Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/085—Angiotensins

Definitions

• Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) result from progressive reduction in signaling through the insulin receptor due to nutritional overload, chronic inflammation, dyslipidemia, and hyperglycemia.
• a common factor of MS and T2DM is the insulin resistance that compromises cell survival, metabolism, and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis T2DM patients typically show significantly lower overall cognitive function, suggesting a link between metabolic dysregulation and central nervous system (CNS) function.
• CNS central nervous system
• these diseases are risk factors for the development of dementia and Alzheimer's disease, recently referred to as type 3 diabetes.
• the PBK/Akt pathway downstream of insulin signaling which is reduced in MS and T2DM, is critical for neuronal survival and synaptic transmission, partially by supporting the energy-transducing capacity of mitochondria, which, in turn, modulate the PBK/Akt pathway, thereby establishing a regulatory device essential for neuronal function.
• the present invention provides methods for limiting development of neurodegeneration, comprising administering to a subject at risk of neurodegeneration an amount effective for limiting development of neurodegeneration of a polypeptide comprising or consisting of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof, All AT2 type 2 receptor agonists, or an agonist of the MAS receptor, or pharmaceutically acceptable salts thereof.
• a polypeptide comprising or consisting of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof, All AT2 type 2 receptor agonists, or an agonist of the MAS receptor, or pharmaceutically acceptable salts thereof.
• the subject is a human subject.
• the subject has metabolic syndrome and/or type 2 diabetes.
• the subject is insulin resistant, or has one or more disorders selected from the group consisting of obesity, hyperglycemia, chronic inflammation, mitochondrial dysfunction, hyperinsuliemia, vasculopathy, hypertension, and hyperlipidemia.
• the methods limit development of one or more disorders selected from the group consisting of dementia, cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
• the subject is administered a polypeptide comprising or consisting of at least four contiguous amino acids of groups 1 8
• R 1 is selected from the group consisting of H, Asp, Glu, Asn, Acpc (1- aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH2), Gly, Asp(N3 ⁇ 4) and Sue, or is absent,
• R 2 is selected from the group consisting of Arg, Lys, Ala, Cit, Orn, Ser(Ac), Sar, D- Arg and D-Lys,
• R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Lys, Pro,
• R 4 is selected from the group consisting of Tyr, Tyr(P(3 ⁇ 4)2, Thr, Ser, homoSer, azaTyr, and Ala;
• R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
• R 6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
• R 7 is selected from the group consisting of Pro or Ala
• R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr, or
• the subject is administered a polypeptide comprising or consisting of at least 4 contiguous amino acids of the general formula II:
• R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
• R 3 -R 8 are as defined above, or pharmaceutically acceptable salts thereof, excluding sequences including R 4 as a terminal Tyr group.
• the subject is administered a polypeptide comprising at least 5 contiguous amino acids of Asp-Arg-Val-Tyr-Ile-His-Pro (SEQ ID NO:4), or a pharmaceutically acceptable salt thereof.
• a polypeptide consisting of Asp-Arg-Val-Tyr-Ile-His-Pro SEQ ID NO:4
• a pharmaceutically acceptable salt thereof Description of the Figures
• Figure 1 (A) Graph showing (Al-7) limiting of motor nerve conduction velocity deficits in a model of type 1 diabetes mellitus (T2DM). (B) Graph showing (Al-7) limiting loss of motor nerve response corresponding to tail flick response in a model of T2DM.
• the present invention provides methods for limiting development of neurodegeneration, comprising administering to a subject at risk of neurodegeneration an amount effective for limiting development of neurodegeneration of a polypeptide comprising or consisting of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof,
• AT2 type 2 receptor agonists or an agonist (polypeptide or otherwise) of the MAS receptor, or pharmaceutically acceptable salts thereof.
• the methods of the present invention may be used to limit development of neurodegeneration, i.e., the progressive loss of structure and/or function of neurons, including neuron death.
• the subject may be any suitable subject, such as a mammal, that is at risk of neurodegeneration, including but not limited to those subjects that suffer from metabolic syndrome, type 1 diabetes, type 2 diabetes, obesity, hyperglycemia, chronic inflammation, mitochondrial dysfunction, hyperinsuliemia, vasculopathy, hypertension, and hyperlipidemia, stroke, trauma, tumors, loss of vascular supply, ischemia, hypoxia, infection (including but not limited to bacterial and viral infection), and exposure to toxins.
• the subject is a human subject.
• the subject has one or more of metabolic syndrome, type 2 diabetes, insulin resistance, obesity, hyperglycemia, chronic inflammation, mitochondrial dysfunction, hyperinsuliemia, vasculopathy, hypertension, and hyperlipidemia.
• the subject has metabolic syndrome and/or type 2 diabetes.
• the methods of the invention can be used to limit development of any number of neurological disorders, including but not limited to dementia, cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), amyloidosis, dystrophia myotonica, Werdnig-Hoffman disease, encephalomyelitis, Dejerine, Scottas disease, Eaton-Lambert syndrome, depression, Walker- Warburg syndrome, schizophrenia, ischemic stroke , blindness, myotonic dystrophy, Startle disease, seizures, areflexia, ataxia telangiectasia, Tay-Sach's disease, spinocerebellar ataxia, dystonia, Wilson's disease, Creutzfeldt- Jakob disease, Becker muscular dystrophy, muscular dystrophy, Duchenne muscular dystorphy, vertigo, dyskenesia, tardive akathisia, Gilles de la Tourette's Syndrome, migraine, spa
• ALS amy
• the term "limit” or “limiting” means to (a) reducing the severity of the neurodegeneration and/or neurological disorder; (b) limiting or preventing development of symptoms characteristic of the neurodegeneration and/or neurological disorder; (c) inhibiting worsening of symptoms characteristic of the neurodegeneration and/or neurological disorder; (d) limiting or preventing recurrence of the neurodegeneration and/or neurological disorder in subjects that have previously had the neurodegeneration and/or neurological disorder; and (e) limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the neurodegeneration and/or neurological disorder.
• the methods may be used in subjects at risk of but without symptoms of neurodegeneration.
• the methods are used in subjects that show symptoms of neurodegeneration; in this embodiment, the methods are used to treat the neurological disorder, including but not limited to treating dementia, cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, or ALS.
• treat or “treating” means accomplishing one or more of the following: (a) reducing the severity of the neurological disorder; (b) limiting or preventing development of symptoms characteristic of the neurological disorder being treated; (c) inhibiting worsening of symptoms characteristic of the neurological disorder being treated; (d) limiting or preventing recurrence of neurological disorder in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the neurological disorder.
• symptoms of Alzheimer's disease include, but are not limited to memory loss, impairments in attentiveness, planning, flexibility, abstract thinking, and/or language; apathy, agnosia, apraxia, paraphasias, increased risk of falling/lack of stability; wandering, irritability, labile affect, aggression, resistance to caregiving, inability to identify family and friends, delusions, anosognosia, urinary incontinence, decreased muscle mass, compulsive behavior, and exhaustion.
• symptoms of Parkinson's disease include, but are not limited to tremors, rigidity, slowness of movement (bradykinesia), postural instability, impaired balance and increased risk of falling, festination (rapid shuffling steps and a forward-flexed posture when walking), speech and swallowing disturbances, neuropsychiatric disturbances including but not limited to disorders of cognition, mood, behavior, and thought; fluctuations in attention and slowed cognitive speed, dementia, depression, apathy, delusions, and anxiety.
• symptoms of Huntington's disease include, but are not limited to jerky, random, and uncontrollable movements (chorea); restlessness, unintentionally initiated or uncompleted motions, lack of coordination, slowed saccadic eye movements, rigidity, writhing motions, abnormal posturing, physical instability, abnormal facial expressions, difficulties chewing, swallowing, and/or speaking; difficulty eating, sleep disturbances, seizures, irritability, apathy, anxiety, depression, memory deficits, impairments in attentiveness, planning, flexibility, abstract thinking, and/or language; and compulsive behavior.
• Symptoms of ALS include, but are not limited to muscle weakness, atrophy, twitching, cramping, and/or stiffness; muscle weakness affecting an arm or a leg; slurred and nasal speech, difficulty speaking clearly or swallowing; loss of tongue mobility, difficulty moving, swallowing, chewing, or speaking/forming words; exaggerated reflexes; and uncontrollable laughter, crying or smiling.
• polypeptides for use in the invention comprise or consist of a sequence of at least four contiguous amino acids of groups R'-R 8 in the sequence of general formula I
• R 1 is selected from the group consisting of H, Asp, Glu, Asn, Acpc (1- aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH2), Gly, Asp(N3 ⁇ 4) and Sue, or is absent,
• R 2 is selected from the group consisting of Arg, Lys, Ala, Cit, Orn, Ser(Ac), Sar, D- Arg and D-Lys,
• R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Lys, Pro, Aib, Acpc and Tyr;
• R 4 is selected from the group consisting of Tyr, Tyr(P(3 ⁇ 4)2, Thr, Ser, homoSer, azaTyr, and Ala;
• R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
• R 6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
• R 7 is selected from the group consisting of Pro or Ala
• R is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R 4 as a terminal Tyr group.
• AT2 agonists useful in the practice of the invention include the All analogues set forth above subject to the restriction that R 6 is p-NEL-Phe.
• R 1 is selected from the group consisting of Asp and Glu, or is absent;
• R 2 is selected from the group consisting of Arg, Lys, and Ala;
• R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Lys, and
• R 4 is selected from the group consisting of Tyr and homoSer
• R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
• R 6 is selected from the group consisting of His and Arg
• R 7 is selected from the group consisting of Pro or Ala
• R 8 is selected from the group consisting of Phe, He, or is absent.
• polypeptides comprise or consist of at least five, six, seven, or eight contiguous amino acids of groups 1 8
• polypeptides consist essentially of a sequence of at least four, five, six, seven, or eight contiguous amino acids of groups R'-R 8 in the sequence of general formula I.
• R 1 and R 2 are Asp-Arg, Asp-Lys, Glu-Arg and
• Glu-Lys Particularly preferred embodiments of this class include the following: AIII or AII(2-8), Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]; AII(3-8), also known as desl-AIII or AIV, Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:3]; A(l-7), Asp-Arg-Val-Tyr-Ile-His-Pro [SEQ ID NO:4]; AII(2-7).
• Arg-norLeu-Tyr-Ile-His-Pro-Phe [SEQ ID NO: l 1] and Arg-Val-Tyr-norLeu-His-Pro-Phe [SEQ ID NO: 12].
• Still another preferred embodiment encompassed within the scope of the invention is a peptide having the sequence Asp-Arg- Pro-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 13].
• the polypeptides for use in the present invention comprise or consists of at least 5 contiguous amino acids of A(l-7) (SEQ ID NO:4), a peptide consisting of the amino acid sequence Asp-Arg-Val- Tyr-Ile-His-Pro (SEQ ID NO: 4).
• the peptide administered to the subject may be Asp-Arg-Val- Tyr-Ile (SEQ ID NO: 9), Asp-Arg-Val-Tyr-Ile-His (SEQ ID NO: 8), or most preferably Asp- Arg- Val-Tyr-Ile-His-Pro (SEQ ID NO: 4).
• polypeptides of particular interest in accordance with the present invention are those of the general formula II:
• R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
• a particularly preferred subclass of the compounds of general formula II has the formula:
• R , R and R are as previously defined. Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]. Other preferred compounds include peptides having the structures Arg-Val-Tyr-Gly-His-Pro-Phe [SEQ ID NO:35] and Arg-Val-Tyr-Ala-His-Pro-Phe [SEQ ID NO:36].
• angiotensin analogues that can be used in the methods of the present invention include the following:
• Analogue 1 1 Asp-Arg-Val-Tyr-Ile-His-Pro-Tyr SEQ ID NO: 27
• polypeptides may be any of those disclosed in
• polypeptide is:
• the methods comprise administering an agonist of the MAS receptor.
• Any suitable polypeptide or non-polypeptide agonist of the MAS receptor may be used, including but not limited to A(l-7) and analogues thereof, A779 (D-Ala A(l-7);
• polypeptides for use in the present invention may be linear or cyclized in any suitable manner, such as those described in WO2008/018792, including but not limited to polypeptides comprising a thioether bridge between positions 4 and 7, or other positions.
• the polypeptides may be administered in any suitable dosage for a given purpose.
• the polypeptide are administered in a dosage of 10 ⁇ g/kg/day, 50 ⁇ g/day ⁇ g/kg/day, 100 ⁇ g/kg/day, 250 ⁇ g/kg/day, 500 ⁇ g/kg/day, 1000 ⁇ g/kg/day or more.
• the amount of polypeptide or pharmaceutical salt thereof is sufficient to provide a dosage to a patient of between 0.01 ⁇ g/kg and 10 mg/kg; 0.1 ⁇ g/kg and 5 mg/kg; 0.1 ⁇ g/kg and 1000 ⁇ g/kg; 0.1 ⁇ g/kg and 900 ⁇ g/kg; 0.1 ⁇ g/kg and 900 ⁇ g/kg; 0.1 ⁇ g/kg and 800 ⁇ g/kg; 0.1 ⁇ g/kg and 700 ⁇ g/kg; 0.1 ⁇ g/kg and 600 ⁇ g/kg; 0.1 ⁇ g/kg and 500 ⁇ g/kg; or 0.1 ⁇ g/kg and 400 ⁇ g/kg.
• the polypeptides can be administered as often as appropriate to achieve the desired result, including but not limited once per day, twice per day, every other day, three times per week, twice per week, or once per week.
• suitable acids which are capable of forming salts with the polypeptides include inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, phosphoric acid and the like; and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, anthranilic acid, cinnamic acid, naphthalene sulfonic acid, sulfanilic acid and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, phosphoric acid and the like
• organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic
• Suitable bases capable of forming salts with the polypeptides include inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide and the like; and organic bases such as mono-, di- and tri-alkyl and aryl amines (e.g., triethylamine, diisopropyl amine, methyl amine, dimethyl amine and the like) and optionally substituted ethanol- amines (e.g., ethanolamine, diethanolamine and the like).
• inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide and the like
• organic bases such as mono-, di- and tri-alkyl and aryl amines (e.g., triethylamine, diisopropyl amine, methyl amine, dimethyl amine and the like) and optionally substituted ethanol- amines (e.g., ethanolamine, diethanolamine and the like).
• compositions for use in the methods of the invention may be made up in a solid form (including granules, powders or suppositories), in aerosolized form, or in a liquid form (e.g., solutions, suspensions, or emulsions).
• the pharmaceutical compositions may be applied in a variety of solutions. Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the polypeptides and are not harmful for the proposed application.
• the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases.
• the compounds of the present invention are soluble in organic solvents and in aqueous solutions at pH 5-8.
• the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants.
• compositions of the present invention may further comprise one or more other therapeutics as needed by a given subject.
• Non- limiting exemplary compounds that may be administered together (either admixed or separately administered) with the polypeptide of the invention include insulin, metformin, sulfonylurea, steroids, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), acetylcholine, dopamine, norepinephrine, serotonin, vitamine B 12, benzodiazepines, lithium, acyclovir, meperidine, tacrolimus, cyclosporine, antidepressants, antispychotics, alcohol, barbiturates, amphetamine, phencyclidine, methylphenidate, valproic acid, lamotrigine, carbamazepine, phenytoin, ethosusimide, topiramate, primidone, phenobarbital, felb
• polypeptides or salts thereof can further be derivatized to provide enhanced half- life, for example, by linking to polyethylene glycol or lipidized to increase oral
• the polypeptides or salts thereof may comprise L-amino acids, D-amino acids (which are resistant to L-amino acid-specific proteases in vivo), a combination of D- and L-amino acids, and various "designer" amino acids (e.g., ⁇ -methyl amino acids, Ca-methyl amino acids, and Na-methyl amino acids, etc.) to convey special properties.
• the N-terminus may be acetylated and/or the C-terminus may be amidated.
• polypeptides or salts thereof can have peptidomimetic bonds.
• a polypeptide may be generated that incorporates a reduced peptide bond, i.e., Ri- CH2-NH-R2, where Ri and R2 are amino acid residues or sequences.
• a reduced peptide bond may be introduced as a dipeptide subunit.
• Such polypeptides are resistant to protease activity, and possess an extended half-live in vivo.
• polypeptides or salts thereof may be chemically synthesized or recombinantly expressed or modified post expression, each of which can be accomplished using standard methods in the art.
• polypeptides or salts or ester analogs of the peptides thereof can be administered by any suitable route, including but not limited to dermal, subcutaneous, intradermal, transdermal (for example, by slow-release polymers), intramuscular, intraperitoneal, intravenous, oral, aural, epidural, anal or vaginal (for example, by suppositories), pulmonary route, intratracheal instillation, intranasal routes, infusion or bolus injection, or absorption through epithelial or mucocutaneous linings.
• administration is systemic.
• the pharmaceutical compositions are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
• the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
• compositions of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, hydroxyethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
• Other adjuvants and modes of administration are well known in the pharmaceutical art.
• the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
• Example 1 A(l-7) improves nervous system function in vivo
• mice Eight week- old male BKS.Cg-Dock7 m +/+ Lepr db li (db/db) mice, a model of overnutrition resulting in metabolic syndrome, insulin resistance, hyperglycemia and obesity leading to type 2 diabetes, and their heterozygous controls were purchased from Jackson Laboratories (Bar Harbor, ME, USA). All mice were quarantined for one week prior to the initiation of treatment, food and water were available ad libitum, and they were kept on a 12 hour light/dark cycle.
• mice were habituated for 20 minutes prior to testing. While recording with a video camera, the distal half of the tail was immersed in a 50 °C water bath. Time from immersion to tail flick was measured in milliseconds.
• Measuring MNCVs was adapted from a previously described protocol (Yorek et al., 1993). Mice were anesthetized with 100/10 mg/kg Ketamine/Xylazine and body temperature was maintained with a heating pad. The sciatic nerve was stimulated subdermally at the sciatic notch and then at the Achilles tendon with a single 0.2 ms 8 V pulse. Recording electrodes were placed at the ipsilateral interosseous muscles. Potentials were recorded with a BioPAC MP 150 with an ECG100C module.
• the MNCV was calculated by subtracting the proximal from the distal latency measured in milliseconds from stimulus artifact to the onset of the compound action potential, and the difference was divided by the distance between the two stimulations sites measured in millimeters with a vernier caliper. MNCV was reported in meters per second.
• FIG. 1A these data were obtained at two weeks after initiation of once daily A(l-7) or saline administration.
• Diabetes reduced sciatic nerve conduction in the db/db mice, which showed an approximately 40% reduction in MCNV compared to heterozygous controls, while administration of A(l-7) to db/db mice limited the reduction in MCNV such that it was virtually indistinguishable from heterozygous controls.
• A(l-7) limited development of damage to the peripheral nerve function associated with a mouse model of overnutrition resulting in metabolic syndrome, hyperglycemia, and obesity leading to diabetes.
• Diabetes is associated with progressive neuropathy that results in reduced sensory and motor function. Diabetic neuropathy contributes to ischemia and tissue destruction due to lack of sensation.
• the examples presented herein demonstrate that the methods of the invention can be used, for example, to limit development of neuropathy, such as in subjects suffering from one or more of metabolic syndrome, hyperglycemia, obesity, and/or diabetes.

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• 2013
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