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WO2018187647A1 - Procédés et compositions destinés au traitement de maladies, troubles ou états neurologiques - Google Patents

Procédés et compositions destinés au traitement de maladies, troubles ou états neurologiques Download PDF

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Publication number
WO2018187647A1
WO2018187647A1 PCT/US2018/026390 US2018026390W WO2018187647A1 WO 2018187647 A1 WO2018187647 A1 WO 2018187647A1 US 2018026390 W US2018026390 W US 2018026390W WO 2018187647 A1 WO2018187647 A1 WO 2018187647A1
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Prior art keywords
bryostatin
pkc
hasf
effective amount
pharmaceutically effective
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PCT/US2018/026390
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English (en)
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Daniel Alkon
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Neurotrope Bioscience, Inc.
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Publication of WO2018187647A1 publication Critical patent/WO2018187647A1/fr

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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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates generally to the field of neurology.
  • disorders and diseases exist which affect aspects of cognition, including attention, learning, and memory. These disorders may be associated with varying degrees of neiu'odegeneration.
  • a pharmaceutically effective amount of HASF and/or of a compound that increases endogenous expression of HASF in the treatment of a neurological disease, disorder, or condition may be from about 0.0000001 mg/kg to about 250 mg/kg per dose or from about 0.00001 mg/kg to about 5.0 mg/kg per dose.
  • a PKC activator activates the PKC ⁇ isozyme and/or the PKC a isozyme.
  • the PKC activator is Hypoxia and Akt induced Stem Cell Factor (HASF), a compound that increases endogenous expression of HASF, or a combination thereof.
  • HASF Hypoxia and Akt induced Stem Cell Factor
  • One or more additional PKC activators can also be administered to the patient.
  • the one or more additional PKC activators can be selected from the group consisting of bryostatin 1, bryostatin 2, bryostatin 3, bryostatin 4, bryostatin 5, bryostatin 6, bryostatin 7, bryostatin 8, bryostatin 9, bryostatin 10, bryostatin 11, bryostatin 12, bryostatin 13, bryostatin 14, bryostatin 15, bryostatin 16, bryostatin 17, bryostatin 18, bryostatin 19, bryostatin 20, a bryolog, a polyunsaturated fatty acid, a potassium channel activator (i.e.
  • a diazoxide a diazoxide
  • a neristatin i.e. , neristatin 1
  • PMA phorbol-12-myristate-13-acetate
  • okadaic acid la,25-dihydroxy vitamin D3, 12-deoxyphorbol-13-acetate (prostratin), 1,2-dioctanoyl-sn-glycerol (DOG), l-oleoyl-2-acetyl-sn-glycerol (OAG), (2S,5S)-(E,E)-8-( 5- ( 4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (a-amyloid precursor protein modulator), cis-9-octadecenoic acid (oleic acid), ingenol 3-angelate, resiniferatoxin, L-a-Phosphatidyl-D-myo-inositol
  • the PKC activator is administered orally, intraperitoneally, subcutaneously, intranasally, buccally, trans -dermally, intramuscularly, intrarectally, intravenously, and/or by inhalation.
  • the pharmaceutically effective amount of the PKC activator is from about 0.0000001 mg/kg to about 250 mg/kg per dose. In some embodiments, the PKC activator is provided in a dose from about 0.01-25 ⁇ g/m 2 IV.
  • the neurological disease, disorder, or condition may be Alzheimer's disease.
  • Figure 1 is a graph showing that Hypoxia and Akt Induced Stem Cell Factor (HASF) expression is lower in human Alzheimer's hippocampus compared to age matched control brains.
  • HASF Hypoxia and Akt Induced Stem Cell Factor
  • neurodegeneration refers to the progressive loss of structure or function of neurons, including death of neurons.
  • any of the compounds disclosed herein may be used for the treatment of one or more neurological diseases, disorders, or conditions.
  • the neurological disease, disorder, or condition may be any disease, disorder, or condition that affects the central nervous system (CNS) or the peripheral nervous system (PNS).
  • CNS central nervous system
  • PNS peripheral nervous system
  • the neurological disease, disorder, or condition may be Alzheimer's disease; congophilic angiopathy (also known as cerebral amyloid angiopathy or CAA), Down syndrome; muiii-infarci dementia (MID), a senile dementia caused by cerebrovascular deficiency; the Lewy-body variant of Alzheimer's disease with or without association with Parkinson's disease; Creutzfekl- Jakob disease: brain damage as the result of a classical stroke or as a result of an anesthetic accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication, vitamin (BL thiamine and B12) deficiency, excessive alcohol use or Korsakow's disorder; traumatic brain injury; mood disorders such as bipolar disorder or depressive disorders; and/or schizophrenia.
  • congophilic angiopathy also known as cerebral amyloid angiopathy or CAA
  • MID muiii-infarci dementia
  • Synaptogenesis refers to the process by which synapses are formed between neurons.
  • Two types of synaptogenesis occur after damage in the adult central nervous system (CNS): regenerative synaptogenesis and reactive synaptogenesis.
  • Regenerative synaptogenesis occurs when injured axons begin sprouting and may result in the axon extending long distances in order to reach its original target, whereas reactive synaptogenesis occurs within 4-5 days of injury when nearby undamaged axons innervate synaptic sites that were previously activated by the injured axons.
  • the protein kinase C (PKC) family of enzymes is responsible for a multitude of cellular processes through the enzymes' ability to regulate proteins via signal transduction cascades.
  • the members of this kinase family are structurally and functionally similar and are categorized into conventional ( ⁇ , ⁇ , ⁇ and ⁇ ), novel ( ⁇ , ⁇ , ⁇ , and ⁇ ), and atypical isoforms ( ⁇ and ⁇ ). These isoforms have been implicated in a variety of diseases and pathological conditions. (See Mellor and Parker (1998) Biochem. J. 332(2): 281-292; Azzi et al. (1992) Eur. J. Biochem. 208:547-557; Cloud-Heflin et al. (1996) Eur. J. Biochem. 239: 796-804; and Mochly-Rosen et al. Nat. Rev. Drug Discov. 11 : 937-957.)
  • AD Alzheimer's disease
  • the PKC ⁇ and PKC a isozymes are responsible for increasing the synthesis of synaptic growth factors including BDNF, IGF, and NGF, thereby increasing the levels of these growth factors. Further, the PKC ⁇ and PKC a isozymes are anti-apoptotic, i.e. , they prevent and/or reduce neuronal and synaptic death. In one embodiment, PKC ⁇ contributes more than PKC a towards the increase in the synthesis of synaptic growth factors including BDNF, IGF, and NGF. In one embodiment, PKC ⁇ is more efficacious at preventing and/or reducing neuronal and synaptic death than PKC a.
  • HASF is a novel paracrine factor secreted by mesenchymal stem cells that promotes cardiomyocyte proliferation. (See Beigi et al., Circ Res. 113:372-80 (2013)). Additionally, HASF also exerts a cytoprotective on ischemia induced cardiomyocyte death. (See Huang et al., J Mol Cell Cardiol 66: 157-164 (2014), which is herein incorporated by reference).
  • HASF has also been shown to activate protein kinase C ⁇ ( ⁇ ) in vivo and in vitro.
  • HASF expression is lower in human AD hippocampus compared to age matched control brains. ⁇ See Figure 1). Moreover, ⁇ -oligomers (ASPDs) have been shown to reduce HASF secretion from SH-SY5Y cells (a human neuroblastoma cell line).
  • HASF may play a role in neuronal survival and/or treatment of AD. Future studies will be performed to determine whether HASF plays a role in synaptogenesis and/or neuroprotection.
  • protein kinase C activator or “PKC activator” refers to a substance that increases the rate of the reaction catalyzed by protein kinase C, upregulates the expression of PKC (e.g. , upregulates the expression of PKCa, PKC ⁇ , PKC ⁇ and/or PKC ⁇ ), or otherwise facilitates the activation of PKC.
  • PKC activator proteins kinase C activators
  • Protein kinase C activators are known to possess potent neurotrophic and neuroprotective activity. However, not all PKC activators exhibit this activity to the same extent.
  • preferred PKC activators for use in the methods disclosed herein will be ones that activate PKC ⁇ and/or PKC a.
  • PKC activators that are tumorigenic and/or toxic should not be used.
  • the PKC activator may be any of bryostatin 1-20, a bryolog, neristatin, a polyunsaturated fatty acid, or any combinations thereof.
  • Bryostatins may be used in the methods of the present disclosure.
  • the bryostatins are a family of naturally occurring macrocyclic compounds originally isolated from marine bryozoa.
  • A, Band C there are about 20 known natural bryostatins which share three six- membered rings designated A, Band C, and which differ mainly in the nature of their substituents at C7 (OR A ) and C20 (R B ).
  • bryostatin 1 Bryostatin 1 and derivatives of bryostatin 1 are described in U. S Pat. No. 4,560,774 (incorporated herein by reference).
  • suitable bryostatins include, bryostatin 1 , bryostatin 2, bryostatin 3, bryostatin 4, bryostatin 5, bryostatin 6, bryostatin 7, bryostatin 8, bryostatin 9, bryostatin 10, bryostatin 1 1 , bryostatin 12, bryostatin 13, bryostatin 14, bryostatin 15, bryostatin 16, bryostatin 17 bryostatin 18, bryostatin 19, and bryostatin 20.
  • bryologs are structural analogues of bryostatin. While bryostatin has two pyran rings and one 6-membered cyclic acetal, in most bryologs one of the pyrans of bryostatin is replaced with a second 6-membered acetal ring. This modification reduces the stability of bryologs, relative to bryostatin, for example, in both strong acid or base, but has little significance at physiological pH.
  • Bryologs also have a lower molecular weight (ranging from about 600 to 755), as compared to bryostatin (988), a property which may facilitate transport across the blood-brain barrier.
  • suitable bryologs include, but are not limited to, analogs and derivatives of bryostatins such as those disclosed in U. S. Pat. Nos. 6,624, 189, 7,256,286 and 8,497,385 (the disclosures of which are incorporated herein by reference).
  • PUFAs or polyenoic fatty acids Polyunsaturated fatty acid esters (PUFAs or polyenoic fatty acids)) or derivatives thereof may be used in the methods of the present disclosure.
  • a PUFA is a fatty acid containing more than one double bond. While PUFAs themselves are unstable in most physiologic circumstances and may themselves possess little or no PKC ⁇ activation efficacy, it is possible to derivatize PUFAs to make them more stable and increase their potency and specificity for PKC ⁇ activation.
  • omega-3 PUFAs There are three classes of PUFAs, omega-3 PUFAs, omega-6 PUFAs, and omega-9 PUFAS.
  • omega-3 PUFAs the first double bond is found 3 carbons away from the last carbon in the chain (the omega carbon).
  • omega-6 PUFAs the first double bond is found 6 carbons away from the chain and in omega-9 PUFAs the first double bond is 9 carbons from the omega carbon.
  • PUFA includes both naturally-occurring and synthetic fatty acids.
  • a major source for PUFAs is from marine fish and vegetable oils derived from oil seed crops.
  • PUFA's suitable for use in the methods of the present disclosure include, but are not limited to, esters of 8-[2-(2-pentylcyclopropylmethyl) cyclopropyl]-octanoic acid (DCPLA), as well as those described in United States patent 8,163,800 and in PCT publication WO 2010014585 Al.
  • DCPLA 2-(2-pentylcyclopropylmethyl) cyclopropyl]-octanoic acid
  • PKC activators include potassium channel activators such as, for example, diazoxide.
  • Neristatins such as neristatin 1
  • neristatin 1 may be used in the methods of the present disclosure for treating lipid storage disorders.
  • PKC activators include, but are not limited to, phorbol-12- myristate-13-acetate (PMA), okadaic acid, l ,25-dihydroxyvitamin D3, 12- deoxyphorbol-13-acetate (prostratin), 1,2-dioctanoyl-sn-glycerol (DOG), l-oleoyl-2- acetyl-sn-glycerol (OAG), (2S,5S)-(E,E)-8-(5- (4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam(a-amyloid precursor protein modulator), cis-9- octadecenoic acid (oleic acid), ingenol 3-angelate, resiniferatoxin, L-a- Phosphatidyl-D-myo-inositol-4,5-bisphosphate, triammonium salt (PIP2), phor
  • HASF has also been shown to be a natural PKCs activator. (See Huang et al, J Mol Cell Cardiol 66: 157-164 (2014), which is herein incorporated by reference).
  • HASF is another PKCs activator that can be used to treat neurological diseases, disorders, and/or conditions.
  • the neurological disease, disorder, or condition may be Alzheimer's disease (AD).
  • pharmaceutically and/or therapeutically effective amounts of exogenously added HASF can be administered to a patient in order to activate PKC8, and thereby prevent synaptic loss and/or treat, ameliorate, or prevent neurodegeneration.
  • one or more compounds that increase endogenous expression of HASF by stem cells can be administered to a patient in order to increase the activation of PKCs, and thereby prevent synaptic loss and/or treat, ameliorate, or prevent neurodegeneration.
  • cells that have been genetically engineered to express or overexpress HASF and/or one or more compounds that increase endogenous expression of HASF by stem cells can be used in order to increase the activation of PKC8, and thereby prevent synaptic loss and/or treat, ameliorate, or prevent neurodegeneration.
  • subject refers to an animal, including, but not limited to, a primate (e.g. , human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g. , human
  • cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse e.g., cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, abating, ameliorating, or preventing a disease, condition or symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • prevent include to keep from developing, occur, hinder or avert a disease or condition symptoms as well as to decrease the occurrence of symptoms.
  • the prevention may be complete (i.e. , no detectable symptoms) or partial, so that fewer symptoms are observed than would likely occur absent treatment.
  • the terms further include a prophylactic benefit.
  • inhibitors also mean reducing an effect (e.g., disease state or expression level of a gene/protein/mRNA).
  • the term "about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term "about.”
  • a pharmaceutically effective amount or "a therapeutically effective amount” is an amount of a pharmaceutical compound or composition having a therapeutically relevant effect.
  • Pharmaceutically effective amount for bryostatins and bryologs may be from about 0.0000001 to about 500 mg per kg host body weight per day, which can be administered in single or multiple doses.
  • the dosage level may be: from about 0.0000001 mg/kg to about 250 mg/kg per day; from about 0.0000005 mg/kg to about 100 mg/kg per day; from at least about 0.0000001 mg/kg to about 250 mg/kg per day; from at least about 0.00000005 mg/kg to about 100 mg/kg per day; from at least about 0.000001 mg/kg to about 50 mg/kg per day; or from about 0.00001 mg/kg to about 5.0 mg/kg per dose.
  • the dosage may be about 0.00000001 mg/kg to about 0.00005 mg/kg; 0.00005 mg/kg to about 0.05 mg/kg; about 0.0005 mg/kg to about 5.0 mg/kg per day; about 0.0001 mg/kg to about 0.5 mg/kg per dose; or 0.001 to 0.25 mg/kg per dose.
  • the dosing is from about 1 ⁇ g/kg (3-25 ⁇ g/m 2 ) to 120 ⁇ g/kg (360-3000 ⁇ g/m 2 ). In other embodiments, the dosing is from about 0.04-0.3 ⁇ g/kg (1 ⁇ g/m 2 ) to about 1-10 ⁇ g/kg (25 ⁇ g/m 2 ). In other embodiments, the dosing is from about 0.01 ⁇ g/m 2 to about 25 ⁇ g/m 2 . In other embodiments, the dosing is from about 0.0002-0.0004 ⁇ g/kg to about 0.05-1 ⁇ g/kg.
  • the PKC activator is a PUFA administered at a dosage of about 0.001 to 100 mg/kg; 0.01 to about 50 mg/kg; about 0.1 to about 10 mg/kg.
  • the PKC activator present in the compositions used in the methods of the present disclosure is a bryostatin or bryolog
  • the bryostatin or bryolog is used in an amount from about 0.0001 to about 1000 milligrams.
  • the bryostatin or bryolog is used in an amount from at least about 0.0001, 0.0005, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, or about 1000.0 milligrams.
  • Pharmaceutically effective amount of HASF and/or one or more compounds that increase endogenous expression of HASF by stem cells may be from about 0.0000001 to about 500 mg per kg host body weight per day, which can be administered in single or multiple doses.
  • the dosage level may be: from about 0.0000001 mg/kg to about 250 mg/kg per day; from about 0.0000005 mg/kg to about 100 mg/kg per day; from at least about 0.0000001 mg/kg to about 250 mg/kg per day; from at least about 0.00000005 mg/kg to about 100 mg/kg per day; from at least about 0.000001 mg/kg to about 50 mg/kg per day; or from about 0.00001 mg/kg to about 5.0 mg/kg per dose.
  • the dosage may be about 0.00000001 mg/kg to about 0.00005 mg/kg; 0.00005 mg/kg to about 0.05 mg/kg; about 0.0005 mg/kg to about 5.0 mg/kg per day; about 0.0001 mg/kg to about 0.5 mg/kg per dose; or 0.001 to 0.25 mg/kg per dose.
  • compositions used in the methods of the present disclosure may be administered via any suitable route; for example, orally, intraperitoneally, subcutaneously, intranasally, buccally, trans -dermally intramuscularly, intrarectally, intravenously, and by oral inhalation.
  • compositions used in the methods of the present disclosure may be administered on a regimen of 1 to 4 times per day, and in some embodiments, the compositions are administered twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks or even less frequently depending on the needs of the patient.
  • compositions used in the methods of the present disclosure may be administered as part of a course of treatment lasting for about 1 to about 30 days; about 1 to about 90 days; about 1 to about 120 days; about 1 to about 180 days; about 1 to 365 days; one year; two years; three years; or for the patient's lifetime.
  • the specific dose level and frequency of dosage for any particular host may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the nature of the disorder, the severity of the particular disorder, and the host undergoing therapy.
  • Example 1 Role of HASF in Neuronal Survival and Alzheimer's disease
  • HASF expression is lower in human AD hippocampus compared to age matched control brains. This, in turn, provides evidence that there is a direct role of HASF in AD. Moreover, this finding has broad implications since HASF is a PKCs activator, and PKCs is a well-known synaptogenic molecule known to be deficient in AD.

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Abstract

L'invention concerne des utilisations de quantités pharmaceutiquement efficaces de HASF et/ou de composés qui augmentent l'expression endogène de HASF dans le traitement d'une maladie, d'un trouble ou d'un état neurologique. L'invention concerne également des méthodes de traitement d'une maladie, d'un trouble ou d'un état neurologique chez un patient par l'administration au patient d'une quantité pharmaceutiquement efficace d'un ou de plusieurs activateurs de PKC tels que HASF et/ou de composés qui augmentent l'expression endogène de HASF.
PCT/US2018/026390 2017-04-06 2018-04-06 Procédés et compositions destinés au traitement de maladies, troubles ou états neurologiques WO2018187647A1 (fr)

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US20220133687A1 (en) * 2020-11-02 2022-05-05 Synaptogenix, Inc. Methods of treating and preventing neurodegenerative diseases with hgf activating compounds
ES2916383A1 (es) * 2020-12-29 2022-06-30 Univ Cadiz Derivados de 12-desoxiforboles y usos de los mismos

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* Cited by examiner, † Cited by third party
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US20220133687A1 (en) * 2020-11-02 2022-05-05 Synaptogenix, Inc. Methods of treating and preventing neurodegenerative diseases with hgf activating compounds
ES2916383A1 (es) * 2020-12-29 2022-06-30 Univ Cadiz Derivados de 12-desoxiforboles y usos de los mismos
WO2022144482A1 (fr) * 2020-12-29 2022-07-07 Universidad De Cádiz Dérivés de 12-désoxyphorboles et leurs utilisations

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