WO2015035002A1 - Treatment of cyr61- and vegf-mediated conditions - Google Patents

Treatment of cyr61- and vegf-mediated conditions Download PDF

Info

Publication number
WO2015035002A1
WO2015035002A1 PCT/US2014/054018 US2014054018W WO2015035002A1 WO 2015035002 A1 WO2015035002 A1 WO 2015035002A1 US 2014054018 W US2014054018 W US 2014054018W WO 2015035002 A1 WO2015035002 A1 WO 2015035002A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyr61
administering
individual
cyr61dr
group
Prior art date
Application number
PCT/US2014/054018
Other languages
French (fr)
Inventor
Mihael H. Polymeropoulos
Louis William LICAMELE
Christian Lavedan
Original Assignee
Vanda Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanda Pharmaceuticals Inc. filed Critical Vanda Pharmaceuticals Inc.
Priority to EP14766342.1A priority Critical patent/EP3041479B1/en
Priority to US14/917,098 priority patent/US11458154B2/en
Priority to CA2923557A priority patent/CA2923557C/en
Priority to ES14766342T priority patent/ES2947557T3/en
Priority to JP2016540371A priority patent/JP2016530295A/en
Publication of WO2015035002A1 publication Critical patent/WO2015035002A1/en
Priority to US17/822,263 priority patent/US20220401464A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • CYR61 The gene cystine-rich, angiogenic inducer, 61 (CYR61) is one member of the CCN gene family, which encode cysteine-rich secreted proteins involved with differentiation and cell growth. CYR61 is known, among other things, to mediate cell adhesion and enhance angiogenesis. Individuals with proliferative diabetic retinopathy (PDR) have been shown to have increased levels of TGB- ⁇ , which induces CYR61 expression.
  • PDR proliferative diabetic retinopathy
  • You et al. have shown an ability of the CYR61 protein to induce endothelial cell chemotaxis and tube formation as well as a synergetic effect between CYR61 expression and vascular endothelial growth factor (VEGF) expression. More specifically, You et al. observed significant decreases in both CYR61- and VEGF- induced chemotaxis and tube formation upon the introduction of an anti-CYR61 antibody.
  • VEGF vascular endothelial growth factor
  • the invention provides a method of treating a CYR61- mediated condition in an individual in need of such treatment, the method
  • CYR61DR CYR61 downregulator
  • the invention provides a method of treating a VEGF- mediated condition in an individual in need of such treatment, the method comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of both the CYR61 gene and the VEGF gene in the individual, in particular, though not necessarily, wherein such CYR61DR decreases transcription by at least about 2-fold.
  • CYR61DR CYR61 downregulator
  • anthracyclines and statins are capable of downregulating expression of the CYR61 gene, making them useful in treating CYR61 -mediated conditions.
  • the synergetic effect of CYR61 expression and VEGF expression makes these compounds similarly useful in the treatment of VEGF- mediated conditions.
  • CYR61 gene expression is down regulated at least about 1-1/2-fold, e.g., 2-fold, i.e., the amount of CYR61 mRNA is at least about 1-1/2 fold less (e.g., 2-fold less) in treated cells than in untreated cells.
  • a human retinal pigment epithelial cell line (ARPE-19/HPV16) was separately treated with an anthracycline (doxorubicin or daunorubicin), a statin (simvastatin or lovastatin), or vehicle for 24 hours and gene expression for 22,238 probe sets covering 12,490 genes was generated using an Affymetrix instrument.
  • the effects of these compounds on the expression of CYR61 are shown below in Table 1.
  • anthracyclines and statins are capable of
  • Anthracyclines suitable for use according to embodiments of the invention include, for example, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone.
  • Statins suitable for use according to embodiments of the invention include, for example, simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin.
  • one or more anthracycline and/or one or more statin may be administered to an individual in an amount sufficient to affect downregulation of CYR61 and/or VEGF.
  • an individual may be administered doxorubicin, daunorubicin, or both.
  • an individual may be administered doxorubicin, a statin, or both.
  • Conditions that may be treated with one or more CYR61DR include those conditions involving neovascularization and/or inflammation, including, for example, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis.
  • neovascularization and/or inflammation including, for example, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis.
  • CYR61DRs may be administered to the individual to be treated in the form of a pharmaceutical composition.
  • Pharmaceutical compositions to be used according to various embodiments of the invention comprise a therapeutically effective amount of CYR61DRs or an active metabolite of a CYR61DR, or a pharmaceutically acceptable salt or other form (e.g., a solvate) thereof, together with one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical composition refers to a composition suitable for administration in medical use. It should be appreciated that the determinations of proper dosage forms, dosage amounts, and routes of administration for a particular patient are within the level of ordinary skill in the pharmaceutical and medical arts.
  • Administration may be oral but other routes of administration may also be employed, e.g., intravitreal, parenteral, nasal, buccal, transdermal, sublingual, intramuscular, intravenous, rectal, vaginal, etc.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compound is admixed with at least one inert pharmaceutically - accep table excipient such as (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example,
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • e) solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents as for example, cetyl alcohol, and glycerol monostearate
  • adsorbents as for example, kaolin and bentonite
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Solid dosage forms such as tablets, drages, capsules, pills, and granules also can be prepared with coatings and shells, such as enteric coatings and others well known in the art.
  • the solid dosage form also may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Such solid dosage forms may generally contain from 1% to 95% (w/w) of the active compound. In certain embodiments, the active compound ranges from 5% to 70% (w/w).
  • Solid compositions for oral administration can be formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg of active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired effect over the course of a treatment period, in association with the required pharmaceutical carrier.
  • CYR61DRs can be formulated, e.g., in a unit dosage form that is a capsule having 1- 500 mg of active in addition to excipients.
  • Liquid dosage forms for oral administration include pharmaceutically- accep table emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • CYR61DRs are provided in a liquid form and administered to an individual intravitreally.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates generally to the treatment of CYR61- and VEGF-mediated conditions and, more particularly to the treatment of such conditions by administering to an individual a CYR61 downregulator. In one embodiment, the invention provides a method of treating a CYR61-mediated condition in an individual in need of such treatment, the method comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual.

Description

TREATMENT OF CYR61- AND VEGF-MEDIATED CONDITIONS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of co-pending US Provisional Patent Application Serial No. 61/874,966, filed 6 September 2013, which is hereby incorporated herein.
BACKGROUND
The gene cystine-rich, angiogenic inducer, 61 (CYR61) is one member of the CCN gene family, which encode cysteine-rich secreted proteins involved with differentiation and cell growth. CYR61 is known, among other things, to mediate cell adhesion and enhance angiogenesis. Individuals with proliferative diabetic retinopathy (PDR) have been shown to have increased levels of TGB-β, which induces CYR61 expression.
You et al. have shown an ability of the CYR61 protein to induce endothelial cell chemotaxis and tube formation as well as a synergetic effect between CYR61 expression and vascular endothelial growth factor (VEGF) expression. More specifically, You et al. observed significant decreases in both CYR61- and VEGF- induced chemotaxis and tube formation upon the introduction of an anti-CYR61 antibody.
SUMMARY
In one embodiment, the invention provides a method of treating a CYR61- mediated condition in an individual in need of such treatment, the method
comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual, in particular, though not necessarily, wherein such CYR61DR decreases transcription by at least about 1-1/2-fold.
In another embodiment, the invention provides a method of treating a VEGF- mediated condition in an individual in need of such treatment, the method comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of both the CYR61 gene and the VEGF gene in the individual, in particular, though not necessarily, wherein such CYR61DR decreases transcription by at least about 2-fold.
DETAILED DESCRIPTION
Applicants have unexpectedly discovered that members of two known classes of compounds— anthracyclines and statins— are capable of downregulating expression of the CYR61 gene, making them useful in treating CYR61 -mediated conditions. In addition, the synergetic effect of CYR61 expression and VEGF expression makes these compounds similarly useful in the treatment of VEGF- mediated conditions.
Typically, in the practice of this invention, CYR61 gene expression is down regulated at least about 1-1/2-fold, e.g., 2-fold, i.e., the amount of CYR61 mRNA is at least about 1-1/2 fold less (e.g., 2-fold less) in treated cells than in untreated cells.
In a study leading to embodiments of the invention, a human retinal pigment epithelial cell line (ARPE-19/HPV16) was separately treated with an anthracycline (doxorubicin or daunorubicin), a statin (simvastatin or lovastatin), or vehicle for 24 hours and gene expression for 22,238 probe sets covering 12,490 genes was generated using an Affymetrix instrument. The effects of these compounds on the expression of CYR61 are shown below in Table 1.
Table 1— CYR61 Downregulation
Probe Rank amplitude CYR61DR cone. Vehicle Fold
210764_s_at 22272 -1.92489 Doxorubicin HC1 lOuM water -52.25522567
201289_at 22282 -1.96653 Doxorubicin HC1 lOuM water -118.510009
201289_at 22255 -1.37773 Simvastatin lOuM DMSO -5.428077844
210764_s_at 22262 -1.3931 Simvastatin lOuM DMSO -5.590871643
210764_s_at 22239 -1.8272 Daunorubicin HC1 lOuM water -22.14814815
201289_at 22278 -1.92127 Daunorubicin HC1 lOuM water -49.80655405
210764_s_at 22264 -1.29662 Lovastatin lOuM Ethanol -4.686826466
201289_at 22271 -1.41167 Lovastatin lOuM Ethanol -5.798905376
210764_s_at 22267 -1.87549 Idarubicin HC1 lOuM Methanol -31.12593366
201289 at 22273 -1.89929 Idarubicin HC1 lOuM Methanol -38.71800218
As can be seen from Table 1 , anthracyclines and statins are capable of
significant downregulation of CYR61. Within these results, anthracycline
downregulation is approximately an order of magnitude or more greater than statin downregulation. Nevertheless, the differences in potential side effects and drug interactions, as well as the extent of CYR61 downregulation desired, make either or both classes of compounds desirable in some circumstances.
Anthracyclines suitable for use according to embodiments of the invention include, for example, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone. Statins suitable for use according to embodiments of the invention include, for example, simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin.
According to some embodiments of the invention, one or more anthracycline and/or one or more statin may be administered to an individual in an amount sufficient to affect downregulation of CYR61 and/or VEGF. For example, in one embodiment, an individual may be administered doxorubicin, daunorubicin, or both. In another embodiment, an individual may be administered doxorubicin, a statin, or both.
Conditions that may be treated with one or more CYR61DR include those conditions involving neovascularization and/or inflammation, including, for example, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis.
CYR61DRs may be administered to the individual to be treated in the form of a pharmaceutical composition. Pharmaceutical compositions to be used according to various embodiments of the invention comprise a therapeutically effective amount of CYR61DRs or an active metabolite of a CYR61DR, or a pharmaceutically acceptable salt or other form (e.g., a solvate) thereof, together with one or more pharmaceutically acceptable excipients or carriers. The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical use. It should be appreciated that the determinations of proper dosage forms, dosage amounts, and routes of administration for a particular patient are within the level of ordinary skill in the pharmaceutical and medical arts. Administration may be oral but other routes of administration may also be employed, e.g., intravitreal, parenteral, nasal, buccal, transdermal, sublingual, intramuscular, intravenous, rectal, vaginal, etc. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is admixed with at least one inert pharmaceutically - accep table excipient such as (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, drages, capsules, pills, and granules also can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage form also may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Such solid dosage forms may generally contain from 1% to 95% (w/w) of the active compound. In certain embodiments, the active compound ranges from 5% to 70% (w/w).
Solid compositions for oral administration can be formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired effect over the course of a treatment period, in association with the required pharmaceutical carrier.
CYR61DRs can be formulated, e.g., in a unit dosage form that is a capsule having 1- 500 mg of active in addition to excipients.
Liquid dosage forms for oral administration include pharmaceutically- accep table emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound or composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances. Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
In some embodiments of the invention, CYR61DRs are provided in a liquid form and administered to an individual intravitreally.
While this invention has been described in conjunction with the specific embodiments outlined above, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art or are otherwise intended to be embraced. Accordingly, the embodiments of the invention as set forth above are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention as defined in the following claims. All patents, patent application, scientific articles and other published documents cited herein are hereby incorporated in their entirety for the substance of their disclosures.

Claims

CLAIMS What is claimed is:
1. A method of treating a CYR61 -mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR),
wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual.
2. The method of claim 1 , wherein the CYR61 -mediated condition is selected from a group consisting of: conditions involving neovascularization and conditions involving inflammation.
3. The method of claim 1 , wherein the CYR61 -mediated condition is selected from a group consisting of: proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis.
4. The method of claim 1 , wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins.
5. The method of claim 4, wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirabicin, idarubicin, valrubicin, and mitoxantrone.
6. The method of claim 4, wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin.
7. The method of claim 1 , wherein administering includes intravitreally administering.
8. The method of claim 1 , wherein administering includes orally administering.
9. The method of claim 1 , wherein administering includes administering intravenously.
10. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR),
wherein the effective amount is an amount sufficient to decrease expression of both the CYR61 gene and the VEGF gene in the individual.
11. The method of claim 10, wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins.
12. The method of claim 11 , wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone.
13. The method of claim 11 , wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin.
14. The method of claim 10, wherein administering includes intravitreally administering.
15. The method of claim 10, wherein administering includes orally administering.
16. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR),
wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene and the VEGF gene in the individual.
PCT/US2014/054018 2013-09-06 2014-09-04 Treatment of cyr61- and vegf-mediated conditions WO2015035002A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP14766342.1A EP3041479B1 (en) 2013-09-06 2014-09-04 Treatment of cyr61- and vegf-mediated conditions
US14/917,098 US11458154B2 (en) 2013-09-06 2014-09-04 Treatment of CYR61- and VEGF-mediated conditions
CA2923557A CA2923557C (en) 2013-09-06 2014-09-04 Treatment of cyr61- and vegf-mediated conditions
ES14766342T ES2947557T3 (en) 2013-09-06 2014-09-04 Treatment of conditions mediated by CYR61 and VEGF
JP2016540371A JP2016530295A (en) 2013-09-06 2014-09-04 Treatment of CYR61 and VEGF-mediated conditions
US17/822,263 US20220401464A1 (en) 2013-09-06 2022-08-25 Treatment of cyr61- and vegf-mediated conditions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361874966P 2013-09-06 2013-09-06
US61/874,966 2013-09-06

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/917,098 A-371-Of-International US11458154B2 (en) 2013-09-06 2014-09-04 Treatment of CYR61- and VEGF-mediated conditions
US17/822,263 Division US20220401464A1 (en) 2013-09-06 2022-08-25 Treatment of cyr61- and vegf-mediated conditions

Publications (1)

Publication Number Publication Date
WO2015035002A1 true WO2015035002A1 (en) 2015-03-12

Family

ID=51541371

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/054018 WO2015035002A1 (en) 2013-09-06 2014-09-04 Treatment of cyr61- and vegf-mediated conditions

Country Status (6)

Country Link
US (2) US11458154B2 (en)
EP (1) EP3041479B1 (en)
JP (3) JP2016530295A (en)
CA (1) CA2923557C (en)
ES (1) ES2947557T3 (en)
WO (1) WO2015035002A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018065219A1 (en) * 2016-10-04 2018-04-12 University College Dublin, National University Of Ireland, Dublin Heparin and statin combinations for preventing metastatic cancer
US11331295B2 (en) 2015-10-14 2022-05-17 Massachusetts Eye And Ear Infirmary High-dose statins for age-related macular degeneration

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992007866A1 (en) * 1990-11-01 1992-05-14 Board Of Regents, The University Of Texas System Anthracycline analogues bearing latent alkylating substituents
US20030065020A1 (en) * 2001-07-13 2003-04-03 Catharine Gale Treatment of macular degeneration
WO2013138343A1 (en) * 2012-03-16 2013-09-19 The Johns Hopkins University Controlled release formulations for the delivery of hif-1 inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2422820A1 (en) * 2000-09-19 2002-03-28 Novimmune S.A. Use of statins (hmg-coa reductase inhibitors) for the preparation of medicament as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent
CA2614324A1 (en) * 2005-07-06 2007-01-18 Kanisa Pharmaceuticals, Inc. Zosuquidar, daunorubicin, and cytarabine for the treatment of cancer
JP2009512423A (en) 2005-09-12 2009-03-26 ザ・ジョンズ・ホプキンス・ユニバーシティ Composition having anti-angiogenic activity and use thereof
US20100034749A1 (en) * 2006-07-10 2010-02-11 Medigene Ag Use of a Cationic Collodal Preparation for the Diagnosis and Treatment of Ocular Diseases
WO2008044339A1 (en) * 2006-10-13 2008-04-17 Aqumen Biopharmaceuticals K.K. Therapeutic/preventive agent for intraocular disease containing statin compound
CN104053655A (en) 2011-09-21 2014-09-17 以色列农业和农村发展部，农业研究组织（Aro）（农业研究中心） Use Of Strigolactones And Strigolactone Analogs For Treating Proliferative Conditions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992007866A1 (en) * 1990-11-01 1992-05-14 Board Of Regents, The University Of Texas System Anthracycline analogues bearing latent alkylating substituents
US20030065020A1 (en) * 2001-07-13 2003-04-03 Catharine Gale Treatment of macular degeneration
WO2013138343A1 (en) * 2012-03-16 2013-09-19 The Johns Hopkins University Controlled release formulations for the delivery of hif-1 inhibitors

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BABIC A M ET AL: "CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 95, 1 May 1998 (1998-05-01), pages 6355 - 6360, XP002175432, ISSN: 0027-8424, DOI: 10.1073/PNAS.95.11.6355 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; July 2013 (2013-07-01), FU PENG ET AL: "Atorvastatin Inhibits Cyr61 Expression in Cultured Rat Vascular Smooth Muscle Cells", XP002732596, Database accession no. PREV201400191441 *
JIE CHEN ET AL: "Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production", MOLECULAR ONCOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 6, no. 1, 11 November 2011 (2011-11-11), pages 62 - 72, XP028452889, ISSN: 1574-7891, [retrieved on 20111122], DOI: 10.1016/J.MOLONC.2011.11.003 *
LI J ET AL: "Systemic administration of HMG-CoA reductase inhibitor protects the blood-retinal barrier and ameliorates retinal inflammation in type 2 diabetes", EXPERIMENTAL EYE RESEARCH, ACADEMIC PRESS LTD, LONDON, vol. 89, no. 1, 15 June 2009 (2009-06-15), pages 71 - 78, XP026145594, ISSN: 0014-4835, [retrieved on 20090228], DOI: 10.1016/J.EXER.2009.02.013 *
MONIQUE C.A. DUYNDAM ET AL: "Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells", BIOCHEMICAL PHARMACOLOGY, vol. 74, no. 2, 1 July 2007 (2007-07-01), pages 191 - 201, XP055153280, ISSN: 0006-2952, DOI: 10.1016/j.bcp.2007.04.003 *
TAKESHI IWASE ET AL: "Safe and Effective Polymeric-Doxorubicin Conjugate Nanoparticles for Prolonged Antiangiogenic Activity in the Eye", INTERNET CITATION, 8 May 2012 (2012-05-08), pages 1 - 2, XP002695866, Retrieved from the Internet <URL:http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2866&sKey=ebc9c74c-9d11-43d0-9d5c-060396c9ca9a&cKey=33638dc5-1717-4e08-8287-5344c389580c&mKey={F0FCE029-9BF8-4E7C-B48E-9FF7711D4A0E}> [retrieved on 20130517] *
YOU J-J ET AL: "Cysteine-rich 61, a Member of the CCN Family, as a Factor Involved in the Pathogenesis of Proliferative Diabetic Retinopathy", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE - IOVS, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 50, no. 7, 1 July 2009 (2009-07-01), pages 3447 - 3455, XP008113788, ISSN: 0146-0404, DOI: 10.1167/IOVS.08-2603 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11331295B2 (en) 2015-10-14 2022-05-17 Massachusetts Eye And Ear Infirmary High-dose statins for age-related macular degeneration
WO2018065219A1 (en) * 2016-10-04 2018-04-12 University College Dublin, National University Of Ireland, Dublin Heparin and statin combinations for preventing metastatic cancer

Also Published As

Publication number Publication date
US20220401464A1 (en) 2022-12-22
ES2947557T3 (en) 2023-08-11
JP6852122B2 (en) 2021-03-31
JP7184448B2 (en) 2022-12-06
CA2923557A1 (en) 2015-03-12
EP3041479A1 (en) 2016-07-13
JP2021102624A (en) 2021-07-15
JP2016530295A (en) 2016-09-29
CA2923557C (en) 2023-10-24
JP2019206530A (en) 2019-12-05
EP3041479B1 (en) 2023-04-26
US11458154B2 (en) 2022-10-04
US20160213696A1 (en) 2016-07-28

Similar Documents

Publication Publication Date Title
US20220401464A1 (en) Treatment of cyr61- and vegf-mediated conditions
US20220339169A1 (en) Methods of treating or selecting a treatment for a subject resistant to tnf inhibitor using a nlrp3 antagonist
US11066667B2 (en) Organic compositions to treat APOC3-related diseases
JP2020534268A5 (en)
JP2022115999A (en) Compositions and methods for protecting against airborne pathogens and irritants
JP2010540556A (en) Azacitidine analogues and uses thereof
US10307401B2 (en) Compositions and methods for treatment of prostate cancer
KR20180117044A (en) Therapy of atherosclerosis, primary biliary cirrhosis and nrlp3 inflammasome-associated disease by htcp inhibitors
CN101541323A (en) Use of an indazolemethoxyalkanoic acid for reducing triglyceride, cholesterol and glucose levels
WO2007083119A2 (en) Methods
EP1212064A2 (en) Use of inhibitors of endotoxin for the treatment of heart failure and of cachexia
KR20220018552A (en) Use of Amlexanox for the manufacture of anti-hepatitis virus drugs
WO2009019473A1 (en) Treatments for inflammatory arthritis
US9073884B2 (en) Anti-inflammatory and quorum sensing inhibition compounds and methods of making and using them
US9446017B2 (en) Compositions and methods for treating herpes simplex virus
WO2022140397A1 (en) Methods of treating cancer
JP7290223B2 (en) IL-1β inhibitor
JP2006169156A (en) Nafamostat mesilate as immunoregulator
RU2491934C2 (en) Treating fibrotic diseases
WO2007013696A1 (en) Anti-tumor agent comprising 6&#39;-amidino-2&#39;-naphthyl4- guanidinobenzoate or salt thereof
Harrison Sy 17-2 inflammation, immunity and hypertension
JP7535786B2 (en) Arthritis treatment
US20240033309A1 (en) Combination therapy for inflammatory disorders of the joints
JP2023532915A (en) Methods for protecting cells from injury
CN102949387A (en) Composition for treating herpes simplex viruses (HSVs), and method thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14766342

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2923557

Country of ref document: CA

Ref document number: 2016540371

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2014766342

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2014766342

Country of ref document: EP