  • Hearts were perfused for 30 min at baseline before treatment was initiated (NPY3-35 or vehicle) and maintained for 60 min. After 15 min of treatment, flow was stopped for 35 min to induce global no flow ischemia. The flow was subsequently reestablished, reperfusing the hearts for 15 min with treatment followed by 105 min without treatment. ECG (panel 1 and 3) and developed pressure (panel 2 and 4) was continuously recorded. The 6 images from each group represent B: baseline , C: 13 min. into treatment but before no flow, D: during no flow, E, F and G: after reperfusion. All hearts lost electrical and mechanical function during no flow ischemia. During reperfusion, all hearts regained sinus rhythm, but some hearts degenerated into ventricular
  • FIG. 4 Effect of NPY3-35 on conduction velocity (mouse model).
  • NPY3- 35 exerts its effect by binding to and subsequent signaling via NCAM and NPY3-35 was therefore tested in wild-type (WT; A) mice and in NCAM knock-out (KO; B) mice.
  • Conduction velocity (CV) measured in right ventricular tissue strips at baseline (10 min, buffer pH 7.4, glucose 5 mM, equilibrated with 100 % 02) followed by treatment with either vehicle (black lines) or NPY3-35 (grey lines) for the remainder of the experiment. After 10 minutes of treatment, strips were subjected to 30 minutes of simulated ischemia (buffer pH 6.8, no glucose, equilibrated with atmospheric air) followed by reperfusion.
  • FIG. 5 Relative conduction velocity (CV) change between time point 20 and 70 min.
  • the CV recovery after ischemia is illustrated as relative CV change for WT and NCAM KO mice treated with either NPY3-35 or vehicle.
  • NCAM KO mice there were no difference in relative CV change between vehicle and NPY3-35 threated hearts.
  • CV increased significantly in WT mice treated with NPY3-35 (15.5 % vs 0.6 % in vehicle treated strips ( * p ⁇ 0.05, Student t-test). Data are presented as mean ⁇ SEM.
  • FIG. 6 Conduction velocity (CV) recovery during reperfusion.
  • the CV recovery after ischemia is illustrated as CV development for every 4 min. (as an average over 2 min) from time point 50 to 70 min. in WT (A) and NCAM KO mice (B) treated with either NPY3-35 or vehicle.
  • the CV recovery in WT mice was significantly influenced by treatment (P ⁇ 0.05, two-way repeated measures ANOVA).
  • CV was significantly higher in the NPY3-35 treated group at time point 62, 66 and 70, compared to the vehicle treated group (Bonferroni post hoc test).
  • NCAM KO mice the CV recovery was not influences by the treatment indicating a role of NCAM for CV recovery.
  • FIG. 7 Effect of NPY3-35 on conduction velocity in rat right ventricular myocardium.
  • Conduction velocity was measured in right ventricular tissue strips at baseline (10 min, buffer pH 7.4, glucose 5 mM, equilibrated with 100 % 02) followed by treatment with either vehicle (black line) or two different doses of NPY3-35 (0.1 mM in dashed line and 1 pM in dotted line) for the remainder of the experiment. After 10 min treatment, strips were subjected to 30 min simulated ischemia (buffer pH 6.8, no glucose, equilibrated with atmospheric air) followed by reperfusion (same buffer as baseline).
  • FIG. 8 Effect of NPY10-35 and NPY21-35 on conduction velocity in rat right ventricular myocardium.
  • Affinity the strength of binding between receptors and their ligands.
  • agonist in the present context refers to a compound as defined herein, capable of binding to and activating a receptor.
  • antagonist in the present context refers to a compound as defined herein, capable of binding to a receptor and blocking or damping a biological response of said receptor.
  • the term“individual” refers to vertebrates, particular members of the mammalian species, preferably primates including humans. As used herein,‘subject’ and ‘individual’ may be used interchangeably.
  • polypeptide is a polymer of amino acid residues preferably joined exclusively by peptide bonds, whether produced naturally or synthetically.
  • polypeptide as used herein covers proteins, peptides and polypeptides, wherein said proteins, peptides or polypeptides may or may not have been post-translationally modified.
  • a peptide is usually shorter in length than a protein, and single-chained.
  • An "isolated polypeptide” is a polypeptide or protein separated and/or recovered from a component of their natural, typically cellular, environment, that is essentially free from contaminating cellular components, such as carbohydrate, lipid, or other proteinaceous impurities associated with the polypeptide in nature. However, the term “isolated” does not exclude the presence of the same polypeptide in alternative physical forms, such as dimers, tetramers or alternatively glycosylated or derived forms.
  • amino acid residue can be a natural or non-natural amino acid residue linked peptide bonds or bonds different from peptide bonds.
  • the amino acid residues can be in D-configuration or L-configuration.
  • An amino acid residue comprises an amino terminal part (NH2) and a carboxy terminal part (COOH) separated by a central part comprising a carbon atom, or a chain of carbon atoms, at least one of which comprises at least one side chain or functional group.
  • NH2 refers to the amino group present at the amino terminal end of an amino acid or peptide
  • COOH refers to the carboxy group present at the carboxy terminal end of an amino acid or peptide.
  • the generic term amino acid comprises both natural and non-natural amino acids.
  • Natural amino acids of standard nomenclature as listed in J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., section 1.822(b)(2) belong to the group of amino acids listed in Table 1 herein below. Non-natural amino acids are those not listed in Table 1. Also, non-natural amino acid residues include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues.
  • an“equivalent amino acid residue” refers to an amino acid residue capable of replacing another amino acid residue in a polypeptide without substantially altering the structure and/or functionality of the polypeptide. Equivalent amino acids thus have similar properties such as bulkiness of the side-chain, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain organization of carbon molecules (aromatic/aliphatic). As such,“equivalent amino acid residues” can be regarded as“conservative amino acid substitutions”.
  • equivalent amino acids refers in one embodiment to the following classes: 1 ) HRK, 2) DENQ, 3) C, 4) STPAG, 5) MILV and 6) FYW.
  • one amino acid may be substituted for another, in one embodiment, within the groups of amino acids indicated herein below: i) Amino acids having polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Tyr, and Cys,)
  • A“Bioactive agent” i. e., biologically active substance/agent
  • biologically active substance/agent is any agent, drug, compound, composition of matter or mixture which provides some pharmacologic, often beneficial, effect that can be demonstrated in vivo or in vitro. It may refer to the peptide sequences according to the present invention, compounds or compositions comprising these and nucleic acid constructs encoding said peptides. As used herein, this term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in an individual.
  • bioactive agents include, but are not limited to, agents comprising or consisting of an oligosaccharide, agents comprising or consisting of a polysaccharide, agents comprising or consisting of an optionally glycosylated peptide, agents comprising or consisting of an optionally glycosylated polypeptide, agents comprising or consisting of a nucleic acid, agents comprising or consisting of an oligonucleotide, agents comprising or consisting of a polynucleotide, agents comprising or consisting of a lipid, agents comprising or consisting of a fatty acid, agents comprising or consisting of a fatty acid ester and agents comprising or consisting of secondary metabolites. It may be used either prophylactically, therapeutically, in connection with treatment of an individual, such as a human or any other animal.
  • drug include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body.
  • treatment refers to the management and care of a patient for the purpose of combating a condition, disease or disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, and refer equally to curative therapy, prophylactic or preventative therapy and ameliorating or palliative therapy, such as administration of the peptide or composition for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, partially arresting the clinical manifestations, disease or disorder; curing or eliminating the condition, disease or disorder;
  • the term "palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering compositions of the present invention.
  • the individual to be treated is preferably a mammal, in particular a human being.
  • mice Treatment of animals, such as mice, rats, dogs, cats, cows, horses, sheep and pigs, is, however, also within the scope of the present disclosure.
  • An“individual in need thereof refers to an individual who may benefit from the present disclosure.
  • said individual in need thereof is a diseased individual, wherein said disease may be a cardiovascular disease, such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • a “treatment effect” or “therapeutic effect” is manifested if there is a change in the condition being treated, as measured by the criteria constituting the definition of the terms “treating” and “treatment.”
  • There is a “change” in the condition being treated if there is at least 5% improvement, preferably 10% improvement, more preferably at least 25%, even more preferably at least 50%, such as at least 75%, and most preferably at least 100% improvement.
  • the change can be based on improvements in the severity of the treated condition in an individual, or on a difference in the frequency of improved conditions in populations of individuals with and without treatment with the bioactive agent, or with the bioactive agent in combination with a pharmaceutical composition of the present invention.
  • a treatment according to the invention may be prophylactic, ameliorating or curative.
  • physiologically effective amount of a“bioactive agent” is the amount of an active agent present in a pharmaceutical composition as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual (e.g. the heart, blood vessels, the lungs, the gastric system, the colorectal system, prostate, etc.) to be treated to give an anticipated physiological response when such composition is administered.
  • the precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e. the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein.
  • an“effective amount” of a bioactive agent can be administered in one administration, or through multiple administrations of an amount that total an effective amount, preferably within a 24-hour period. It can be determined using standard clinical procedures for determining appropriate amounts and timing of administration. It is understood that the "effective amount” can be the result of empirical and/or
  • enhancing and“improving” a beneficial effect refers to the therapeutic effect of the bioactive agent against placebo, or an increase in the therapeutic effect of a state-of-the-art medical treatment above that normally obtained when a pharmaceutical composition is administered without the bioactive agent of this invention.
  • An increase in the therapeutic effects is manifested when there is an acceleration and/or increase in intensity and/or extent of the therapeutic effects obtained as a result of administering the bioactive agent(s). It also includes extension of the longevity of therapeutic benefits.
  • the enhancing effect preferably, but not necessarily, results in treatment of acute symptoms for which the pharmaceutical composition alone is not effective or is less effective therapeutically. Enhancement is achieved when there is at least a 5% increase in the therapeutic effects, such as at least 10% increase in the therapeutic effects when a bioactive agent of the present invention is co-administered with a pharmaceutical composition compared with administration of the pharmaceutical composition alone.
  • the increase is at least 25%, more preferably at least 50%, even more preferably at least 75%, most preferably at least 100%.
  • "Coadministering" or "co-administration" of bioactive agents / peptides of the invention and state-of-the-art medicaments refer to the administration of one or more bioactive agents of the present invention, or administration of one or more bioactive agents of the present invention and a state-of-the-art pharmaceutical composition within a certain time period.
  • the time period is preferably less than 72 hours, such as 48 hours, for example less than 24 hours, such as less than 12 hours, for example less than 6 hours, such as less than 3 hours.
  • these terms also mean that the bioactive agent and a therapeutic composition can be administered together.
  • Neuropeptide Y (NPY; NPY1-36; SEQ ID NO: 1 ) is a highly conserved 36-amino acid endogenous peptide neurotransmitter, the most abundant neuropeptide in the brain and the autonomic nervous system of humans.
  • NPY neuropeptide Y
  • SEQ ID NO: 1 Neuropeptide Y
  • NPY neuropeptide Y
  • SEQ ID NO: 1 the effects of NPY1-36 are mediated through binding to cognate NPY-receptors with varying degree.
  • At least six NPY receptors have been identified so far; Y1 , Y2, Y3, Y4, Y5 and Y6; five NPY receptors in mammals: Y1 , Y2, Y4, Y5 and Y6 (or y6; used interchangeably herein). They are G-protein coupled receptors belonging to the 7TM (7 transmembrane domains) family.
  • the Y1 receptor has highest affinity for full-length NPY, while Y2 and Y5 bind and are stimulated by full- length NPY and N-terminally truncated NPY.
  • the physiological effects associated with the Y1 and Y2 receptors are the best known; exposure to a Y1 agonist causes an increase in blood pressure and potentiates postsynaptically the action of other vasoactive substances, whereas Y2 receptors are mainly located presynaptically, and upon stimulation mediate the inhibition of neurotransmitter release.
  • Y2 exerts a negative-feedback pathway in that its activation by NPY or NPY fragments in turn negatively regulates NPY release.
  • NPY is a prototype of peptide whose function can be altered by proteases. Among peptidases displaying a high affinity for NPY, the primary role appears to be played by serine-type protease dipeptidyl peptidase IV (CD26) that releases an N-terminal dipeptide. By cleaving the N-terminal Tyr-Pro dipeptide off NPY CD26 generates NPY3-36, a truncated form that loses its affinity for the Y1 receptor and becomes a Y2/Y5 receptor agonist.
  • CD26 serine-type protease dipeptidyl peptidase IV
  • NPY can also be degraded by aminopeptidase P (AmP) by removing the N-terminal tyrosine from NPY to generate NPY2-36, a selective Y2 agonist. It has been indicated that the 36th, 35th, and 33rd residues of NPY analogues may also be removed by carboxypeptidases.
  • AmP aminopeptidase P
  • NPY and its receptors are expressed throughout the body, both in the central nervous system (CNS) and in the sympathetic nervous system.
  • CNS central nervous system
  • NPY regulates cardiovascular and other sympathetic functions together with norepinephrine.
  • NPY displays vasoconstrictor activity exerted by inhibiting Ca 2+ -activated K + channels in vascular smooth muscle, and it has been implicated in the control of blood pressure, sexual behaviour, food intake, neurological disorders, alcoholism, bone physiology, regulation of energy, circadian rhythms, balance, memory and learning.
  • NPY plays an important role in mood disorders, anxiety, epilepsy and depression. Central NPY levels in the cerebrospinal fluid are low in subjects suffering from depression and correlate inversely with anxiety. Anti-depressant-like effects can be achieved in mice by administering a Y2 antagonist or a Y1 agonist. Y1 has also been implicated in the mediation of adult neuronal proliferation and hippocampal neurogenesis. Importantly, the effects of NPY are commonly accepted to be a result of its interactions with its 7TM receptors.
  • NPY1-36 is characterised by C-terminal amidation of the amino acid at position 36 (Tyr36). The Tyr36 amino acid and its amidation is important for the classical binding of NPY1-36 to the cognate NPY-receptors (Y1-Y6/y6) (Berglund et al. 2003). NPY is also known to interact with NCAM (WO 2014/166497).
  • NPY1-36 This interaction is shown not only for full-length NPY1-36 and certain N-terminally truncated fragments, but to a greater extent for specified NPY fragments not comprising Tyr36, including NPY3-35 (SEQ ID NO: 4).
  • This interaction occurs predominantly through binding to the Ig1 module of NCAM (i.e. where two NCAM molecules usually interact - NCAM homophilic c/ ' s-interaction). No binding is observed to the Ig3 module of NCAM.
  • NPY1-36 retains its binding capability to its cognate NPY-receptors (Y1-Y6) besides the interaction with NCAM.
  • peptide fragments not comprising Tyr36 SEQ ID NO:s 2-22
  • NPY3-35 SEQ ID NO: 4
  • the NCAM binding of SEQ ID NO:s 2 to 22 is highly specific. This holds great potential in reducing the risk of adverse effects associated with administering NPY1-36, by avoiding the general activation of the cognate NPY- receptors.
  • NCAM Neural Cell Adhesion Molecule
  • NCAM is a homophilic binding glycoprotein expressed on the surface of neurons, glia, striated muscle (skeletal and cardiac) and natural killer cells. NCAM has been implicated as having a role in cell-cell adhesion, neurite outgrowth, synaptic formation and plasticity, path-finding of axons, early synaptogenesis, synaptic maturation and learning and memory. Many aspects of neuronal development involve cell-cell adhesion mechanisms; these include neuronal cell migration, axon-bundle and synapse formation, formation of glial networks surrounding axons and synapses. NCAM is a member of the Ig superfamily Cell Adhesion Molecules (CAMs) and is found predominantly in the synapses. Evidence suggests that NCAM mediates
  • NCAM Fibroblast growth factor receptor
  • FGFR Fibroblast growth factor receptor
  • FNIII fibronectin type III
  • NCAM is known to have heterophilic and homophilic interactions with various ligands at the synapses. The different domains of NCAM have different roles, with the Ig domains being involved in homophilic (NCAM-NCAM) binding, while the FNIII domains are involved in signalling leading to neurite outgrowth.
  • NCAM-120kDa GPI anchored
  • NCAM-140kDa short cytoplasmic domain
  • NCAM-180kDa long cytoplasmic domain
  • NCAM can also be modified by the insertion of minor exons, which can modulate its activities.
  • NCAM can further be modified by the addition to its fifth Ig domain of the negatively charged, polysialic acid (PSA) which appears to play an important role in the synapse formation mediated by NCAM. PSA has indeed been shown to be important for long-term potentiation (LTP).
  • PSA polysialic acid
  • LTP long-term potentiation
  • NCAM further interacts with brain derived neurotrophic factor (BDNF) and Glial cell-derived neurotrophic factor (GDNF).
  • BDNF brain derived neurotrophic factor
  • GDNF Glial cell-derived neurotrophic factor
  • the present inventors have surprisingly found and demonstrated herein that NPY fragments not comprising the C-terminal amino acid of native NPY1-36; Tyr36 increase cardiac conduction velocity (CV), and that this effect occurs through a specific interaction with NCAM. It has previously been shown that NPY fragments not comprising the C-terminal amino acid of native NPY1-36; Tyr36 do not bind to the cognate NPY-receptors, and hence said NPY fragments not comprising Tyr36 provides for a more specific approach to targeting NCAM; in the present setting for targeting NCAM in the heart.
  • the present disclosure concerns a compound that is capable of binding to NCAM for use in the treatment of a cardiovascular disease in particular cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • the compounds disclosed herein are capable of interacting (i.e. interacts) with NCAM and/or are capable of binding to (i.e. binds to) NCAM.
  • the binding of the compound to NCAM causes an increase in cardiac conduction velocity.
  • the compounds disclosed herein are capable of interacting with and/or binding to NCAM via the Ig1 module, and/or the Ig2 module of NCAM, and/or not the Ig3 module of NCAM.
  • the present peptides bind to the NCAM Ig1 module.
  • the peptides bind to the NCAM Ig1 module and not the NCAM Ig3 module.
  • the peptides do not bind to the NCAM Ig3 module.
  • binding of the compounds disclosed herein to NCAM results in a modulation of NCAM mediated cell-cell adhesion or cell-extracellular matrix interaction.
  • said NCAM mediated cell-cell adhesion is homophilic or heterophilic.
  • said NCAM mediated cell-cell adhesion or cell- extracellular matrix interaction is a cis-interaction or a trans-interaction.
  • binding of the compounds disclosed herein to NCAM results in a modulation of NCAM-induced signalling.
  • binding of the compound of the present invention to NCAM results in an increase in NCAM-induced signalling.
  • the present disclosure provides a compound that is capable of binding to NCAM for use in the treatment of a cardiovascular disease.
  • said compound binding to NCAM is a peptide, such as a peptide derived from NPY.
  • a peptide consisting of a peptide sequence of from 15 to 35 contiguous amino acid residues derived from NPY (SEQ ID NO: 1 ), wherein said peptide does not comprise the amino acid of position 36 of SEQ ID NO: 1 , for use in a method of treating a cardiovascular disease, such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • said peptide does not comprise the Tyr amino acid of position 36 of SEQ ID NO: 1. In one embodiment, said peptide does not comprise any amino acid corresponding to position 36 of SEQ ID NO: 1. In one embodiment, the amino acid at the C-terminal is not a Tyr amino acid.
  • peptide consisting of from 15 to 35 contiguous amino acid residues derived from NPY (YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY;
  • said peptide is an isolated peptide.
  • the terms‘peptide’ and ‘isolated peptide’ may be used interchangeably herein. When reference is made to a ‘peptide’, this term will encompass both references to a peptide per se, and also to a peptide for use according to the present invention.
  • said peptide comprises at least the sequence YSALRHYINLITRQR
  • NPY21-35 SEQ ID NO: 22
  • a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 22; such as at least 65% sequence identity, for example at least 70% sequence identity, such as at least 75% sequence identity, such as at least 80% sequence identity, such as at least 85% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, for example at least 99% sequence identity to SEQ ID NO: 22.
  • the peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22), or a functional variant thereof with 6 amino acids substitutions, such as 5 amino acid substitutions, such as 4 amino acid substitutions, such as 3 amino acid substitutions, such as 2 amino acid substitutions, such as 1 amino acid substitutions.
  • the peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22), or a functional variant thereof having one or more conservative amino acid substitutions, such as 6 conservative amino acids
  • substitutions such as 5 conservative amino acid substitutions, such as 4 conservative amino acid substitutions, such as 3 conservative amino acid substitutions, such as 2 conservative amino acid substitutions, such as 1 conservative amino acid substitutions.
  • the peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22).
  • a peptide consisting of from 15 to 35 contiguous amino acid residues derived from NPY (YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY; SEQ ID NO: 1 ), wherein said peptide does not comprise the Tyr amino acid of position 36 of SEQ ID NO: 1 ,
  • peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22),
  • cardiac disease such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia.
  • a functional variant is a variant that retains the same biological activity or capabilities as the peptide from which it is derived.
  • Variants of peptides as disclosed herein are meant to be the functional equivalents of said sequences, i.e. retaining the functional capabilities of the native or unmodified sequences, such as retaining their ability to bind to NCAM and/or retaining their ability not to bind to cognate NPY receptors and/or retaining their ability to increase cardiac conduction velocity.
  • a peptide that‘comprises or consist of a sequence means that the peptide may comprise the sequence, consist of the sequence, or comprise at least the full sequence.
  • a peptide that‘comprises at least’ a peptide sequence, such as‘comprising at least the sequence YSALRHYINLITRQR’ means that the peptide includes all of the peptide sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22). It does not, however, exclude that additional components or amino acids may be present.
  • the peptide for use according to the present disclosure is selected from the group consisting of:
  • YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 1-35, SEQ ID NO: 2) PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 2-35, SEQ ID NO: 3) SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 3-35, SEQ ID NO: 4) KPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY4-35, SEQ ID NO: 5), PDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY5-35, SEQ ID NO: 6), DNPGEDAPAEDMARYYSALRHYINLITRQR (NPY6-35, SEQ ID NO: 7), NPGEDAPAEDMARYYSALRHYINLITRQR (NPY7-35, SEQ ID NO: 8),
  • GEDAPAEDMARYYSALRHYINLITRQR (NPY9-35, SEQ ID NO: 10),
  • PAEDMARYYSALRHYINLITRQR (NPY13-35, SEQ ID NO: 14),
  • AEDMARYYSALRHYINLITRQR (NPY14-35, SEQ ID NO: 15), EDMARYYSALRHYINLITRQR (NPY15-35, SEQ ID NO: 16),
  • said peptide is a functional variant having at least 60% sequence identity to a peptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22.
  • said peptide variant has at least 60% sequence identity, such as at least 65% sequence identity, for example at least 70% sequence identity, such as at least 75% sequence identity, for example at least 80% sequence identity, such as at least 85% sequence identity, for example at least 90% sequence identity, such as at least 95% sequence identity, for example at least 99% sequence identity to a peptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22.
  • said peptide variant comprises one or more amino acid
  • said peptide variant comprises one amino acid substitution, such as two amino acid substitutions, such as three amino acid substitutions, such as four amino acid substitutions, such as five amino acid substitutions, such as six amino acid substitutions, such as seven amino acid substitutions to the peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22.
  • said peptide variant comprises one or more conservative or equivalent amino acid substitutions as compared to any one of SEQ ID NO:s 2 to 22.
  • the peptide for use according to the present disclosure is a peptide consisting of 35 contiguous amino acid residues having the sequence
  • YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY1-35, SEQ ID NO: 2), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:2, or YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 34 contiguous amino acid residues having the sequence
  • PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY2-35, SEQ ID NO: 3), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:3, or PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 33 contiguous amino acid residues having the sequence
  • SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY3-35, SEQ ID NO: 4), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:4, or SKPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid
  • the peptide for use according to the present disclosure is a peptide consisting of 32 contiguous amino acid residues having the sequence
  • KPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY4-35, SEQ ID NO: 5), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:5, or KPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 31 contiguous amino acid residues having the sequence PDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY5-35, SEQ ID NO: 6), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:6, or PDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 30 contiguous amino acid residues having the sequence
  • DNPGEDAPAEDMARYYSALRHYINLITRQR (NPY6-35, SEQ ID NO: 7), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:7, or
  • DNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 29 contiguous amino acid residues having the sequence
  • NPGEDAPAEDMARYYSALRHYINLITRQR (NPY7-35, SEQ ID NO: 8), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:8, or
  • NPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 28 contiguous amino acid residues having the sequence
  • PGEDAPAEDMARYYSALRHYINLITRQR (NPY8-35, SEQ ID NO: 9), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:9, or
  • the peptide for use according to the present disclosure is a peptide consisting of 27 contiguous amino acid residues having the sequence
  • GEDAPAEDMARYYSALRHYINLITRQR (NPY9-35, SEQ ID NO: 10), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 10, or
  • GEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 26 contiguous amino acid residues having the sequence
  • EDAPAEDMARYYSALRHYINLITRQR (NPY10-35, SEQ ID NO: 1 1 ), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:1 1 , or
  • the peptide for use according to the present disclosure is a peptide consisting of 25 contiguous amino acid residues having the sequence DAPAEDMARYYSALRHYINLITRQR (NPY1 1-35, SEQ ID NO: 12), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:12, or
  • the peptide for use according to the present disclosure is a peptide consisting of 24 contiguous amino acid residues having the sequence
  • APAEDMARYYSALRHYINLITRQR (NPY12-35, SEQ ID NO: 13), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 13, or
  • the peptide for use according to the present disclosure is a peptide consisting of 23 contiguous amino acid residues having the sequence
  • PAEDMARYYSALRHYINLITRQR (NPY13-35, SEQ ID NO: 14), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 14, or
  • PAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 22 contiguous amino acid residues having the sequence
  • AEDMARYYSALRHYINLITRQR (NPY14-35, SEQ ID NO: 15), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 15, or
  • AEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 21 contiguous amino acid residues having the sequence
  • EDMARYYSALRHYINLITRQR (NPY15-35, SEQ ID NO: 16); or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:16, or
  • EDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 20 contiguous amino acid residues having the sequence
  • DMARYYSALRHYINLITRQR (NPY16-35, SEQ ID NO: 17), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:17, or
  • the peptide for use according to the present disclosure is a peptide consisting of 19 contiguous amino acid residues having the sequence MARYYSALRHYINLITRQR (NPY17-35, SEQ ID NO: 18), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 18, or
  • the peptide for use according to the present disclosure is a peptide consisting of 18 contiguous amino acid residues having the sequence
  • ARYYSALRHYINLITRQR (NPY18-35, SEQ ID NO: 19), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:19, or ARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 17 contiguous amino acid residues having the sequence
  • RYYSALRHYINLITRQR (NPY19-35, SEQ ID NO: 20), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:20, or RYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 16 contiguous amino acid residues having the sequence
  • YYSALRHYINLITRQR (NPY20-35, SEQ ID NO: 21 ), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:21 , or YYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is a peptide consisting of 15 contiguous amino acid residues having the sequence
  • YSALRHYINLITRQR (NPY21-35, SEQ ID NO: 22), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO:22, or YSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide for use according to the present disclosure is selected from the group consisting of:
  • SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY3-35; SEQ ID NO: 4), a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 4, and SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (SEQ ID NO: 4) with 1 , 2 or 3 amino acid substitutions;
  • EDAPAEDMARYYSALRHYINLITRQR (NPY10-35, SEQ ID NO: 11 ), a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 11 , and EDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions; and YSALRHYINLITRQR (NPY21-35, SEQ ID NO: 22), a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 22, and YSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions.
  • the peptide variants according to the present disclosure may comprise one or more amino acid substitutions introduced independently of one another.
  • said one or more amino acid substitutions are each selected from conservative and non-conservative amino acid substitutions.
  • said one or more amino acid substitution is a conservative amino acid substitution (or synonymous or equivalent substitution), that is the substitution of amino acids whose side chains have similar biochemical properties and thus do not affect the function of the peptide.
  • a “conservative amino acid substitution” can also be illustrated by a substitution among amino acids within each of the following groups: (1 ) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine, and tryptophan, (3) serine and threonine, (4) aspartate and glutamate, (5) glutamine and asparagine, and (6) lysine, arginine and histidine.
  • Conservative substitutions may be introduced in any one or more positions of a peptide according to the invention or a fragment thereof, as long as the variant remains functional. It may however also be desirable to introduce non-conservative
  • a non-conservative substitution leading to the formation of a variant of the peptide according to the invention would for example differ substantially in polarity, for example a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, lie, Leu, Phe or Met) substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gin or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or a polar residue for a non-polar one; and/or ii) differ substantially in its effect on peptide backbone orientation such as substitution of or for Pro or Gly by another residue;
  • a residue with a non-polar side chain Al, Leu, Pro, Trp, Val, lie, Leu, Phe or Met
  • a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gin or a charged amino acid such as Asp
  • substitution of amino acids may in one embodiment be made based upon their hydrophobicity and hydrophilicity values and the relative similarity of the amino acid side-chain substituents, including charge, size, and the like.
  • a peptide according to the disclosure in one embodiment may also comprise one or more non-naturally occurring amino acid residues (unnatural, non-proteinogenic or non-standard amino acids).
  • Non-naturally occurring amino acids include e.g., without limitation, beta-2-naphthyl-alanine, trans-3-methylproline, 2,4-methanoproline, cis-4- hydroxyproline, trans-4-hydroxyproline, N-methylglycine, allo-threonine,
  • methylthreonine hydroxyethylcysteine, hydroxyethylhomocysteine, nitroglutamnine, homoglutamine, pipecolic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4- methylproline, 3,3-dimethylproline, tert-leucine, norleucine, norvaline, 2- azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine, and 4-fluorophenylalanine.
  • any amino acids according to the present disclosure may be in the L- or D- configuration, apart from glycine, which does not comprise a stereocenter. If nothing is specified, reference to the L-isomeric form is preferably meant.
  • one or more of said amino acid residues of the peptide are L amino acid residues. In one embodiment, all amino acid residues of the peptide are L amino acid residues. In another embodiment, one or more of the amino acid residues of the peptide are D amino acid residues. In one embodiment, all amino acid residues of the peptide are D amino acid residues.
  • the standard and/or non-standard amino acids may be linked by peptide bonds (to form a linear peptide chain), or by non-peptide bonds (e.g. via the variable side-chains of the amino acids).
  • the amino acids of the present invention are linked by peptide bonds.
  • peptide also embraces post-translational modifications introduced by chemical or enzyme-catalyzed reactions, as are known in the art. These include acetylation, phosphorylation, methylation, glucosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation and sulfation of one or more amino acid residues, and also proteolytic modification by known proteinases including lysosomal kathepsins, and also calpains, secretases and matrix-metalloproteinases.
  • peptides may comprise chemical modifications such as ubiquitination, labeling (e.g., with radionuclides, various enzymes, etc.), pegylation (derivatization with polyethylene glycol), or by insertion (or substitution by chemical synthesis) of amino acids such as ornithine, which do not normally occur in human proteins (non-proteinogenic).
  • Sterically similar compounds may be formulated to mimic the key portions of the peptide structure. This may be achieved by techniques of modelling and chemical designing known to those of skill in the art. For example, esterification and other alkylations may be employed to modify the amino terminus of e.g a di-arginine peptide backbone, to mimic a tetra peptide structure. It will be understood that all such sterically similar constructs fall within the scope of the present invention. Peptides with N-terminal and C-terminal alkylations and esterifications are also encompassed within the present invention.
  • the C-terminal amino acid of a peptide according to the present invention exists as the free carboxylic acid, this may also be specified as“-OH”.
  • the C-terminal amino acid of a peptide for use according to the invention may in another embodiment be the amidated derivative, which is indicated as“-NH 2 ” (or CONH 2 ”).
  • the C-terminal amino acid of the peptide exists as the free carboxylic acid (“-OH”).
  • the C-terminal amino acid of the peptide is amidated (-NH 2 ).
  • the N-terminal amino acid of the peptide comprises a free amino-group, this may also be specified as“H-“ (or“NH 2 ”).
  • the N-terminal amino acid of a peptide according to the invention may in another embodiment be the acetylated derivative, which is indicated as“Acetyl” or“COCH 3 ”.
  • the C-terminal amino acid of the peptide according to the present invention exists as the free carboxylic acid (“-OH”). In another embodiment the C- terminal amino acid of the peptide according to the present invention is an amidated derivative (“-NH 2 ”). In one embodiment the N-terminal amino acid of the peptide according to the present invention comprises a free amino-group (“H-“). In another embodiment the N-terminal amino acid of the peptide according to the present invention is the acetylated derivative (“-Acetyl” or“COCH 3 ”).
  • a contiguous or consecutive peptide sequence is a sequence of consecutive amino acids being linked linearly by peptide bonds. Contiguous and consecutive amino acid sequence is used interchangeably herein.
  • the peptide according to the present disclosure comprises a contiguous amino acid sequence of 32 amino acids, such as 31 amino acids, for example 30 amino acids, for example 29 amino acids, such as 28 amino acids, for example 27 amino acids, such as 26 amino acids, for example 25 amino acids, such as 24 amino acids, for example 23 amino acids, such as 22 amino acids, for example 21 amino acids, such as 20 amino acids, for example 19 amino acids, such as 18 amino acids, for example 17 amino acids, such as 16 amino acids, for example 15 amino acids derived from NPY (SEQ ID NO: 1 ) which comprises at least NPY21-35 (SEQ ID NO: 22) or a variant thereof.
  • a peptide variant of a sequence as defined herein is a functional variant, i.e. a variant retaining some biological function and/or activity associated with the native sequence.
  • a peptide variant according to the present invention is capable of binding to NOAM.
  • a variant is capable of binding to the NOAM Ig1 module.
  • said peptide does not bind to and/or does not activate cognate NPY-receptors Y1 , Y2 and/or Y5.
  • the peptide does not bind to and/or does not stimulate or activate the cognate NPY-receptors.
  • said cognate NPY-receptors comprise G-protein coupled receptors, in one embodiment receptors Y1 , Y2 and/or Y5.
  • said peptide or functional variant thereof increases conduction velocity (CV). In one embodiment said peptide or functional variant thereof increases conduction velocity (CV) during reperfusion. In one embodiment said peptide or functional variant thereof increases conduction velocity (CV) after ischemic stress. In one embodiment said peptide or functional variant thereof increases ischemia- reperfusion conduction velocity (CV). In one embodiment said peptide or functional variant thereof increases cardiac conduction velocity (CV).
  • said peptide or functional variant thereof suppresses reperfusion arrhythmias. In one embodiment said peptide or functional variant thereof reduces or suppresses cardiac arrhythmia. In one embodiment said peptide or functional variant thereof has antiarrhythmic effect.
  • peptides for use in methods of treating a cardiovascular or cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia, in particular NPY-derived peptides.
  • cardiac diseases associated with arrhythmias such as cardiac arrhythmia, in particular NPY-derived peptides.
  • said peptide is formulated as a monomer (i.e. comprising 1 copy of the peptide), whereas in another embodiment, said peptide is formulated as a multimer.
  • the peptide according to the present disclosure is formulated as a multimer.
  • a multimer is a protein comprising or consisting of multiple monomers.
  • a peptide sequence of the present invention may be connected to another (identical or non-identical) peptide sequence of the present invention by a chemical bond or through a linker group.
  • a peptide of the invention may be formulated as an oligomer or multimer of monomers, wherein each monomer is as a peptide sequence as defined according to the present disclosure.
  • a multimeric compound may be a polymer comprising two or more peptide sequences of the invention, said peptide sequences being identical or non-identical, wherein at least one of the two or more peptide sequences is a peptide according to the present invention.
  • both peptide sequences are a peptide according to the present disclosure.
  • a multimeric peptide consisting of i) two or more peptides, such as consisting of two peptides, three peptides or four peptides; or wherein said peptide consist of a dendrimer, such as a dendrimer consisting of 4 peptides, 8 peptides, 16 peptides, or 32 peptides, and ii) optionally a linker group, wherein each of said two or more peptides are selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO:
  • the multimeric compound is a dimer, comprising two peptides according to the present disclosure, said two peptides being identical or non-identical with respect to each other.
  • the multimeric compound is a trimer, comprising three peptides according to the present disclosure, said peptides being identical or non-identical with respect to each other.
  • the multimeric compound is a tetramer, comprising four peptides according to the present disclosure, said peptides being identical or non identical with respect to each other.
  • the multimeric compound is a dendrimer, such as a tetrameric or octameric dendrimer.
  • Dendrimers are repeatedly branched, roughly spherical large molecules, typically symmetric around the core, and often adopts a spherical three- dimensional morphology.
  • Dendrimers according to the present disclosure may comprise 4 peptides, 8 peptides, 16 peptides, or 32 peptides.
  • said dendrimer comprises four peptides (i.e. a tetrameric dendrimer) or eight peptides (octameric dendrimer).
  • the multimeric compound may comprise two identical amino acid sequences of the present invention (dimer) or the compound may comprise four identical copies of an amino acid sequence of the present invention (tetrameric dendrimer).
  • the multimers according to the disclosure may be made by linking two or more peptide monomers via a peptide bond or a linker group. They may be linked to a lysine backbone, such as a lysine residue (each peptide chain is linked to a single lysine residue), or coupled to a polymer carrier, for example a protein carrier.
  • Said linker group in one embodiment comprises a plurality of lysine residues, such as a core moiety having a plurality of lysine residues, such as seen in a lysine-based
  • the linking may in one embodiment occur at the N-terminal or C-terminal end of the peptide monomers.
  • nucleic acid construct encoding for and being capable of expressing a peptide according to the present disclosure.
  • nucleic acid construct is understood a genetically engineered nucleic acid.
  • the nucleic acid construct may be a non-replicating and linear nucleic acid, a circular expression vector or an
  • a nucleic acid construct may comprise several elements such as, but not limited to genes or fragments of same, promoters, enhancers, terminators, poly-A tails, linkers, polylinkers, operative linkers, multiple cloning sites (MCS), markers, STOP codons, internal ribosomal entry sites (IRES) and host homologous sequences for integration or other defined elements. It is to be understood that the nucleic acid construct according to the present invention may comprise all or a subset of any combination of the above-mentioned elements.
  • nucleic acid constructs are well known in the art (see, e.g., Molecular Cloning: A Laboratory Manual, Sambrook et al., eds., Cold Spring Harbor Laboratory, 2nd Edition, Cold Spring Harbor, N.Y., 1989). Further, nucleic acid constructs according to the present invention may be synthesized without template, and may be obtained from various commercial suppliers.
  • the nucleic acid construct are naked DNA constructs comprising sequences encoding the peptide of the disclosure.
  • nucleic acid construct will be able to continuously express a peptide according to the present invention for a prolonged period of time, such as at least 1 month, for example at least 2 months, such as at least 3 months, for example at least 4 months, such as at least 5 months, for example at least 6 months, such as at least 7 months, for example at least 8 months, such as at least 9 months, for example at least 12 months.
  • said nucleic acid construct encodes a peptide consisting of a peptide sequence of from 15 to 35 contiguous amino acid residues derived from neuropeptide Y (NPY) (SEQ ID NO: 1 ), wherein said peptide comprises at least, or consists of, the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22), or a functional variant having at least 60% sequence identity to SEQ ID NO: 22, wherein said peptide does not comprise the amino acid of position 36 of SEQ ID NO: 1. In one embodiment, said peptide does not comprise an amino acid, such as the Tyr amino acid, of position 36 of SEQ ID NO: 1.
  • said nucleic acid construct encodes a peptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22; or a functional variant thereof.
  • the encoded peptide of the a nucleic acid construct is a variant having at least 60% sequence identity to any one of SEQ ID NO:s 2 to 22, such as at least 65% sequence identity, for example at least 70% sequence identity, such as at least 75% sequence identity, for example at least 80% sequence identity, such as at least 85% sequence identity, for example at least 90% sequence identity, such as at least 95% sequence identity, for example at least 99% sequence identity to any one of
  • said nucleic acid construct as described herein above is comprised within a delivery vehicle.
  • a delivery vehicle is an entity whereby a nucleotide sequence or polypeptide or both can be transported from at least one media to another. Delivery vehicles are generally used for expression of the sequences encoded within the nucleic acid construct and/or for the intracellular delivery of the construct or the polypeptide encoded therein.
  • a delivery vehicle comprising the nucleic acid construct according to the present disclosure.
  • a delivery vehicle may be selected from the group consisting of: RNA based vehicles, DNA based vehicles/ vectors, lipid based vehicles (such as a liposome), polymer based vehicles (such as a cationic polymer DNA carrier), colloidal gold particles (coating) and virally derived DNA or RNA vehicles or vectors.
  • Methods of non-viral delivery include physical (carrier-free delivery) and chemical approaches (synthetic vector-based delivery).
  • electroporation, ultrasound, and hydrodynamic delivery employ a physical force that permeates the cell membrane and facilitates intracellular gene transfer.
  • Said physical force may be electrical or mechanical.
  • chemical delivery vehicles include, but are not limited to: biodegradable polymer microspheres, lipid based formulations such as liposome carriers, cationically charged molecules such as liposomes, calcium salts or dendrimers,
  • lipopolysaccharides polypeptides and polysaccharides.
  • a vector which herein is denoted a viral vector (i.e. not a virus) as a delivery vehicle.
  • Viral vectors according to the present invention are made from a modified viral genome, i.e. the actual DNA or RNA forming the viral genome, and introduced in naked form. Thus, any coat structures surrounding the viral genome made from viral or non-viral proteins are not part of the viral vector according to the present invention.
  • the virus from which the viral vector is derived may be selected from the non- exhaustive group of: adenoviruses, retroviruses, lentiviruses, adeno-associated viruses, herpesviruses, vaccinia viruses, foamy viruses, cytomegaloviruses, Semliki forest virus, poxviruses, RNA virus vector and DNA virus vector.
  • adenoviruses retroviruses, lentiviruses, adeno-associated viruses, herpesviruses, vaccinia viruses, foamy viruses, cytomegaloviruses, Semliki forest virus, poxviruses, RNA virus vector and DNA virus vector.
  • said viral vectors may be selected from the group consisting of adenoviruses, lentiviruses, adeno-associated viruses (AAV) and recombinant adeno- associated viruses (rAAV).
  • said viral vector is a therapeutic rAAV vector such as a therapeutic rAAV vector.
  • An adenovirus is a group of double-stranded DNA containing viruses. Adenoviruses can be genetically modified making them replication incompetent or conditionally replication incompetent. In this form, as adenoviral constructs or adenovectors, they can be used as gene delivery vehicles for vaccination or gene therapy.
  • AAV vectors using AAV can infect both dividing and quiescent cells and persist in an extrachromosomal state without integrating into the genome of the host cell. These features make AAV a very attractive candidate for creating viral vectors for gene therapy. To date, AAV vectors have been used in over 80 clinical trials worldwide.
  • At least 11 serotypes of AAV exists, and all of these are encompassed by the present invention.
  • Viral expression vectors that have been utilized to target retinal cells include
  • adenoviruses adenoviruses, lentiviruses, and recombinant adeno-associated viruses (rAAV).
  • rAAV recombinant adeno-associated viruses
  • rAAV Recombinant adeno-associated viral vectors
  • the present disclosure provides compounds that binds to NCAM for use in the treatment of a cardiovascular disease.
  • cardiovascular disease as used herein relates to a range of conditions that affect the heart, its vessels, muscles, valves, or internal electric pathways responsible for muscular contraction, as well as diseases affecting vessels of the systemic or pulmonary circulation.
  • Cardiovascular diseases include:
  • Coronary artery diseases CAD
  • CAD Coronary artery diseases
  • cerebrovascular disease - disease of the blood vessels supplying the brain such as stroke
  • heart failure hypertensive heart disease
  • rheumatic heart disease damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria
  • peripheral artery disease - disease of blood vessels supplying the arms and legs as well as internal organs;
  • the cardiovascular disease is selected from the group consisting of Cardiac arrhythmias; Coronary artery disease; Acute Myocardial infarction (AMI); Cardiomyopathy; Hypertensive heart disease; Heart failure; Pulmonary heart disease (cor pulmonale); Inflammatory heart disease such as Endocarditis and carditis, Inflammatory cardiomegaly, Myocarditis or Eosinophilic myocarditis; Valvular heart disease; Congenital heart disease; Rheumatic heart disease; Aortic aneurysms; Long or short QT syndrome; Brugada syndrome; Arrhythmogenic cardiomyopathy (ACM); Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT); Cerebrovascular disease; Peripheral artery disease; Thromboembolic disease; and Venous thrombosis.
  • AMI Acute Myocardial infarction
  • Cardiomyopathy Hypertensive heart disease
  • Heart failure Pulmonary heart disease (cor pulmonale);
  • the present disclosure provides compounds that binds to NCAM for use in the treatment of a cardiac disease or heart disease.
  • a cardiac disease as used herein describes a range of conditions that affect the heart. These include cardiac blood vessel diseases, such as coronary artery disease; heart rhythm problems (arrhythmias); and inborn heart defects (congenital heart defects), among others. Cardiac diseases include a subset of the cardiovascular diseases namely those directly affecting the heart and heart vessels. Cardiovascular diseases that are not considered cardiac diseases include for example Cerebrovascular disease; Peripheral artery disease; Thromboembolic disease; and Venous thrombosis.
  • Cardiac diseases include: Coronary artery diseases (CAD), such as angina and myocardial infarction; heart failure; hypertensive heart disease; rheumatic heart disease; cardiomyopathy; cardiac arrhythmias; congenital heart disease; valvular heart disease; carditis and aortic aneurysms.
  • CAD Coronary artery diseases
  • the cardiac disease is selected from the group consisting of Cardiac arrhythmias; Coronary artery disease; Acute Myocardial infarction (AMI); Cardiomyopathy; Hypertensive heart disease; Heart failure; Pulmonary heart disease (cor pulmonale); Inflammatory heart disease such as Endocarditis and carditis, Inflammatory cardiomegaly, Myocarditis or Eosinophilic myocarditis; Valvular heart disease; Congenital heart disease; Rheumatic heart disease; Aortic aneurysms; Long or short QT syndrome; Brugada syndrome; Arrhythmogenic cardiomyopathy (ACM); and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).
  • AMI Acute Myocardial infarction
  • Cardiomyopathy Hypertensive heart disease
  • Heart failure Pulmonary heart disease (cor pulmonale); Inflammatory heart disease such as Endocarditis and carditis, Inflammatory cardiomegaly, Myocarditis or
  • the cardiac disease is Coronary artery disease (CAD), also known as ischemic heart disease (IHD).
  • CAD Coronary artery disease
  • IHD ischemic heart disease
  • the cardiac disease is a cardiac disease associated with arrhythmia, such as a cardiac disease presenting with arrhythmia; such as a cardiac disease with arrhythmia; such as arrhythmic cardiac disease.
  • the cardiac disease of the present disclosure is cardiac arrhythmia.
  • Cardiac (or heart) arrhythmia also known as arrhythmia, dysrhythmia, or irregular heartbeat, is a group of conditions in which the heartbeat is irregular. Ventricular arrhythmias occur in the lower chambers of the heart, called the ventricles.
  • Supraventricular arrhythmias occur in the area above the ventricles, usually in the upper chambers of the heart, called the atria.
  • the irregular beats can either be too slow, such as below 60 beats per minute (called bradycardia), or too fast, such as above 100 beats per minute in adults (tachycardia).
  • the cardiac arrhythmia is congenital.
  • the cardiac arrhythmia is a bradycardia. Bradycardia (or bradyarrhythmia) happens when the electrical impulse that signals the heart to contract is not formed in the sinoatrial node (SA node), or is not sent to the heart’s lower chambers (the ventricles) through the proper conduction pathway in the atrioventricular node (AV node).
  • the cardiac arrhythmia is a tachycardia. There are many forms of tachycardia, classified depending on where the fast heart rate begins. If it begins in the ventricles, it is called ventricular tachycardia. If it begins above the ventricles, it is called supraventricular tachycardia. Arrhythmia may be classified by rate (tachycardia, bradycardia), mechanism
  • the cardiac disease is a cardiac arrhythmia selected from the group consisting of:
  • Supraventricular tachycardias including atrial fibrillation, atrial flutter, and
  • Ventricular arrhythmias including ventricular fibrillation and ventricular
  • the cardiac arrhythmia is a junctional arrhythmia (or junctional rhythm).
  • Junctional rhythm results from impulses coming from a locus of tissue in the area of the atrioventricular node, i.e. the "junction" between atria and ventricles.
  • the cardiac disease is a bradycardia. In one embodiment, the cardiac disease is a tachycardia. In one embodiment, the cardiac disease is Supraventricular tachycardia (SVT). SVT is an abnormally fast regular heart rate arising from improper electrical activity in the upper part of the heart, i.e. above the bundle of His. In one embodiment, the cardiac disease is Atrial fibrillation (AF or A-fib). AF is one of the most common abnormal heart rhythms. In AF, the atria beat out of coordination with the ventricles, which leads to a rapid and irregular heart rhythm.
  • SVT Supraventricular tachycardia
  • AF Atrial fibrillation
  • AF is a main cause of stroke, especially among elderly people AF may be classified as “First detected”, “Paroxysmal”, “Persistent” or “Permanent”. Furthermore, AF may be “Seconday AF”, i.e. when AF occurs in the setting of a primary condition which may be the cause of the AF.
  • the cardiac disease is Atrial flutter (AFL)
  • AFL is a type of SVT, which often degenerates into AF.
  • the atria are activated by a single re-entry loop with a stable but faster than normal rhythm, and the atria beat more frequently than the ventricles.
  • AF and AFL with rapid ventricular response are classified as SVT:s, but without rapid ventricular response, fibrillation and flutter are usually not classified as SVT.
  • AF and AFL may be classified under I48 in ICD-10.
  • the cardiac disease is Atrioventricular nodal re-entrant tachycardia (AVNRT).
  • AVNRT is a type of SVT, and may be classified under I47 in ICD-10.
  • the anterograde conduction is via the slow pathway and the retrograde conduction is via the fast pathway (“slow-fast” AVNRT).
  • the anterograde conduction is via the fast pathway and the retrograde conduction is via the slow pathway (“fast-slow” AVNRT), or both anterograde and retrograde conduction are over slow pathways (“slow-slow” AVNRT).
  • the heart disease is Wolff-Parkinson-White (WPW) syndrome, which is a group of abnormalities caused by extra muscle pathways between the atria and the ventricles. The pathways cause the electrical signals to arrive at the ventricles too soon, and the signals are sent back to the atria. The result is a very fast heart rate.
  • WPW Wolff-Parkinson-White
  • the cardiac disease is an arrhythmia selected from the group consisting of Atrial arrhythmias; Junctional arrhythmias; Ventricular arrhythmias and Heart blocks.
  • the cardiac arrhythmia is an atrial arrhythmia.
  • Atrial arrhythmias include Sinus bradycardia; Premature atrial contractions (PACs); Wandering atrial pacemaker; Atrial tachycardia; Multifocal atrial tachycardia; Supraventricular tachycardia (SVT); Atrial flutter; and Atrial fibrillation.
  • the cardiac arrhythmia is a junctional arrhythmia (or junctional rhythm).
  • Junctional rhythm results from impulses coming from a locus of tissue in the area of the atrioventricular node, i.e. the "junction" between atria and ventricles.
  • junctional arrhythmias include AV nodal re-entrant tachycardia; Junctional rhythm; Junctional tachycardia and Premature junctional contraction.
  • the cardiac arrhythmia is a ventricular arrhythmia.
  • Ventricular arrhythmias include Premature ventricular contractions (PVCs); Ventricular extra beats (VEBs); Accelerated idioventricular rhythm; Monomorphic ventricular tachycardia; Polymorphic ventricular tachycardia; Ventricular fibrillation; and Torsades de pointes.
  • the cardiac arrhythmia is a heart block.
  • Heart blocks, or AV blocks are the most common causes of bradycardia and includes First degree heart block; Second degree heart block; and Third degree heart block.
  • Heart block is a disorder in the heart's rhythm, caused by an obstruction - a block - in the electrical conduction system of the heart.
  • the cardiac arrhythmia is selected from the group consisting of Sinoatrial nodal re-entrant tachycardia (SNRT); Ectopic (unifocal) atrial tachycardia (EAT); Multifocal atrial tachycardia (MAT); Atrial fibrillation (AF); Atrial flutter (AFL); Junctional tachycardia; Atrioventricular nodal re-entrant tachycardia (AVNRT) or junctional reciprocating tachycardia (JRT); Permanent (or persistent) junctional reciprocating tachycardia (PJRT); Atrioventricular reciprocating tachycardia (AVRT); Wolff-Parkinson-White syndrome and Junctional ectopic tachycardia (JET).
  • SNRT Sinoatrial nodal re-entrant tachycardia
  • EAT Ectopic (unifocal) atrial tachycardia
  • MAT Multifocal atrial tachycardia
  • SVT atrial fibrillation
  • atrial flutter atrial flutter
  • paroxysmal supraventricular tachycardia a paroxysmal supraventricular tachycardia
  • Wolff-Parkinson-White syndrome a syndrome that is characterized by the following main types of SVT.
  • SVT:s may be classified under I47 to I49 in the International Statistical Classification of Diseases and Related Health Problems - Tenth Revision (ICD-10).
  • Cardiac arrhythmias are generally produced by one of three mechanisms: enhanced automaticity, triggered activity, or re-entry.
  • Re-entry occurs when a propagating impulse fails to die out after normal activation of the heart and persists to re-excite the heart after the refractory period has ended.
  • Re entry is the electrophysiological mechanism responsible for the majority of clinically important arrhythmias, such as sustained ventricular fibrillation and sudden cardiac death. Included among the arrhythmias caused by re-entry are atrial fibrillation, atrial flutter, atrioventricular (AV) nodal re-entry, AV re-entry involving a bypass tract, ventricular tachycardia after myocardial infarction (Ml) with the presence of left ventricular scar, and ventricular fibrillation.
  • AV atrioventricular
  • Ml myocardial infarction
  • the cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, atrioventricular (AV) nodal re-entry, AV re-entry involving a bypass tract, ventricular tachycardia after myocardial infarction (Ml) with the presence of left ventricular scar, and ventricular fibrillation.
  • atrial fibrillation atrial fibrillation
  • atrial flutter atrioventricular (AV) nodal re-entry
  • AV re-entry involving a bypass tract
  • ventricular tachycardia after myocardial infarction (Ml) with the presence of left ventricular scar and ventricular fibrillation.
  • Cardiac arrhythmia can be underlain or triggered by several causes, such as cardiac causes.
  • Said cardiac causes include acute or chronic ischemic heart disease, vascular heart disease, valvular heart disease, or degenerative primary electrical disease.
  • the causes act by three mechanisms: depressed automaticity of the heart, conduction slowing or block, or escape pacemakers and rhythms.
  • the cardiac arrhythmia is a secondary disease, i.e. a cardiac arrhythmia that follows and results from an earlier disease, injury, or event.
  • said cardiac arrhythmia may be secondary to another cardiac disease.
  • Cardiac arrhythmias may also lead to (or cause) sudden cardiac arrest or stroke.
  • the cardiac arrhythmia may be caused by Long or short QT syndrome.
  • Said Long or short QT syndrome may be congenital or drug induced.
  • the cardiac arrhythmia is caused by a cardiomyopathy.
  • cardiomyopathy may be classified as hypertrophic cardiomyopathy, dilated
  • the cardiac arrhythmia is caused by Brugada syndrome. In another embodiment, the cardiac arrhythmia is caused by Arrhythmogenic cardiomyopathy (ACM); ACM is also known as Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) and
  • the cardiac arrhythmia is caused by catecholaminergic polymorphic ventricular tachycardia (CPVT). In one embodiment, the cardiac arrhythmia occurs after cardiac surgery or other surgery (post-operative cardiac arrhythmia or post-operative atrial fibrillation).
  • CPVT catecholaminergic polymorphic ventricular tachycardia
  • the cardiac arrhythmia is part of, or associated with, another cardiac disease.
  • Cardiac arrhythmias may be diagnosed by an electrocardiogram (ECG).
  • ECG electrocardiogram
  • a compound as defined herein is administered to individuals in need of treatment in pharmaceutically effective doses or a therapeutically effective amount.
  • the dosage requirements will vary with the particular drug composition employed, the route of administration and the particular subject being treated, which depend on the severity and the sort of the disorder as well as on the weight and general state of the subject. It will also be recognized by one skilled in the art that the optimal quantity and spacing of individual dosages of a compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optima can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound given per day for a defined number of days, can be ascertained using conventional course of treatment determination tests.
  • the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location of the tissue to be treated in the body and the active ingredient chosen.
  • the compound for use in the treatment of a cardiovascular disease such as a cardiac disease, such as cardiac diseases associated with arrhythmias, such as cardiac arrhythmia, as described herein is administered by means of parental administration.
  • Parenteral administration is any administration route not being the oral/enteral route whereby the medicament avoids first-pass degradation in the liver.
  • parenteral administration includes any injections and infusions, for example bolus injection or continuous infusion, such as intravenous administration, intramuscular administration or subcutaneous administration.
  • parenteral administration includes inhalations and topical administration.
  • the parental administration is intraperitoneal (IP), intravenous (IV) or subcutaneous (SC).
  • the compound is to be administered in combination with one or more second bioactive agents.
  • NCAM Neural Cell Adhesion Molecule
  • peptide consists of from 15 to 35 contiguous amino acid residues derived from neuropeptide Y (NPY, SEQ ID NO:1 ), and said peptide does not comprise an amino acid at position 36 of SEQ ID NO:1.
  • the peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22), or a functional variant thereof having at least 60% sequence identity to SEQ ID NO: 22.
  • the peptide comprises at least the sequence YSALRHYINLITRQR (NPY21-35; SEQ ID NO: 22), or a functional variant thereof wherein no more than 6 amino acids have been substituted, such as no more than 5 amino acids, such as no more than 4 amino acids, such as no more than 3 amino acids, such as no more than 2 amino acids, such as no more than 1 amino acid has been substituted.
  • YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 1-35, SEQ ID NO: 2) PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 2-35, SEQ ID NO: 3) SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY 3-35, SEQ ID NO: 4) KPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY4-35, SEQ ID NO: 5), PDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY5-35, SEQ ID NO: 6), DNPGEDAPAEDMARYYSALRHYINLITRQR (NPY6-35, SEQ ID NO: 7), NPGEDAPAEDMARYYSALRHYINLITRQR (NPY7-35, SEQ ID NO: 8),
  • GEDAPAEDMARYYSALRHYINLITRQR (NPY9-35, SEQ ID NO: 10),
  • PAEDMARYYSALRHYINLITRQR (NPY13-35, SEQ ID NO: 14),
  • AEDMARYYSALRHYINLITRQR (NPY14-35, SEQ ID NO: 15),
  • the peptide is a functional variant having at least 60% sequence identity to a peptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22.
  • the peptide variant has at least 60% sequence identity, such as at least 65% sequence identity, for example at least 70% sequence identity, such as at least 75% sequence identity, for example at least 80% sequence identity, such as at least 85% sequence identity, for example at least 90% sequence identity, such as at least 95% sequence identity, for example at least 99% sequence identity to a peptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO:
  • SEQ ID NO: 4 SEQ ID NO: 5
  • SEQ ID NO: 6 SEQ ID NO: 7
  • SEQ ID NO: 8 SEQ ID NO: 9
  • SEQ ID NO: 10 SEQ ID NO: 1 1
  • SEQ ID NO: 12 SEQ ID NO:
  • the peptide variant comprises one or more amino acid substitution, such as one amino acid substitution, such as two amino acid substitutions, such as three amino acid substitutions, such as four amino acid substitutions, such as five amino acid substitutions, such as six amino acid substitutions, such as seven amino acid substitutions.
  • PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR NPY2-35, SEQ ID NO: 3
  • PSKPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions
  • KPDNPGEDAPAEDMARYYSALRHYINLITRQR NPY4-35, SEQ ID NO: 5
  • KPDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions
  • peptide consisting of 31 contiguous amino acid residues having the sequence PDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY5-35, SEQ ID NO: 6) or PDNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions,
  • a peptide consisting of 30 contiguous amino acid residues having the sequence DNPGEDAPAEDMARYYSALRHYINLITRQR (NPY6-35, SEQ ID NO: 7) or DNPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions,
  • NPGEDAPAEDMARYYSALRHYINLITRQR NPY7-35, SEQ ID NO: 8
  • NPGEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions
  • GEDAPAEDMARYYSALRHYINLITRQR NPY9-35, SEQ ID NO: 10
  • GEDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions
  • a peptide consisting of 26 contiguous amino acid residues having the sequence EDAPAEDMARYYSALRHYINLITRQR (NPY10-35, SEQ ID NO: 1 1 ) or EDAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid
  • DAPAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions, a peptide consisting of 24 contiguous amino acid residues having the sequence APAEDMARYYSALRHYINLITRQR (NPY12-35, SEQ ID NO: 13)
  • APAEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions
  • AEDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions a peptide consisting of 21 contiguous amino acid residues having the sequence EDMARYYSALRHYINLITRQR (NPY15-35, SEQ ID NO: 16)
  • EDMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions, a peptide consisting of 20 contiguous amino acid residues having the sequence DMARYYSALRHYINLITRQR (NPY16-35, SEQ ID NO: 17)
  • DMARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions, a peptide consisting of 19 contiguous amino acid residues having the sequence MARYYSALRHYINLITRQR (NPY17-35, SEQ ID NO: 18)
  • MARYYSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions, a peptide consisting of 18 contiguous amino acid residues having the sequence ARYYSALRHYINLITRQR (NPY18-35, SEQ ID NO: 19)
  • YSALRHYINLITRQR with 1 , 2 or 3 amino acid substitutions, and a peptide consisting of 15 contiguous amino acid residues having the sequence YSALRHYINLITRQR (NPY21-35, SEQ ID NO: 22)
  • peptide consists of SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY3- 35; SEQ ID NO: 4),
  • peptide is formulated as a multimer comprising two or more peptides.
  • peptide is formulated as a multimer consisting of two or more peptides, and optionally a linker group.
  • RNA based vehicles RNA based vehicles
  • DNA based vehicles DNA based vehicles
  • lipid based vehicles lipid based vehicles
  • colloidal gold particles virally derived DNA or RNA vehicles.
  • the vehicle is a viral vector selected from the group consisting of adenoviruses, retroviruses, lentiviruses, adeno-associated viruses, herpesviruses, vaccinia viruses, foamy viruses, cytomegaloviruses, Semliki forest virus, poxviruses, RNA virus vector and DNA virus vector.
  • a viral vector selected from the group consisting of adenoviruses, retroviruses, lentiviruses, adeno-associated viruses, herpesviruses, vaccinia viruses, foamy viruses, cytomegaloviruses, Semliki forest virus, poxviruses, RNA virus vector and DNA virus vector.
  • cardiovascular disease is selected from the group consisting of Cardiac arrhythmias; Coronary artery disease; Acute Myocardial infarction (AMI);
  • Cardiomyopathy Hypertensive heart disease; Heart failure; Pulmonary heart disease; Inflammatory heart disease such as Endocarditis, Inflammatory cardiomegaly, Myocarditis or Eosinophilic myocarditis; Valvular heart disease; Congenital heart disease; Rheumatic heart disease; Cerebrovascular disease; Aortic aneurysms; Thromboembolic disease; Venous thrombosis; Peripheral artery disease; Long or short QT syndrome; Brugada syndrome;
  • ACM Arrhythmogenic cardiomyopathy
  • CPVT Catecholaminergic Polymorphic Ventricular Tachycardia
  • cardiovascular disease is selected from the group consisting of Cardiac dysrhythmias; Cardiomyopathy; Hypertensive heart disease; Heart failure; Pulmonary heart disease; Inflammatory heart disease such as Endocarditis, Inflammatory cardiomegaly, Myocarditis or Eosinophilic myocarditis; Valvular heart disease; Congenital heart disease; Rheumatic heart disease; Long or short QT syndrome; Brugada syndrome; Arrhythmogenic cardiomyopathy (ACM); and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).
  • Cardiac dysrhythmias Cardiac dysrhythmias
  • Cardiomyopathy Hypertensive heart disease
  • Heart failure Pulmonary heart disease
  • Inflammatory heart disease such as Endocarditis, Inflammatory cardiomegaly, Myocarditis or Eosinophilic myocarditis
  • Valvular heart disease Congenital heart disease
  • Rheumatic heart disease Long or short QT syndrome
  • cardiovascular disease is selected from the group consisting of cardiac arrhythmia; coronary artery disease; cerebrovascular disease; heart failure; hypertensive heart disease; rheumatic heart disease; cardiomyopathy;
  • congenital heart disease congenital heart disease; valvular heart disease; carditis, aortic aneurysms; peripheral artery disease; thromboembolic disease; and venous thrombosis.
  • cardiovascular disease is Coronary artery disease.
  • AMI Acute Myocardial infarction
  • NCAM Neural Cell Adhesion Molecule
  • NCAM mediated cell-cell adhesion is a cis-interaction or a trans-interaction.
  • cardiac arrhythmia is caused by or part of a disease selected from the group consisting of Long or short QT syndrome; cardiomyopathy; Brugada syndrome; Arrhythmogenic cardiomyopathy (ACM); catecholaminergic polymorphic ventricular tachycardia (CPVT).
  • a disease selected from the group consisting of Long or short QT syndrome; cardiomyopathy; Brugada syndrome; Arrhythmogenic cardiomyopathy (ACM); catecholaminergic polymorphic ventricular tachycardia (CPVT).
  • cardiac arrhythmia is selected from the group consisting of Supraventricular tachycardia, Ventricular arrhythmia, Extra beats and Bradycardia.
  • cardiac arrhythmia is selected from the group consisting of Atrial fibrillation (AF); Atrial flutter (AFL); Sinoatrial nodal re-entrant tachycardia (SNRT); Ectopic (unifocal) atrial tachycardia (EAT); Multifocal atrial tachycardia (MAT);
  • AF Atrial fibrillation
  • AFL Atrial flutter
  • SNRT Sinoatrial nodal re-entrant tachycardia
  • EAT Ectopic (unifocal) atrial tachycardia
  • MAT Multifocal atrial tachycardia
  • junctional tachycardia Atrioventricular nodal re-entrant tachycardia (AVNRT) or junctional reciprocating tachycardia (JRT); Permanent (or persistent) junctional reciprocating tachycardia (PJRT); Atrioventricular reciprocating tachycardia (AVRT); Wolff-Parkinson-White syndrome and Junctional ectopic tachycardia (JET).
  • Atrioventricular nodal re-entrant tachycardia Atrioventricular nodal re-entrant tachycardia (AVNRT) or junctional reciprocating tachycardia (JRT); Permanent (or persistent) junctional reciprocating tachycardia (PJRT); Atrioventricular reciprocating tachycardia (AVRT); Wolff-Parkinson-White syndrome and Junctional ectopic tachycardia (JET).
  • cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, and Wolff-Parkinson- White syndrome.
  • cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, and atrioventricular (AV) nodal re-entry.
  • IP intraperitoneal
  • IV intravenous
  • SC subcutaneous
  • a composition comprising a compound that binds to Neural Cell Adhesion
  • NCAM Molecule
  • a method for treatment of a cardiac disease comprising administration of
  • Example 1 Antiarrhythmic effect of NPY3-35 in Langendorff perfused hearts subjected to ischemia-reperfusion
  • NPY3-35 SEQ ID NO: 4
  • vehicle treatment on electrical and mechanical recovery was investigated, as well as infarct size after no flow ischemia in Langendorff perfused rat hearts.
  • NPY3-35 SEQ ID NO: 4
  • Hearts were perfused for 30 min at baseline before treatment was initiated (NPY3- 35 (1 mM) or vehicle) and maintained for 60 min (see fig. 1 A for protocol timeline). After 15 min of treatment, flow was stopped for 30 min to induce global no flow ischemia. Hearts were subsequently reperfused for 15 min with treatment followed by 105 min without treatment.
  • mice were wrapped in vita wrap and placed at - 80° for 10 min. Subsequently, the hearts were sliced transversely into 7 pieces of 2 mm thickness and incubated in 2,3,5-triphenyltetrazoliumchloride (TTC) (10 mg/ml in 0.1 M phosphate buffer (pH 7.4)) for 10 min at 37 °C while shaked. The tissue slices were then washed 3 times in ELGA and stored in 4 % formalin overnight. The tissue slices were weighed and scanned on both sides at 1200 DPI to determine infarct size. Images were analyzed using ImageJ software by two persons with the treatment blinded to the operator.
  • TTC 2,3,5-triphenyltetrazoliumchloride
  • Relative infarct size was determined as the total volume of diseased myocardium (pale in images) divided by the area at risk (whole volume) and statistical significance evaluated by an unpaired two-sample Student’s t-test (p ⁇ 0.05 considered significant).
  • Arrhythmogenesis was determined from the number of hearts in arrhythmia at the end of reperfusion (failed recovery) versus hearts in sinus rhythm (successful recovery). Statistical significance was evaluated using Fisher’s exact test (p ⁇ 0.05 considered significant).
  • NPY3-35 had a significant antiarrhythmic effect.
  • Vehicle treated hearts failed to recover sinus rhythm in 7 of 10 cases, whereas NPY3-35 treated hearts only failed in 1 of 8 cases (p ⁇ 0.05, fig. 1 and 2).
  • Infarct size not significantly different between vehicle and NPY3-35 treated hearts (fig. 3), showing that the antiarrhythmic affect is independent of infarct area.
  • Example 2 Improvement of cardiac conduction after ischemia in NPY3-35 treated tissue strips
  • NPY3-35 suppresses reperfusion arrhythmias in isolated rat hearts.
  • NPY3-35 exerts its effect by binding to and subsequent signaling via NCAM and we therefore tested NPY3-35 in wild-type (WT) mice and in NCAM knock-out (KO) mice.
  • NPY3-35, NPY10-35 and NPY21-35 were demonstrated to increase conduction velocity after ischemic stress, which was demonstrated in the following way:
  • mice Male mice (either WT of NCAM KO) were euthanized by cervical dislocation. A thoracotomy was performed and the hearts were quickly removed and immersed in oxygenated HEPES-Tyrodes buffer (HT-buffer), with a pH of 7.4. (in mM: 136 NaCI, 4 KCI, 5 HEPES, 5 MES, 0.8 MgCh, 1 CaCI 2 and 10 glucose).
  • HEPES-Tyrodes buffer a pH 7.4.
  • Strips of right ventricular tissue were dissected in a Petri-dish with HT-buffer and a loop sutured to each end.
  • the tissue was connected to a force-transducer and a stationary hook in a fluid filled chamber (1.7 ml.) with the endocardium facing upward.
  • the ventricular strip was paced with a unipolar stimulation electrode at 2 Hz, impulse duration 0.5 ms and double threshold voltage. The tissue was subsequently allowed to rest for 15-30 min.
  • the ventricular strip was perfused at baseline (10 min, buffer pH 7.4, glucose 5 mM, equilibrated with 100 % 0 2 ) followed by treatment with either vehicle or NPY3-35 (1 mM) for the remainder of the experiment. After 10 minutes of pre-treatment, strips were subjected to 30 minutes of simulated ischemia (buffer pH 6.8, no glucose, equilibrated with atmospheric air) followed by 20 minutes of reperfusion.
  • Time of local activation under the first and second microelectrode was determined as the time of minimum dU/dt by custom written MatLab script. Conduction velocity was calculated as the inter-electrode distance divided by the inter-electrode delay.
  • Average conduction velocity was determined during the last two minutes of each period and we used a linear mixed-effects model analysis (R, Ime) to test for statistical significance (p ⁇ 0.05 considered significant).
  • FIG. 6 To further analyze the time-course of the increase in CV, we plotted CV after reperfusion with a 4 minute time resolution (figure 6).
  • Figure 6A shows that CV was significantly higher in the NPY3-35 treated tissue from WT animals from 12 minutes after reperfusion (time points 62, 64 and 70 minutes) compared to vehicle treated tissue.
  • NPY3-35 treatment did not affect tissue from NCAM KO animals.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des fragments peptidiques dérivés du neuropeptide Y (NPY) qui se lient à une molécule d'adhérence des cellules nerveuses (NCAM), destinés à être utilisés dans le traitement de maladies cardiovasculaires, en particulier d'une maladie cardiaque, telles que des maladies cardiaques associées à des arythmies, telles qu'une arythmie cardiaque.
PCT/EP2019/083077 2018-11-29 2019-11-29 Traitement de maladies cardiovasculaires WO2020109546A1 (fr)

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WO1996012489A1 (fr) * 1994-10-20 1996-05-02 Eli Lilly And Company Antagonistes du recepteur du neuropeptide y bicyclique
US6426330B1 (en) 1995-04-17 2002-07-30 East Carolina University Satiety inducing composition comprising Neuropeptide Y analogues and methods of inducing satiety and treating a disease or condition associated with it
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US20100168215A1 (en) 2003-10-14 2010-07-01 Neurologix, Inc. Methods and compositions for the treatment of neurological disease
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