WO2021182900A2 - Procédé de prévention ou de traitement de maladies associées à mtor par la régulation de l'expression de vegfr -3 - Google Patents

Procédé de prévention ou de traitement de maladies associées à mtor par la régulation de l'expression de vegfr -3 Download PDF

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WO2021182900A2
WO2021182900A2 PCT/KR2021/003051 KR2021003051W WO2021182900A2 WO 2021182900 A2 WO2021182900 A2 WO 2021182900A2 KR 2021003051 W KR2021003051 W KR 2021003051W WO 2021182900 A2 WO2021182900 A2 WO 2021182900A2
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vegfr
disease
mtor
composition
protein
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WO2021182900A3 (fr
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김원주
정경훈
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연세대학교 산학협력단
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    • C12Q2600/00—Oligonucleotides characterized by their use
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Definitions

  • the present invention relates to a method for treating mTOR-related diseases using an inhibitor or activator of VEGFR-3 based on the new discovery that the expression regulation of VEGFR-3 regulates the activity of the mTOR (mammalian target of rapamycin) signaling pathway will be.
  • Epilepsy is a disease that causes intermittent nervous system disorders due to episodic discharge of cranial nerve cells due to organic lesions or functional disorders, and exhibits symptoms such as neurological symptoms, loss of consciousness, convulsions, and sensory disturbances. It is the third most common neurological disease after Alzheimer's disease and stroke, affecting about 0.5 - 2% of the world's population with epilepsy. In addition, it is estimated that there are about 45 new cases per 100,000 people worldwide every year, and about 300,000 to 400,000 epilepsy patients in Korea. Looking at the age distribution of epilepsy patients, it is known that 70% of all epilepsy begins at the age of children and adolescents, and the incidence is particularly high in infancy. In addition, the incidence and prevalence rates were highest within the first year of life and then rapidly decreased, and showed a U-shape that rapidly increased again in the elderly over 60 years of age, and the prevalence of experiencing seizures during life reached 10 to 15%.
  • Epilepsy is a chronic disease in which epileptic seizures occur repeatedly, and the cause is very diverse and the exact etiology is unknown.
  • the identification of the cause of epilepsy is gradually expanding.
  • the epilepsy epidemiologic survey published by the Korean Epilepsy Society in 2012 more than two-thirds of epilepsy patients are idiopathic or latent with no specific cause, and the rest are serious causes that can be found.
  • epilepsy may be induced. It is known that there is a past history of neuropathological changes or brain damage such as stroke, congenital anomaly, head trauma, encephalitis, brain tumor, degenerative encephalopathy, childbirth injury, central nervous system developmental disorder and genetic predisposition. It is known that there is
  • epilepsy treatment can be largely divided into drug treatment and non-drug treatment, that is, surgery, ketogenic diet, and vagus nerve stimulation.
  • drug treatment since non-drug treatment is being performed only for patients who are resistant to drugs, drug treatment has been used as a major method for epilepsy treatment.
  • Conventional drugs include phenytoin (Dilantin®), valproate (Orfil®, Depakine®, Depakote®), carbamazepine (Tegretol®), phenobarbital (Luminal®), etosuccimide.
  • the present inventors made intensive research efforts to discover effective and fundamental therapeutic compositions for various diseases caused by the lack of activity of the mTOR signaling pathway, including epilepsy.
  • the expression of VEGFR-3 in astrocytes in the hippocampus and mTOR signaling activity are closely related, and when VEGFR-3 expression or activity is increased, the expression of glutamate transporter 1 (GLT-1) increases and mTOR
  • GLT-1 glutamate transporter 1
  • an object of the present invention is to provide a composition for preventing or treating a disease related to mTOR signal deficiency and a screening method thereof.
  • Another object of the present invention is to provide a composition for preventing or treating mTOR-mediated diseases and a screening method thereof.
  • the present invention provides an mTOR signal deficiency-related disease comprising at least one selected from the group consisting of VEGFR-3 protein, a nucleic acid molecule encoding the VEGFR-3 protein, and an activator of VEGFR-3 as an active ingredient It provides a composition for the prevention or treatment of.
  • the present inventors made intensive research efforts to discover effective and fundamental therapeutic compositions for various diseases caused by the lack of activity of the mTOR signaling pathway, including epilepsy.
  • the expression of VEGFR-3 in astrocytes in the hippocampus and mTOR signaling activity are closely related, and when VEGFR-3 expression or activity is increased, the expression of glutamate transporter 1 (GLT-1) increases and mTOR It was found that the activation of the signaling pathway effectively eliminates the pathogenesis of diseases caused by mTOR inactivation.
  • mTOR (mammalian target of rapamycin) is a serine/threonine kinase belonging to the PIKK (PI3K-related kinase) family.
  • PIKK PI3K-related kinase
  • mTOR signal deficiency-related disease is meant to encompass a series of diseases caused by the malfunction of the mTOR signaling pathway, which broadly regulates this comprehensive cellular metabolic process.
  • GLT-1 in astrocytes is increased by mTOR activation mediated by VEGFR-3, hyperexcitability in epilepsy is blocked and a neuroprotective effect is confirmed.
  • activation of mTOR can promote BMP-induced muscle hypertrophy and prevent muscle atrophy, and promote protein synthesis in skeletal muscle (Gazzerro E, et al., Rev Endocr Metab Disord 2006; 7:51-65).
  • mTOR signaling was observed in mood disorders including depression, and mTOR signaling causes synaptic neurotransmission and plasticity.
  • mTOR signaling promotes limb skeletal growth by inducing the synthesis of factors necessary for growth in chondrocytes, and inhibits growth of limb mesenchymal cells by mTOR signal deficiency and reduces the growth of transcription factors involved in chondrogenesis. It has been reported that inhibition of expression can lead to skeletal developmental disorders (Jiang M, Fu X, et al., J Cell Biochem. 2017;118(4):748-753).
  • the disease related to mTOR signal deficiency that can be prevented or treated with the composition of the present invention is selected from the group consisting of epilepsy, muscular atrophy, depression and bone disease.
  • bone disease refers to any disease in which degeneration or damage of bone or cartilage tissue leading to quantitative loss of bone or cartilage tissue is caused by pathological or physical causes, for example, osteoporosis, osteomalacia, It includes, but is not limited to, rickets, fibrous osteomyelitis, bone damage due to bone metastasis of cancer cells, aplastic bone disease, metabolic bone disease, and osteoarthritis.
  • the present invention provides a composition for preventing or treating mTOR-mediated diseases comprising an inhibitor of VEGFR-3 protein as an active ingredient.
  • the term “inhibitor” refers to a substance that causes a decrease in the activity or expression of a target protein, whereby the activity or expression of the target protein becomes undetectable or exists at an insignificant level, as well as when the target protein is It refers to a substance that reduces the activity or expression to such an extent that the biological function can be significantly reduced.
  • Inhibitors of VEGFR-3 protein include, for example, shRNA, siRNA, miRNA, ribozyme, and peptide nucleic acids (PNA) that inhibit the expression of VEGFR-3, whose coding nucleotide sequence is known in the art at the gene level.
  • Antisense oligonucleotides or CRISPR systems comprising a guide RNA for recognizing a target gene, and antibodies or aptamers that inhibit VEGFR-3 at the protein level, as well as compounds, peptides and natural products that inhibit their activity. All gene and protein level suppression means known in the art without limitation can be used.
  • RNA small hairpin RNA
  • shRNA small hairpin RNA
  • a long RNA of 19-29 nucleotides is base-paired on both sides of a loop of 5-10 nucleotides to form a double-stranded stem, and in order to always be expressed, it is introduced into a cell through a vector containing a U6 promoter. It is transduced and is usually passed on to daughter cells so that suppression of the expression of the target gene is inherited.
  • RNA refers to a short double-stranded RNA capable of inducing an RNAi (RNA interference) phenomenon through cleavage of a specific mRNA. It is composed of a sense RNA strand having a sequence homologous to the mRNA of a target gene and an antisense RNA strand having a sequence complementary thereto. The total length is 10 to 100 bases, preferably 15 to 80 bases, most preferably 20 to 70 bases, and if the expression of the target gene can be inhibited by the RNAi effect, blunt ends or cohesive ends Both ends are possible.
  • the structure of the adhesive end can be both a structure in which the three-terminal protrudes and a structure in which the five-terminal side protrudes.
  • microRNA refers to a single-stranded RNA molecule that is not expressed in cells, has a short stem-loop structure, and inhibits the expression of a target gene through complementary binding to the mRNA of the target gene. do.
  • ribozyme is a type of RNA and refers to an RNA molecule having the same function as an enzyme that recognizes the base sequence of a specific RNA and cuts it by itself.
  • a ribozyme is a complementary nucleotide sequence of a target mRNA strand and consists of a region that binds with specificity and a region that cuts the target RNA.
  • PNA peptide nucleic acid
  • antisense oligonucleotide refers to a nucleotide sequence complementary to a sequence of a specific mRNA, which binds to a complementary sequence in a target mRNA and translates its protein into a protein, translocation into the cytoplasm, maturation, or any other It refers to a nucleic acid molecule that inhibits an essential activity for an overall biological function.
  • Antisense oligonucleotides may be modified at one or more bases, sugars or backbone positions to enhance efficacy (De Mesmaeker et al., Curr Opin Struct Biol. , 5(3):343-55, 1995). .
  • the oligonucleotide backbone can be modified with phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyls, cycloalkyls, short chain heteroatomics, heterocyclic sugarscholphonates, and the like.
  • gRNA guideRNA
  • CRISPR Clustered Regularly Interspaced Short Palindromic Repeats
  • the expression inhibitor of the present invention may be a specific antibody that inhibits the activity of the protein encoded by the genes.
  • the antibody specifically recognizing the target protein is a polyclonal or monoclonal antibody, preferably a monoclonal antibody.
  • Antibodies of the present invention can be prepared by methods routinely practiced in the art, for example, fusion methods (Kohler and Milstein, European Journal of Immunology , 6:511-519 (1976)), recombinant DNA methods (U.S. Patent No. 4,816,567). ) or phage antibody library methods (Clackson et al, Nature , 352:624-628 (1991) and Marks et al, J. Mol. Biol. , 222:58, 1-597 (1991)). .
  • fusion methods Kelham and Milstein, European Journal of Immunology , 6:511-519 (1976)
  • the present invention may inhibit its activity by using an aptamer that specifically binds to a target protein instead of an antibody.
  • aptamer refers to a single-stranded nucleic acid (RNA or DNA) molecule or peptide molecule that binds to a specific target material with high affinity and specificity.
  • RNA or DNA nucleic acid
  • peptide molecule that binds to a specific target material with high affinity and specificity.
  • mTOR-mediated disease is meant to encompass a series of diseases caused by overactivation of the mTOR signaling pathway.
  • the present inventors found that when a selective inhibitor of VEGFR-3 was administered, GLT-1 expression and reactivity of astrocytes were inhibited while the mTOR pathway was inhibited.
  • the mTOR pathway is overactive in a number of cancer patients, and the major tumor suppressor genes TP53 and LKB1 not only inhibit TSC1 and TSC2, which are upstream regulators of mTORC1, but also mTOR signaling also causes apoptosis. It contributes to tumorigenesis by activating Akt, which induces proliferation processes such as glucose uptake and glycolysis while inhibiting Accordingly, inhibition of mTOR through inhibition of VEGFR-3 can be a significant anticancer target.
  • mTOR pathway is a central mechanism of anabolic and catabolic pathways of lipid metabolism, and it has been reported that excessive activity of mTOR causes metabolic abnormalities such as obesity and insulin resistance (Zoncu R. , et al., Molecular Cell Biology 2011;12:21-35).
  • mTOR contributes to synaptic connections through the growth of axons and formation of dendrites.
  • the mTOR signal is excessively increased, it leads to a decrease in memory storage capacity and causes the progression of various neurodegenerative diseases (Bove J. , et al., NATURE REVIEWS 2011;12:437-52).
  • inhibitors of mTOR including rapamycin, have a strong immunosuppressive function by inhibiting the proliferation of T cells induced by growth factors. It can be a therapeutic target for immune diseases.
  • the mTOR-mediated disease that can be prevented or treated with the composition of the present invention is selected from the group consisting of cancer, neurodegenerative disease, metabolic disease, inflammatory disease and actrocytosis.
  • the cancer is selected from the group consisting of kidney cancer, breast cancer, lung cancer, stomach cancer, bladder cancer, prostate cancer, ovarian cancer, cervical cancer, lymphoma, leukemia and myelodysplastic syndrome.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, myasthenia gravis and Pick's disease ( Pick's disease).
  • the metabolic disease is selected from the group consisting of obesity, diabetes, dyslipidemia, fatty liver and insulin resistance syndrome.
  • metabolic disease conceptualizes the phenomenon in which the risk factors of various cardiovascular diseases and type 2 diabetes, which are caused by metabolic abnormalities, cluster with each other as one disease group, and insulin resistance and related complex and It is a concept that encompasses various metabolic abnormalities and clinical aspects.
  • the term “obesity” refers to a state in which the amount of energy intake exceeds energy consumption over a long period of time and the excess energy is stored as fat, resulting in an excess of adipose tissue in the body.
  • body mass index Body mass index: weight (kg)/[height (m)] 2
  • the body mass index is 25 or more, it is defined as fertilely obese.
  • diabetes refers to a chronic disease characterized by a relative or absolute lack of insulin resulting in glucose-intolerance.
  • Diabetes treated or prevented by the composition of the present invention includes all types of diabetes, for example, type 1 diabetes, type 2 diabetes, and hereditary diabetes.
  • Type 1 diabetes is insulin-dependent diabetes mellitus, mainly caused by destruction of ⁇ -cells.
  • Type 2 diabetes is non-insulin-dependent diabetes mellitus, caused by insufficient insulin secretion after a meal or by insulin resistance.
  • dislipidemia refers to a pathologic condition in which the level of fat concentration in the blood is outside the normal range, for example, hypercholesterolemia, hypertriglyceridemia, low-HDL-cholesterol. In addition to hyperlipidemia and hyper-LDL-cholesterolemia, it includes all abnormal lipid states caused by abnormal lipoprotein metabolism.
  • fatty liver refers to a state in which fat is accumulated in hepatocytes in an excessive amount due to a disorder of fat metabolism in the liver, which causes various diseases such as angina pectoris, myocardial infarction, stroke, arteriosclerosis, fatty liver and pancreatitis.
  • insulin resistance refers to a state in which cells cannot effectively burn glucose because the function of insulin to lower blood sugar is low. When insulin resistance is high, the body makes too much insulin, which can lead to high blood pressure or dyslipidemia, as well as heart disease and diabetes. In particular, in type 2 diabetes mellitus, an increase in insulin in muscle and adipose tissue is not noticed, and the action of insulin does not occur.
  • insulin resistance syndrome is a concept that collectively refers to diseases induced by insulin resistance.
  • VLDL very low density lipoprotein
  • HDL high density lipoprotein
  • the dyslipidemia prevented or treated with the composition of the present invention is hyperlipidemia.
  • hyperlipidemia refers to a disease caused by maintaining a high lipid concentration in the blood because fat metabolism such as triglycerides and cholesterol is not properly performed. More specifically, hyperlipidemia includes hypercholesterolemia or hypertriglyceridemia with a high incidence in a state in which lipid components such as triglycerides, LDL cholesterol, phospholipids and free fatty acids in the blood are increased.
  • the fatty liver to be prevented or treated by the composition of the present invention is non-alcoholic fatty liver.
  • non-alcoholic fatty liver refers to a disease in which an excessive amount of fat is accumulated in liver cells regardless of alcohol absorption, and includes simple fatty liver (steatosis) and non-alcoholic non-alcoholic steatohepatitis (NASH).
  • simple fatty liver has a good clinical prognosis
  • NASH with inflammation or fibrosis is a progressive liver disease and is recognized as a progenitor disease that causes cirrhosis or liver cancer.
  • Obesity and insulin resistance are major risk factors for nonalcoholic fatty liver disease.
  • Risk factors for the progression of liver fibrosis include obesity (BMI > 30), blood liver function index ratio (AST/ALT > 1), and diabetes. can 69-100% of nonalcoholic fatty liver patients are obese, and 20-40% of obese patients have nonalcoholic fatty liver. This is because obesity is the most important risk factor for nonalcoholic liver disease.
  • the inflammatory disease (or autoimmune disease) that can be prevented or treated with the composition of the present invention is rheumatoid arthritis, reactive arthritis, type 1 diabetes, type 2 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis , idiopathic fibroal alveolitis, polymyositis, dermatomyositis, localized scleroderma, systemic scleroderma, colitis, inflammatory bowel disease, Sjorgen's syndrome, Raynaud's phenomenon, Bechet's disease, Kawasaki Kawasaki's disease, primary biliary sclerosis, primary sclerosing cholangitis, ulcerative colitis or Crohn's disease.
  • astrocytosis refers to an abnormal increase in astrocytes due to damage to adjacent neurons, such as trauma of the central nervous system, tissue damage caused by tumors, infection, ischemia, stroke, neurodegenerative disease, etc. Or it is meant to encompass all pathological conditions that cause activation. Astrocytes that are activated or proliferated in the lesion area where brain tissue is damaged by various causes have some protective effect on the regeneration process of brain tissue, but the increase in astrocytes appearing after injury inhibits the regeneration process by secreting various inflammatory substances. .
  • the astrocytosis is glioma, glioblastoma, astrocytoma, stroke, traumatic brain injury, and amyotrophic lateral sclerosis.
  • prevention refers to inhibiting the occurrence of a disease or disease in a subject who has never been diagnosed with a disease or disease, but is likely to have the disease or disease.
  • the term “treatment” refers to (a) inhibiting the development of a disease, disorder or condition; (b) alleviation of the disease, condition or condition; or (c) eliminating the disease, condition or symptom.
  • the composition of the present invention When the composition of the present invention is administered to a subject, it regulates the mTOR signaling pathway by inhibiting or increasing the activity or expression level of VEGFR-3, inhibits the development of symptoms of various diseases caused by deficiency or excessive mTOR activity, or removes it or act as a mitigator.
  • the composition of the present invention may be a composition for treating these diseases by itself, or may be administered together with other pharmacological ingredients and applied as a therapeutic adjuvant for the above diseases.
  • the term “treatment” or “therapeutic agent” includes the meaning of “therapeutic adjuvant” or “therapeutic adjuvant”.
  • administering refers to directly administering a therapeutically effective amount of the composition of the present invention to a subject so that the same amount is formed in the subject's body.
  • the term “therapeutically effective amount” refers to the content of the composition in which the pharmacological component in the composition is sufficient to provide a therapeutic or prophylactic effect to an individual to whom the pharmaceutical composition of the present invention is to be administered. prophylactically effective amount”.
  • the term “subject” includes, without limitation, humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, monkeys, chimpanzees, baboons or rhesus monkeys. Specifically, the subject of the present invention is a human.
  • the pharmaceutical composition of the present invention when prepared as a pharmaceutical composition, includes a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a talct, a talct, a talct, a talct, a sorbitol, mannitol, mannitol
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and specifically may be administered orally, intravenously, subcutaneously or intraperitoneally.
  • a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient. can be A preferred dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg/kg for adults.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container.
  • the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
  • the present invention provides a method for screening a composition for preventing or treating a disease related to mTOR signal deficiency, comprising the following steps:
  • the test substance is determined as a composition for preventing or treating mTOR signal deficiency related diseases.
  • biological sample refers to any sample containing VEGFR-3 expressing cells obtained from mammals including humans, including, but not limited to, tissue, organ, cell or cell culture medium.
  • test substance used while referring to the screening method of the present invention is added to a sample containing cells expressing VEGFR-3 and used in screening to test whether it affects the activity or expression level of VEGFR-3 It means an unknown substance.
  • the test substance includes, but is not limited to, compounds, nucleotides, peptides and natural extracts.
  • the step of measuring the expression level or activity of VEGFR-3 in the biological sample treated with the test substance may be performed by various methods for measuring the expression level and activity known in the art. As a result of the measurement, when the expression level or activity of VEGFR-3 is increased, the test substance may be determined as a composition for preventing or treating mTOR signal deficiency related diseases.
  • the term “increase in expression or activity” refers to an increase in the expression level of VEGFR-3 or intrinsic function of VEGFR-3 in vivo to such an extent that mTOR activation mediated by VEGFR-3 is increased to a measurable level. it means. Specifically, it may refer to a state in which the activity or expression level is increased by 20% or more, more specifically, a state increased by 40% or more, more specifically, a state increased by 60% or more compared to the control group.
  • the present invention provides a method for screening a composition for preventing or treating an mTOR-mediated disease, comprising the steps of:
  • the test substance is determined as a composition for preventing or treating mTOR-mediated diseases.
  • the term “reduction of expression or activity” refers to inhibiting the expression level of VEGFR-3 or the intrinsic function of VEGFR-3 in vivo to such an extent that mTOR activation mediated by VEGFR-3 is reduced to a measurable level. it means. Specifically, it may refer to a state in which the activity or expression level is reduced by 20% or more, more specifically, a state in which the activity or expression is reduced by more than 40%, more specifically, a state in which the activity or expression level is reduced by more than 60% compared to the control.
  • the biological sample is a biological sample including astrocytes.
  • the present invention provides a pharmaceutical composition comprising at least one selected from the group consisting of VEGFR-3 protein, a nucleic acid molecule encoding the VEGFR-3 protein, and an activator of VEGFR-3 as an active ingredient. It provides a method for preventing or treating a disease related to mTOR signal deficiency, comprising administering to a subject.
  • the present invention provides a method for preventing or treating mTOR-mediated diseases, comprising administering to a subject a pharmaceutical composition comprising an inhibitor of VEGFR-3 protein as an active ingredient.
  • the present invention provides a composition for preventing or treating mTOR signaling deficiency-related diseases and mTOR (mammalian target of rapamycin)-mediated diseases, and a screening method thereof.
  • the present invention provides an effective therapeutic target for various diseases caused by excessive activity or lack of activity of mTOR based on the new discovery that regulation of VEGFR-3 expression leads to regulation of mTOR signaling pathway activity
  • the present invention can be usefully used as a fundamental therapeutic agent for overlapping epilepsy, an intractable disease, by blocking the hyperexcited state in epilepsy and protecting nerves through VEGFR-3 activation, in particular.
  • FIG. 1 is a diagram showing the time-dependent expression patterns of pS6 and VEGFR-3 in the hippocampus after epilepsy overlap is induced with pilocarpine.
  • panel A, E shows that p6S-positive neuron-like cells are expressed in the hippocampus of the normal control panel.
  • Panels B, F show that pS6-positive signal is slightly increased compared to that of the normal control group on the 1st day after epilepsy superposition induction. The figure shows that pS6-positive cells increased remarkably on the 4th day after induction of epilepsy superposition.
  • Figure 1b shows the results of confirming that the protein expression changes appear the same as the immunohistochemical staining results through western blot analysis of pS6, S6, VEGFR-3, and GFAP.
  • FIG. 2 is a diagram showing the results of confirming the expression of pS6 in VEGFR-3 positive reactive astrocytes after induction of epilepsy overlap.
  • Panels A-C show that in normal controls, most pS6 expression (green) was not observed in GFAP-positive astrocytes (blue), but some VEGFR-3 expression (red) was observed on the surface of GFAP-positive astrocytes.
  • FIG. 3 is a diagram showing that VEGFR-3 expression in astrocytes is reduced by inhibiting mTOR activation.
  • Figure 3b is a schematic diagram of the hippocampal sub-pyramid region subjected to quantitative analysis of the number of VEGFR-3 expressing cells.
  • Figure 3c is a picture showing the results of quantitative analysis of VEGFR-3 expression in the indicated hippocampal sub-pyramid region, it was confirmed that the number of VEGFR-3 positive astrocytes increased by induction of epilepsy overlap was significantly reduced by the administration of rapamycin.
  • Figure 3d is a result of analyzing the VEGFR-3 protein expression pattern through Western blot, it shows that the expression of VEGFR-3 increased by the induction of epilepsy overlap is again reduced by the administration of rapamycin.
  • Figure 3e is a diagram showing the density-based quantitative analysis result as a histogram of the VEGFR-3 protein band (normalized to ⁇ -actin). Also, the increase in VEGFR-3 expression due to epilepsy overlap is significant by rapamycin administration.
  • FIG. 4 is a diagram showing that mTOR activation in astrocytes is reduced when VEGFR-3 expression in the hippocampus is suppressed after induction of epilepsy overlap.
  • Figure 4b is a diagram showing that the quantitative analysis result confirms that the number of astrocytes pS6-positive cells increased by epilepsy overlap is significantly reduced by SAR administration.
  • 5 is a diagram showing that RA treatment reduces GLT-1 expression in the hippocampus after SE induction.
  • FIG. 6 is a diagram showing that inhibition of VEGFR-3 attenuates GLT-1 expression and activation of astrocytes in the hippocampus after induction of epilepsy overlap.
  • GLT-1 expression red
  • Scale bar 50 ⁇ m.
  • Figure 6b shows that, as a result of quantitative analysis, the number of GLT-1 expressing cells in the hippocampus after induction of epilepsy superimposition is significantly increased compared to the normal control group, but when VEGFR-3 is suppressed due to SAR administration, GLT-1 expression of astrocytes is decreased.
  • Figure 6c shows the results confirmed through Western blot that SAR administration reduces the expression of GLT-1 protein.
  • VEGFR-3 is a diagram showing the effect of an increase in VEGFR-3 in reactive astrocytes after SE induction. Elevated VEGFR-3 affects mTOR activation in reactive astrocytes following the same prolonged seizure behavior. Furthermore, VEGFR-3-mediated mTOR activation may reduce SE-induced hyperexcitability during interstitial subacute phase (gray arrow) by increasing GLT-1 expression in astrocytes. Taken together, the increase in VEGFR-3 in reactive astrocytes appears to play an important role in calming hyperexcitability in the hippocampus.
  • 8 is a diagram showing the effect of RA treatment on Akt/mTOR activation in the hippocampus in normal and epilepsy conditions.
  • 8A is a Western blot analysis result showing the change in the expression level of phosphorylated Akt (pAkt) after RA treatment.
  • pAkt phosphorylated Akt
  • RA treatment significantly increased the expression level of pAkt in the hippocampus in sham-manipulated mice compared to the Sham-Veh group.
  • the expression level of pAkt in the hippocampus of SE 4d-Veh and SE 4d-RA groups was significantly increased compared to Sham-Veh group.
  • the results of quantitative analysis of each sample based on the density of the pAkt band were shown as histograms (normalized to ⁇ -actin).
  • 8B is a Western blot result showing the change in the expression level of RA-treated pS6. Although there was no significant difference between Sham-Veh and Sham-Veh groups, pS6 expression in the hippocampus of mice (SE 4d-RA) 4 days after epilepsy induction by RA treatment was significantly suppressed compared to the SE 4d-Veh group. became The results of quantitative analysis of each sample based on the density of the pS6 band were shown as histograms (normalized to ⁇ -actin).
  • FIG. 9 is a diagram showing the effect of VEGFR-3 inhibition on acute epilepsy induced by pilocarpine injection.
  • SAR 50 mg/kg; ip
  • vehicle solution vehicle solution
  • seizure behavior was recorded after pilocarpine injection until the end of the seizure.
  • mice Male C57BL/6 mice (8 weeks old, Orient Bio, Gyeonggi, Korea) were treated in a light-controlled environment (from 8:00 am to 8:00 pm) under standard temperature (22 ⁇ 1 °C) and humidity (50 ⁇ 1%). ) was bred with free access to food and drinking water. All experiments were conducted in accordance with the guidelines of the Animal Experimentation Ethics Committee of Yonsei University, and the number and suffering of experimental animals were minimized.
  • a pilocarpine-induced status epilepticus (SE) mouse model was established by a previously reported method (Cho et al., 2019; Jeong, Lee, Kim, & Cho, 2011). Briefly, 30 min after treatment with atropine methyl nitrate (1 mg/kg; ip; Sigma-Aldrich), mice were treated with pilocarpine hydrogen chloride (280-300 mg/kg; Sigma-Aldrich; St. Louis, MO, USA) or Or saline (normal control) was intraperitoneally injected. After pilocarpine treatment, the seizure stage was determined according to the Racine scale (Racine, 1972).
  • stage 4 Animals that have reached stage 4 (standing on hind legs, rearing) and stage 5 (rearing and falling) and exhibiting general tonic-clonic seizures are considered to have superposition epilepsy (SE). and selected for further study.
  • SE superposition epilepsy
  • seizure frequency and latency were recorded from immediately after pilocarpine injection to the end of seizures.
  • the number of seizures refers to the total number of convulsive seizures (stages 3-5) after pilocarpine injection.
  • the onset times of seizures and SE were measured as the time elapsed from pilocarpine injection to the first convulsive seizure (stage 3) and SE, respectively.
  • rapamycin (RA; LC laboratories; Woburn, MA, USA) was first administered (6 mg/kg; ip) 1 hour before pilocarpine treatment and 3 days from the 1st day after SE induction. It was administered daily (3 mg/kg; ip).
  • rapamycin was dissolved in 100% ethanol and immediately before injection 5% Tween 80, 5% polyethylene glycol 400 (Sigma-Aldrich) and Dilute in vehicle solution containing 4% ethanol.
  • SAR131675 (SAR; Selleck Chemicals; Kunststoff, Germany), a VEGFR-3 inhibitor, was dissolved in 5% DMSO with saline according to a previously reported method (Bhuiyan, Kim, Hwang, Lee, & Kim, 2015).
  • SAR was administered 1 hour before pilocarpine treatment (50 mg/kg; ip), and after induction of SE with pilocarpine, daily injections were performed for 3 days after 1 day (25 mg/kg; ip). ).
  • mice were anesthetized with 15% chloral hydrate and cardiac perfused with saline followed by 4% paraformaldehyde dissolved in 0.1 M phosphate buffer (PB; pH 7.4). Thereafter, brains were rapidly excised as previously reported (Cho et al., 2019) and cryopreserved with 30% sucrose solution for 3 days. Next, the samples were rapidly frozen in liquid nitrogen. Serial sections (20 ⁇ m thick) were cut coronal at 120 ⁇ m intervals (720 ⁇ m in total, between -1.58 and -2.30 from the grand sac in every 7th slice) (Franklin & Paxinos, 2008). All sections were washed with 0.01 M PBS (pH 7.4).
  • sections were incubated with 3% H 2 O 2 and 10% methanol in 0.01M PBS to remove endogenous peroxidase activity.
  • the sections were fixed with 10% goat serum (VectorLaboratories; Burlingame, CA, USA) dissolved in 0.01M PBS for 1 hour at 4°C and anti-phospho S6 ribosomal protein antibody (pS6; 1:200; Cell Signaling Technology). ; Beverly, MA, USA) and incubated overnight.
  • the sections were incubated with biotinylated anti-rabbit IgG (1:200; Vector Laboratories) at room temperature for 2 hours and placed in an avidin-biotin peroxidase complex solution (Vector Laboratories) for 1 hour. Finally, the sections were stained with 0.1% diaminobenzidine tetrahydrochloride and 0.005% H 2 O 2 dissolved in 0.05M Tris-HCl (pH7.4). The stained sections were observed with an optical microscope (BX51; Olympus; Tokyo, Japan).
  • sections were prepared from anti-neuronal nuclei (NeuN; 1:100; Millipore; Temecula, CA, USA), anti-glial fibrillary acidic protein (GFAP; 1:400; Millipore), anti-VEGFR-3 (1:500; Abnova; Taipei, Taiwan, China), anti-VEGFR-3 (1:100; Abcam; Cambridge, A, USA), anti-pS6 (1:200; Cell) Signaling Technology), and anti-GLT-1 (1:200; Thermo Scientific; Rockford, IL, USA) antibodies, followed by Cy3- (1:500; Jackson ImmunoResearch; West Grove, PA, USA), Cy5- (1:500; Jackson ImmunoResearch) and Alexa fluor 488-conjugated IgG (1:300; Invitrogen; Carlsbad, CA, USA) were incubated overnight at 4°C. Sections were mounted and observed under a confocal microscope (LSM 700; Carl Zeiss; Thornwood, NY, USA),
  • VEGFR-3 To analyze the expression changes of VEGFR-3, pS6 and GLT-1-positive cells in the hippocampus of the normal control group and 4 days after seizure induction, 6 coronal sections were obtained. The number of cells was measured according to a previously reported method (Cho et al., 2019; Jeong et al., 2011). The number of VEGFR-3, pS6 and GLT-1-positive cells was measured in the region including the stratum radiatum, lacunosum moleculare, and dentate gyrus molecular layers ( FIG. 3B ). The number of VEGFR-3, pS6 and GLT-1-labeled cells in each section was measured using ZEN image inspection software (Carl Zeiss).
  • Brain tissue samples for Western blot analysis were prepared by a previously reported method (Jeong, Lee, & Kim, 2015).
  • the mouse hippocampal tissue was homogenized and centrifuged at 14,000 g for 15 minutes at 4°C. The supernatant was transferred to a new tube, and the concentration was measured using a bicinchoninic acid assay kit (Thermo Scientific). Proteins were separated by gel electrophoresis and transferred to a polyvinylidene difluoride membrane (Millipore) using an electrophoretic transfer system (Bio-Rad Laboratories; Hercules, CA, USA).
  • Membranes were incubated overnight at 4°C with the following primary antibodies: anti-VEGFR-3 (Abcam), anti-phosphorylated Akt (Cell Signaling Technology), anti-Akt (Cell Signaling Technology), anti-pS6 (Cell Signaling Technology) ), anti-S6 (Cell Signaling Technology), anti-GFAP (Millipore), anti-GLT-1 (Thermo Scientific), and anti- ⁇ -actin (Santa Cruz Biotechnology; Dallas, TX, USA). After washing, the membrane was again incubated with a secondary antibody (Enzo Life Science; Farmingdale, NY, USA), and blotting was performed using ECL western blotting detection reagent (Amersham Biosciences; Piscataway, NJ, USA). The density of the band was measured using computer imaging equipment and related software (Fuji Film; Tokyo, Japan).
  • pS6 phosphorylated ribosomal protein S6
  • Glue-like pS6 expression was slightly increased in the emissive layer and the subfield CA1 subfields 1 day after SE induction (panels B and F of FIG. 1A ).
  • the expression of glial-like pS6 reached a maximum level on day 4 after SE induction (panels C and G of FIG. 1A ) and gradually decreased from day 7 after SE induction (panels D and H of FIG. 1A ).
  • FIG. 2 After confirming the expression change of pS6 and VEGFR-3 after SE induction, it was investigated whether pS6 and VEGFR-3 coexist in astrocytes by triple-immunofluorescence staining (FIG. 2).
  • pS6 expression in GFAP-expressing astrocytes was not observed, but VEGFR-3 expression was more or less observed on the surface of GFAP-expressing astrocytes (FIG. 2 panels A-C).
  • SE-induced pS6 expression was significantly increased in hippocampal VEGFR-3-expressing reactive astrocytes 4 days after SE induction (FIG. 2 panels D-F).
  • VEGFR-3 specific inhibitors Effect of VEGFR-3 specific inhibitors on reactive astrocytosis after SE induction
  • the PI3K/Akt/mTOR pathway has been reported to affect GLT-1 regulation in primary cultures of astrocytes (Wu, Kihara, Akaike, Niidome, & Sugimoto, 2010). Therefore, we aimed to investigate whether mTOR inhibition by RA treatment regulates GLT-1 expression in the hippocampus after SE. As a result, it was confirmed that the number of glial-like GLT-1-positive cells increased in the hippocampus 4 days after SE induction (SE 4d-Veh; FIG. 5a ). On the other hand, SE-induced glial GLT-1 expression was found to be decreased by RA treatment (SE 4d-RA; FIG. 5A ).

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Abstract

La présente invention concerne une composition destinée à prévenir ou à traiter une cible mammifère de maladies médiées par la rapamycine (mTOR) et des maladies associées à une signalisation de mTOR déficiente. La présente invention concerne une cible thérapeutique efficace pour diverses maladies provoquées par une hyperactivité ou une activité déficiente de mTOR, sur la base de la nouvelle découverte que la régulation de l'expression de VEGFR -3 conduit à la régulation de l'activité de la voie de signalisation de mTOR. La présente invention, en particulier par activation de VEGFR -3, bloque les états hyperexcitatifs de l'épilepsie et protège les nerfs et peut ainsi être efficacement utilisée en tant qu'agent thérapeutique fondamental pour l'état épileptique, qui est une maladie incurable.
PCT/KR2021/003051 2020-03-11 2021-03-11 Procédé de prévention ou de traitement de maladies associées à mtor par la régulation de l'expression de vegfr -3 WO2021182900A2 (fr)

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