WO2023039245A1 - Biomarqueurs pour la stéatohépatite non alcoolique et leurs traitements - Google Patents
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- 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
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/08—Hepato-biliairy disorders other than hepatitis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
Definitions
- the invention is directed to biomarkers for metabolic disease and methods of treatment thereof.
- CVD cardiovascular disease
- NAFLD non-alcoholic steatohepatitis
- the metabolic disease comprises non-alcoholic steatohepatitis (NASH), atherosclerosis, non-alcoholic fatty liver disease (NAFLD), Type 2 diabetes, obesity, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- Type 2 diabetes obesity
- coronary heart disease disease of the blood vessels supplying the brain
- peripheral arterial disease rheumatic heart disease
- congenital heart disease cerebrovascular disease
- aortic aneurysm deep vein thrombosis
- embodiments comprise measuring in a sample isolated from a subject the concentration of a first polyamine and the concentration of a second polyamine; and identifying the subject as being afflicted with or at risk of developing a metabolic disease if the ratio of the concentration of the first polyamine to the concentration of the second polyamine is non- homeostatic.
- Embodiments can further comprise isolating the sample from the subject.
- Embodiments can further comprise administering a treatment to the subject.
- the treatment comprises increasing the concentration of spermidine in the subject, decreasing the concentration of putrescine in the subject, increasing AMD1 expression or activity, or a combination thereof.
- the concentration of spermidine is increased to at least about 6 pM.
- the concentration of putrescine is decreased to below about 150 pM in the subject.
- Embodiments can comprise administering to the subj ect spermidine, an agent that increases AMD1 expression, an agent that increases AMD1 activity, or a combination thereof.
- Embodiments can further comprise calculating the ratio of the concentration of the first polyamine to the concentration of the second polyamine.
- Embodiments can further comprise classifying the ratio as a homeostatic ratio or a non- homeostatic ratio, wherein the non-homeostatic ratio is indicative of a subject afflicted with or at risk of developing a metabolic disease.
- the sample comprises plasma, blood, cerebrospinal fluid (CSF), urine, tissues, or a combination thereof.
- the first polyamine comprises spermidine.
- the second polyamine comprises putrescine.
- the first polyamine comprises spermidine, and wherein the second poly amine comprises putrescine.
- the polyamine concentration is determined by mass spectrometry, high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC- MS), liquid chromatography with tandem mass spectrometry (LC-MS/MS), or a combination thereof.
- HPLC high performance liquid chromatography
- LC- MS liquid chromatography-mass spectrometry
- LC-MS/MS liquid chromatography with tandem mass spectrometry
- the metabolic disease comprises non-alcoholic steatohepatitis (NASH), atherosclerosis, non-alcoholic fatty liver disease (NAFLD), Type 2 diabetes, obesity, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- Type 2 diabetes obesity
- coronary heart disease disease of the blood vessels supplying the brain
- peripheral arterial disease rheumatic heart disease
- congenital heart disease cerebrovascular disease
- aortic aneurysm deep vein thrombosis
- the method comprises isolating a test sample from a subject afflicted with a metabolic disease; measuring in the sample the concentration of a first polyamine and the concentration of a second polyamine; identifying a biomarker for the metabolic disease if NASH if the ratio of the concentration of the first polyamine and the concentration of the second polyamine is non-homeostatic.
- Embodiments further comprise comparing the ratio of the test sample to that of a control sample.
- Embodiments further comprise calculating the ratio of the concentration of the first polyamine to the concentration of the second polyamine.
- the sample comprises plasma, blood, cerebrospinal fluid (CSF), urine, tissues, or a combination thereof.
- CSF cerebrospinal fluid
- the first polyamine comprises spermidine.
- the second polyamine comprises putrescine.
- the first polyamine comprises spermidine
- the second polyamine comprises putrescine.
- the polyamine concentration is determined by mass spectrometry, high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC- MS), liquid chromatography with tandem mass spectrometry (LC-MS/MS), or a combination thereof.
- aspects of the invention are drawn towards methods of treating a subject afflicted with and/or ameliorating a symptom of a metabolic disease.
- the symptom comprises reduction of liver damage, itching, ascites, bruising and bleedingjaundice, spider veins, hepatic encephalopathy, cirrhosis, liver cancer, angina, pain, cramping, shortness of breath, fatigue, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- CKD chronic kidney disease
- the metabolic disease comprises non-alcoholic steatohepatitis (NASH), atherosclerosis, non-alcoholic fatty liver disease (NAFLD), Type 2 diabetes, obesity, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- NASH non-alcoholic steatohepatitis
- NAFLD non-alcoholic fatty liver disease
- Type 2 diabetes obesity
- coronary heart disease disease of the blood vessels supplying the brain
- peripheral arterial disease rheumatic heart disease
- congenital heart disease cerebrovascular disease
- aortic aneurysm deep vein thrombosis
- Embodiments comprise increasing the concentration of spermidine in the subject, decreasing the concentration of putrescine in the subject, increasing AMD1 expression, or a combination thereof.
- Embodiments can further comprise administering to the subject spermidine, an agent that increases AMD1 expression, or a combination thereof.
- Embodiments can further comprise measuring in a sample isolated from the subject the concentration of a first polyamine and the concentration of a second polyamine; and identifying the subject as being afflicted with or at risk of developing a metabolic disease if the ratio of the concentration of the first polyamine to the concentration of the second polyamine is non- homeostatic. [0032] Embodiments can further comprise isolating the sample from the subject.
- Embodiments can further comprise calculating the ratio of the concentration of the first polyamine to the concentration of the second polyamine.
- Embodiments can further comprise classifying the ratio as a homeostatic ratio or a non- homeostatic ratio, wherein the non-homeostatic ratio is indicative of a subject afflicted with or at risk of developing a metabolic disease.
- the sample comprises plasma, blood, cerebrospinal fluid (CSF), urine, tissues, or a combination thereof.
- CSF cerebrospinal fluid
- the first polyamine comprises spermidine.
- the second polyamine comprises putrescine.
- the first polyamine comprises spermidine, and wherein the second polyamine comprises putrescine.
- the polyamine concentration is determined by mass spectrometry, high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC- MS), liquid chromatography with tandem mass spectrometry (LC-MS/MS), or a combination thereof.
- HPLC high performance liquid chromatography
- LC- MS liquid chromatography-mass spectrometry
- LC-MS/MS liquid chromatography with tandem mass spectrometry
- FIG. 1 shows data of impaired polyamine homeostasis during NASH.
- FIG. 2 shows data of impaired spermidine:putrescine raios negatively correlate with key indices of NASH disease.
- FIG. 3 shows a schematic of embodiments of the disclosure.
- FIG. 4 shows the structure of polyamines putrescine, spermidine, and spermine.
- FIG. 5 shows a schematic of a molecular pathway of polyamine biosynthesis.
- Ornithine is de-carboxylated by Odel in putrescine.
- Spermidine is synthesized from putrescine using an aminopropyl group donated from decarboxylated S-adenosyl-L-methionine (S-adeno met-DC) catalyzed by spermidine synthase.
- S-adeno met-DC decarboxylated S-adenosyl-L-methionine
- Spermine is synthesized from spermidine with S-adeno met- DC catalyzed by spermine synthase.
- FIG. 6 shows graphs of representative data. AMD1 expression declines with palmitate treatment and during NASH in both mice and humans.
- FIG. 7 shows representative data. AMD1 declines during NASH and loss in AMD1 reduces the S:P ratio.
- PMFI mean fluorescence intensity
- n 5 mice per group.
- FIG. 8 shows representative data and a shematic of the disclosure. Representative data for gene expresion in hepatocytes during NASH and model for Aim 1.1 is shown.
- Panel A Male C57BL6/J mice were injected with AAV8-TBG-GFP and fed a NASH diet for 24 weeks. Livers were collected and immunostained with anti-GFP and anti-ARGl (hepatocyte marker for liver) antibodies. The upper row was not stained for GFP to serve as a primary antibody control, scale bar: 50 pM.
- Panel B Eight-week-old mice fed a NASH diet for 12 weeks will be injected with AAV8-TBG viruses to drive hepatocyte-specific expression of either GFP (control) or AMD1. Mice will then be fed a NASH diet for an additional 12 weeks for a total of 24 weeks of NASH diet feeding.
- FIG. 9 shows a schematic of a representative experimental design for an in vivo experiment as proposed in Aim 1.2. 8-week-old mice will be fed a NASH diet for 12 weeks foiled by a switch from normal drinking water to water supplemented with 3 mM spermidine. The mice will then be fed a NASH diet for an additional 12 weeks for a total of 24 weeks of NASH diet feeding.
- FIG. 10 shows a shematic of embodiments of the disclosure.
- FIG. 11 shows images of figures of results of the defects in polyamine homeostasis during atherosclerosis.
- FIG. 12 shows histology images and graphs of results of defects in polyamine homeostasis during NASH.
- FIG. 13 shows graphs of representative data of impairments in poly amine homeostatis negatively correlating with plaque clacification and plasma AST.
- FIG. 14 shows representative AMD1 expression in hepatocytes decreases during NASH.
- FIG. 15 shows graphs of representative data of hepatic AMD1 expression is lower during NASH and atherosclerosis.
- FIG. 16 shows graphs of representative data indicating AMD1 silencing impairs polyamine homeostasis.
- Panel B HepG2 cells were treated as in
- FIG. 17 shows graphs of representative data indicating AMD1 silencing primes an inflammatory response in hepatocytes.
- FIG. 18 shows graphs of representative data indicating that polyamine homeostatisis is impaired during NASH in humans.
- Panel A putrescine
- Panel B spermidine
- FIG. 19 shows graphs of representative data indicating that impaired polyamine homeostasis negatively correlates with key indices of NASH in humans.
- Plasma AST Panel A
- ALT Panel B
- liver fibrosis scoring Panel C
- the data were analyzed by linear regression, with the r and P values indicated.
- the term “about” can refer to approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).
- aspects of the invention are directed towards methods of detecting a condition in a patient, treating a condition in a patient, preventing a condition in a patient, or a combination thereof, wherein the condition is characterized by a metabolic condition.
- a “metabolic disease” can refer to a disease or condition characterized by an alteration or disturbance of a metabolic function.
- Metabolic and “metabolism” are terms well known in the art and include the full range of biochemical processes that occur in a living organism. “Metabolic disease” can be used interchangeably with “metabolic condition”, “metabolic syndrome”, or “metabolic disorder”.
- Such a condition can comprise non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), atherosclerosis, Type 2 diabetes, obesity, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- embodiments comprise administering to a subject an effective amount of a pharmaceutical formulation or composition as described herein for the treatment of the condition.
- the metabolic condition comprises a cardiometabolic condition.
- a cardiometabolic condition can be characterized by abdominal obesity, insulin-resistant glucose metabolism (hyperinsulinemia, impaired fasting glucose, impaired glucose tolerance, type 2 diabetes), dyslipidemia (high serum triglyceride and low serum high-density lipoprotein cholesterol concentrations), and increased blood pressure.
- the term cardiometabolic condition can refer to metabolic abnormalities that are risk factors for cardiovascular disease.
- the terms “cardiometabolic condition” and “cardiometabolic syndrome” can be used interchangeably.
- the concentration of a first polyamine and the concentration of a second polyamine can be measured.
- the term “measuring” can refer to a quantitative or qualitative analysis of a species (i.e., a polyamine), such as by mass spectrometry, high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography with tandem mass spectrometry (LC-MS/MS), or a combination thereof.
- the polyamine concentration can be determined by analytical means such as those known in the art.
- the concentration of the poly amines in a sample can be determined by comparing to a standard of known molar concentration. Once the concentration is determined, the ratio of the polyamines can be calculated by dividing the amount of spermidine in the sample by the amount of putrescine in the sample.
- the polyamine concentration may be above or below a threshold.
- threshold for example a spermidine threshold and/or a putrescine threshold, can refer to a value derived from a plurality of biological samples, such as donor blood samples, for the biomarker, above or below which threshold is associated with an increased likelihood of having and/or developing a metabolic condition.
- “changed as compared to a known” sample or subject is understood as having a level of the analyte or diagnostic or therapeutic indicator (e.g., marker) to be detected at a level that is statistically different than a sample from a normal, untreated, or abnormal state control sample. Determination of statistical significance is within the ability of those skilled in the art, e.g., the number of standard deviations from the mean that constitute a positive or negative result.
- aspects of the invention are drawn towards method for identifying a subject being afflicted with or at risk of developing a metabolic disease.
- the method comprises measuring in a sample isolated from a subject the concentration of a first polyamine and the concentration of a second polyamine; and identifying the subject as being afflicted with or at risk of developing a metabolic disease if the ratio of the concentration of the first polyamine to the concentration of the second polyamine is non-homeostatic.
- aspects of the invention are drawn towards a method of treating a subject afflicted with and/or ameliorating a symptom of a metabolic disease, the method comprising increasing the concentration of spermidine in the subject, decreasing the concentration of putrescine in the subject, increasing AMD1 expression, or a combination thereof.
- a biological sample can be isolated from a subject.
- a “biological sample” can refer to any sample that is obtained or otherwise derived from a biological subject, including sample of biological tissue or fluid origin obtained in vivo or in vitro.
- biological samples include tissue biopsy, stool, blood, plasma, serum, cord blood, neonatal blood, cerebral spinal fluid (CSF), tears, vomit, saliva, urine, feces, and meconium.
- Embodiments described herein can involve “obtaining” or “isolating” a biological sample from the subject, such as a subject afflicted with a metabolic disease.
- obtaining a biological sample” or “isolating a biological sample” can refer to any process for directly or indirectly acquiring a biological sample from a subject.
- a biological sample may be obtained (e.g., at a point-of-care facility, e.g., a physician's office, a hospital, laboratory facility) by procuring a tissue or fluid sample (e.g., blood draw, marrow sample, spinal tap) from a subject.
- tissue or fluid sample e.g., blood draw, marrow sample, spinal tap
- a biological sample may be obtained by receiving the biological sample (e.g., at a laboratory facility) from one or more persons who procured the sample directly from the subject.
- the biological sample may be, for example, a tissue (e.g., blood), cell (e.g., hematopoietic cell such as hematopoietic stem cell, leukocyte, or reticulocyte, stem cell, or plasma cell), vesicle, biomolecular aggregate or platelet from the subject.
- a biological sample can be prepared to enhance detectability of the biomarkers.
- a sample from the subject can be fractionated, such as by size exclusion chromatography, ion exchange chromatography, heparin chromatography, affinity chromatography, sequential extraction, gel electrophoresis, liquid chromatography, and the like.
- the concentration of a first polyamine in the sample and a second polyamine in the sample can be measured.
- polyamine can refer to an organic compound comprising carbon, nitrogen, and hydrogen, and contains two or more amino groups.
- polyamines of the disclosure can comprise spermidine, putrescine, spermine, and metabolites thereof.
- spermidine is a polyamine compound (C7H19N3) found in ribosomes and living tissues and having various metabolic functions within organisms.spermidine is a precursor to other polyamines, such as spermine.
- Putrescine is a polyamine compound ((CEEXNEE ⁇ ) that, together with spermine and spermidine, play a role in cell growth.
- spermine is a polyamine compound (NH2(CH2)3NH(CH2)4NH(CH2)3NH2) that is involved in cellular metabolism.
- the concentration of first polyamine can be compared with that of the second polyamine to calculate a ratio.
- the ratio can be about 1 :25 or about 0.04, spermidine:putrescine (S:P). In other embodiments, the ratio can be about 25: 1 putrescine: spermidine (P:S).
- the ratio can then be classified as a homeostatic ratio or a non-homeostatic ratio.
- Homeostatic ratio can refer to a ratio that indicates a state of homeostasis.
- Homeostasis can refer to a state of balance of a bodily process.
- a homeostatic ratio can indicate that the bodily process observed is balanced, and/or the tendency of a biological system to maintain internal constancy regardless of its surrounding environment.
- non- homeostatic ratio is indicative of a bodily process that is not balanced, or without internal constancy.
- S-adeno met-DC decarboxylated S-adenosyl-L-methionine
- ALD1 adenosylmethionine decarboxylase
- an S:P ratio that is greater than about 0.035 can be classified as homeostatic.
- the homeostatic ratio can be about 1 :25.
- the homeostatic ratio can be between about 1 : 10 and about 1 : 100, such as about 1 :25.
- the homeostatic ratio can be greater than about 1 :25.
- a homeostatic S:P ratio comprises an S:P ratio greater than about 0.0001, greater than about 0.00025, greater than about 0.0005, greater than about 0.00075, greater than about 0.001, greater than about 0.0025, greater than about 0.005, greater than about 0.0075, greater than about 0.01, greater than about 0.015, greater than about 0.02, greater than about 0.025, greater than about 0.03, greater than about 0.035, greater than about 0.04, greater than about 0.045, greater than about 0.050, greater than about 0.055, greater than about 0.060, greater than about 0.065, greater than about 0.070, greater than about 0.075, greater than about 0.080, greater than about 0.085, greater than about 0.090, greater than about 0.095, greater than about 0.1, greater than about 0.15, greater than about 0.2, greater than about 0.25, greater than about 0.3, greater than about 0.35, greater than 0.4, greater than about 0.45, greater than about 0.5, greater than about 0.6,
- an S:P ratio that is less than about 0.035 can be classified as non- homeostatic. If the S:P ratio is classified as non-homeostatic, a subject can be identified as being at risk of developing or afflicted with a metabolic disease.
- an S:P ratio that is less than about 1 : 10000, less than about 1 :4000, less than about 1 :2000, less than about 3:4000, less than about 1 : 1000, less than about 1 :400, less than about 1 :200, less than about 3:400, less than about 1 : 100, less than about 3:200, less than about 1 :50, less than about 1 :40, less than about 3: 100, less than about 7:200, less than about 1 :25, less than about 9:200, less than about 1 :20, less than about 11 :200, less than about 3:50, less than about 13:200, less than about 7: 100, less than about 3:40, less than about 2:25, less than about 17:200, less than about 9: 100, less than about 19:200, less than about 1 : 10, less than about 3:20, less than about 1 :5, less than about 1 :4, less than about 3: 10, less than about 7:20, less than about 2:5,
- a non-homeostatic S:P ratio comprises an S:P ratio less than 0.0001, less than 0.00025, less than 0.0005, less than 0.00075, less than 0.001, less than 0.0025, less than 0.005, less than 0.0075, less than 0.01, less than 0.015, less than 0.025, less than 0.03, less than 0.035, less than 0.04, less than 0.045, less than 0.050, less than 0.055, less than 0.060, less than 0.065, less than 0.070, less than 0.075, less than 0.080, less than 0.085, less than 0.090, less than 0.095, less than 0.1, less than 0.15, less than 0.2, less than 0.25, less than 0.3, less than 0.35
- the method further comprises comprising administering a treatment to the subject.
- administration can refer to introducing a substance, such as spermidine, an agent that increases AMD1 expression, an agent that increases AMD1 activity, an agent that decreases the concentration of putrescine in the subject, or a combination thereof, into a subject.
- any route of administration can be utilized including, for example, orally, parentally, intravenously, or any combination thereof.
- the concentration of spermidine can be increased to a level such that homeostasis is restored.
- the concentration of spermidine such as in circulating serum, blood, and/or plasma and/or tissue (e.g., liver tissue) can be increased to at least about at least about InM, at least about 5 nM, at least about 10 nM, at least about 15 nM, at least about 20 nM, at least about 25 nM, at least about 30 nM, at least about 35 nM, at least about 40 nM, at least about 45 nM, at least about 50 nM, at least about 55 nM, at least about 60 nM, at least about 65 nM, at least about 70 nM, at least about 75 nM, at least about 80 nM, at least about 85 nM, at least about 90 nM, at least about 95 nM, at least about 100 nM, at least about 110 nM, at least about 120 .
- the concentration of putrescine can be reduced to a level such that homeostasis is restored.
- the concentration of putrescine in circulating serum or blood can be decreased to below about 150 pM, below about 140 pM, below about 130 pM, below about 120 pM, below about 110 pM, below about 100 pM, below about 90 pM, below about 95 pM, below about 90 pM, below about 80 pM, below about 85 pM, below about 80 pM, below about 75 pM, below about 70 pM, below about 65 pM, below about 60 pM, below about 55 pM, below about 50 pM, below about 45 pM, below about 40 pM, below about 35 pM, below about 30 pM, below about 25 pM, below about 20 pM, below about 15 pM, below about 10 pM, below about 5 pM, and below about 1 pM in the subject.
- the treatment can comprise administering to a subject an agent that can increase AMD1 expression or activity.
- AMD1 expression can be increased using gene therapy.
- the agent can comprise mRNA for AMD1.
- the mRNA for AMD1 can be contained inside of a nanoparticle.
- the gene therapy can be delivered via a viral vector.
- the viral vector is AAv8-TBG.
- the treatment can comprise a pharmaceutical that can activate AMD1.
- the therapeutic agent can be administering to a subject in an amount sufficient to effect beneficial or desired clinical results.
- the “effective amount”, “sufficient amount” or “therapeutically effective amount” can be sufficient to reduce fatigue, pain the in the upper right abdomen, loss of appetite, nausea, swelling in legs, confusion, drowsiness, slurred speech, liver damage, itching, ascites, bruising and bleeding jaundice, spider veins, hepatic encephalopathy, cirrhosis, liver cancer, angina, pain, cramping, shortness of breath, fatigue, any other known complication with NASH, atherosclerosis, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis,
- CKD chronic kidney disease
- compositions as described herein can be administered to a subject by any suitable means, such as oral, intravenous, parenteral, subcutaneous, intrapulmonary, topical, intravitreal, dermal, transmucosal, rectal, and intranasal administration.
- Parenteral infusions include intramuscular, intravenous, intraarterial, or intraperitoneal administration.
- the formulations can also be administered transdermally, for example in the form of a slow-release subcutaneous implant or as a transdermal patch. They can also be administered by inhalation.
- direct oral administration can cause some loss of desired activity, the compounds can be packaged in such a way to protect the active ingredient(s) from digestion by use of enteric coatings, capsules or other methods known in the art.
- the pharmaceutical formulation can be administered to the subject one time (e.g., as a single injection or deposition).
- administration can be once or twice daily to a subject in need thereof.
- the administration can be daily for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or for longer than 28 days. It can also be administered once or twice daily to a subject for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 times per year, or a combination thereof.
- a compound or pharmaceutically formulation thereof described herein can be administered about once every day, about once every two days, about once every 3 days, about once every 4 days, about once every 5 days, about once every 6 days, about once every 7 days, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, about once every 14 days, about once every 15 days, about once every 16 days, about once every 17 days, about once every month, about once every two months, about once every 3 months, about once every 6 months, or about once every year.
- any of the therapeutic applications described herein can be applied to any subject or patient in need of such therapy, including, for example, a mammal such as a mouse, a rat, a dog, a cat, a cow, a horse, a rabbit, a monkey, a pig, a sheep, a goat, or a human.
- a mammal such as a mouse, a rat, a dog, a cat, a cow, a horse, a rabbit, a monkey, a pig, a sheep, a goat, or a human.
- the subject is a mouse, rat, pig, or human.
- a “biomarker” can refer to a measurable substance in an organism whose presence is indicative of a disease, infection, or environmental exposure.
- the method can comprise measuring in a sample isolated from a subject afflicted with a metabolic disease the concentration of a first polyamine and the concentration of a second polyamine, and identifying a biomarker for the metabolic disease if the ratio of the concentration of the first polyamine and the concentration of the second polyamine is non-homeostatic.
- Embodiments as described herein can further comprise comparing the ratio obtained from a subject’s sample to that of a control sample.
- a “control sample” can refer to one or more biological samples obtained from a healthy subject or from a subject diagnoses with a disease other than a metabolic disease.
- aspects of the invention are drawn to identifying a subject afflicted with or at risk of developing a metabolic disease, and, in embodiments, treating the subject.
- treat can refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of a metabolic disease.
- beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- subject or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
- Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.
- phrases such as "to a patient in need of treatment” or "a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from administration of a composition as described herein.
- Treatment can be used to treat subjects diagnosed with metabolic diseases.
- diseases can comprise non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), atherosclerosis, Type 2 diabetes, obesity, coronary heart disease, disease of the blood vessels supplying the brain, peripheral arterial disease, rheumatic heart disease, congenital heart disease, cerebrovascular disease, aortic aneurysm, deep vein thrombosis, pulmonary embolism, hypertension, dyslipidemia, chronic kidney disease (CKD), hepatic steatosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, myocardial infarction, or a combination thereof.
- embodiments comprise administering to a subject an effective amount of a pharmaceutical formulation or composition as described herein for the treatment of the condition.
- the method can comprise administering to the subject spermidine, an agent that increases AMD1 expression or activity, agent that decreases putrescine, or a combination thereof.
- embodiments as described herein can comprise administering to the subject spermidine, or a chemical compound according to following structure:
- embodiments as described herein can comprise administering to the subject an agent that increases adenosylmethionine decarboxylase 1 (AMD1) expression or activity.
- AMD1 encodes an important intermediate enzyme in polyamine biosynthesis.
- the polyamines spermine, spermidine, and putrescine are low-molecular-weight aliphatic amines essential for cellular proliferation and tumor promotion. Multiple alternatively spliced transcript variants have been identified, and pseudogenes of this gene are found on chromosome 5, 6, 10, X and Y.
- a nucleic acid encoding AMD1 or a biologically active fragment thereof, or an AMD1 polypeptide or biologically active fragment thereof can be administered to the subject.
- nucleic acid can comprise a sequence, fragment, or variant thereof, according to:
- polypeptide can comprise a sequence, fragment, or variant thereof, according to:
- embodiments as described herein can comprise administering to the subject an agent that decreases putrescine expression or activity.
- the agent can comprise a genetic therapy, such as those that reduce the expression or silence the expression of ornithine decarboxylase 1 (ODC1).
- ODC1 ornithine decarboxylase 1
- the agent can be a pharmacological agent that is a non-specific inhibitors of ODC1 or a specific inhibitor of ODC1, such as L-a- Difluoromethylornithine (DFMO).
- DFMO L-a- Difluoromethylornithine
- biologically active can refer to an AMD1 fragment, mutant, or variant that maintains at least a substantial amount (e.g., at least about 25%, at least about 50%, at least about 70%, and/or at least about 90%) of the activity of the AMD1 protein.
- nucleic acids can comprise nucleic acids encoding AMD1, and uses of the same.
- a “nucleic acid” or “polynucleotide” is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA.
- a “polynucleotide sequence” or “nucleic acid sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching.
- polymorphism can refer to the coexistence of more than one form of a gene or portion thereof.
- a portion of a gene of which there are at least two different forms, i.e., two different nucleotide sequences, can be referred to as a "polymorphic region of a gene".
- a polymorphic region can be a single nucleotide, the identity of which differs in different alleles.
- polynucleotide and “oligonucleotide” can be used interchangeably and can refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown.
- polynucleotides a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, dsRNA, siRNA, miRNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers.
- a polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
- modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide.
- the sequence of nucleotides can be interrupted by non-nucleotide components.
- a polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component.
- the term also refers to both double- and single- stranded molecules. Unless otherwise specified or required, any embodiment of this disclosure that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double- stranded form.
- encode as it is applied to polynucleotides can refer to a polynucleotide which is said to "encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, it can be transcribed and/or translated to produce the mRNA for the polypeptide and/or a fragment thereof.
- the antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom.
- Nucleic acids as described herein can be expressed from vectors.
- a “vector” can refer to any genetic element capable of serving as a carrier for genetic transfer, expression or replication for a foreign polynucleotide into a host cell.
- the vector can be an artificial chromosome or plasmid, and can stably integrate into the genome of the host cell, or it may exist as an independent gene element (eg, episomes, plasmids).
- Expression vectors may include, without limitation, eukaryotic plasmid vectors, eukaryotic viral vectors, prokaryotic plasmids, bacteriophage vectors, shuttle vectors (e.g., a vector that can replicate in eukaryotic and prokaryotic cells), mini chromosomes, and various artificial chromosomes (e.g., bacterial artificial chromosomes (BAC), artificial chromosomes of yeast (YAC)).
- eukaryotic plasmid vectors eukaryotic viral vectors
- prokaryotic plasmids eukaryotic viral vectors
- bacteriophage vectors e.g., a vector that can replicate in eukaryotic and prokaryotic cells
- mini chromosomes e.g., bacterial artificial chromosomes (BAC), artificial chromosomes of yeast (YAC)
- the expression vector used in the present invention is a plasmid, more preferably a plasmid expression vector that stably integrates into the genome of the host cell, and even more preferably, a plasmid expression vector that is stably expressed in the genome of the host cell by non-homologous recombination.
- a “shuttle vector” refers to any vector that can replicate in more than one type of organism.
- a shuttle vector that can replicate to both Escherichia coli (E. coli) and Saccharomyces cerevisiae (S. cerevisiae) can be constructed by linking sequences from the E. coli plasmid to 2 pm yeast plasmid sequences.
- Expression systems can include an expression vector and a suitable (homologous) host cell that will express the recombinant protein (s) encoded in the expression vector.
- the expression system may be a stable expression system or a transient expression system.
- the expression vector is stably integrated into the genome of the host cell or is continuously replicated, and successfully transferring to both daughter cells, so that the host cells are able to continue to express recombinant protein (s) upon cultivation under appropriate conditions.
- the expression vector molecules do not remain in both daughter cells and, over time, are lost or so reduced in the growing cell culture that the expression of the recombinant protein (s) from the culture will eventually cease or be so low that it will not be applicable to most purposes of obtaining.
- the expression vectors used in the examples below are types of shuttle vectors that can replicate to a relatively high number of copies when inserted (e.g., by transformation) into E. coli cells and which can also be integrated (e.g., by transfection ) into stable Chinese hamster oocytes (CHO) to obtain stable expression of the encoded gene product (s) of interest (Kaufman et al., Molec. Cell.
- rEVE polynucleotide molecule described in this application can be used to enhance the expression of recombinant protein (s) of interest in both stable and transient expression systems.
- Exemplary eukaryotic vectors that may be used in the present invention include, but are not limited to, viral and non-viral vectors.
- Viral vectors include, but are not limited to, retroviral vectors (including lentiviral vectors); adenoviral vectors, including those capable of replication, incapable of replication and "gutless" their forms; adeno-associated viral vectors (AAV); monkey virus vectors 40 (SV-40); cattle papilloma virus vectors; Epstein-Barr virus vectors; herpes virus vectors; smallpox virus vectors; Moloni mouse leukemia virus vectors; Harvey mouse sarcoma virus vectors, mouse mammary tumor virus vectors, and Routh sarcoma virus vectors.
- retroviral vectors including lentiviral vectors
- adenoviral vectors including those capable of replication, incapable of replication and "gutless" their forms
- AAV adeno-associated viral vectors
- SV-40 monkey virus vectors 40
- Baculovirus vectors are also well known and suitable for expression in insect cells.
- a variety of vectors suitable for expression in eukaryotic or prokaryotic cells are well known in the art and many are commercially available. Commercial sources include, but are not limited to, Stratagene (La Jolla, California), Invitrogen (Carlsbad, California), Promega (Madison, Wisconsin), and Sigma-Aldrich (St. Louis, Missouri). Many vector sequences are available through GenBank, and additional information regarding vectors is available online through the Riken BioSource Center.
- a vector molecule usually contains one replication start point and may also contain a “marker” or “selectable marker” gene, by which the vector can be identified or selected when included in the host cell.
- suitable markers can, without limitation, confer resistance to antibiotics, provide functions that provide selective growth advantages over cells that lack such functions, or provide a means for easily identifying cells that have a vector (e.g., the Colorigenic system).
- markers are well known in the art and the selection of appropriate breeding marecra (markers) for use in the vector molecule will depend on the host cell used and what properties are desired for the host cell containing the vector.
- the terms “functional gene construct”, “functional gene”, and “gene” can refer to a polynucleotide that contains a coding sequence for one or more proteins that is operably linked to a promoter sequence and possibly other transcriptional regulatory sequences to direct the correct transcription of the coding sequence into messenger RNA (mRNA) and which also contains any of a number of translational regulatory sequences that may be necessary we are or are desirable to direct the correct translation of mRNA into the desired protein in a given host cell.
- a translational start codon (e.g., ATG) and a ribosome binding site are typically required in mRNA for translation occurring in prokaryotic and eukaryotic cells.
- Translational regulatory sequences may also be used, depending on the host cell, including, but not limited to, an RNA splicing site and a polyadenylation site.
- the term "recombinant” is used in this application to describe altered nucleic acids or nucleic acids that have been manipulated, nucleic acids isolated from the environment in which they are found in nature, host cells transfected or otherwise manipulated to contain exogenous nucleic acids, or proteins expressed synthetically by manipulating isolated DNA or transforming host cells. “Recombinant” is a term that especially encompasses DNA molecules that have been constructed in vitro using genetic engineering methods, and the use of the term “recombinant” as an adjective to describe a molecule, construct, vector, cell, protein, polypeptide or polynucleotide specifically excludes such natural molecules, constructs, vectors, cells, proteins, polypeptides or polynucleotides.
- a “recombinant protein” for the purposes of the present invention is a protein that is expressed by a host cell that has been manipulated by including at least one genetic element that was not found in nature in the host cell before expression of the protein.
- a protein whose coding sequence has been artificially inserted into a host cell capable of expressing this protein, for example, transfected with an expression vector containing a protein coding sequence, is a “recombinant protein” expressed by the host cell.
- a "host cell” can refer to any cell, i.e. any eukaryotic or prokaryotic cell into which a vector molecule can be inserted.
- the preferred host cells are eukaryotic or prokaryotic cells, including, but not limited to, animal cells (e.g., mammalian, bird and fish host cells), plant cells (including eukaryotic algae cells), fungal cells, bacterial cells and protozoan cells.
- animal cells e.g., mammalian, bird and fish host cells
- plant cells including eukaryotic algae cells
- fungal cells e.g., fungal cells
- bacterial cells eukaryotic cells
- protozoan cells eukaryotic cells used in the present invention can be of any genetic construct, but are preferably haploid or diploid cells.
- Preferred mammalian host cells used in the present invention include, but are not limited to, Chinese Hamster Oocytes (CHO), COS cells, Vero cells, SP2 / 0 cells, NS / 0 myeloma cells, human embryonic kidney cells (HEK 293), cells baby hamster (BHK), HeLa cells, human B cells, CV-1 / EBNA cells, L cells, 3T3 cells, HEPG2 cells, PerC6 cells and MDCK cells.
- Preferred insect cells are Sf9.
- Fungal cells that can serve as host cells in this invention include, without limitation, ascomycete cells such as Aspergillus, Neurospora, and yeast cells, in particular yeast of the genera Saccharomyces, Pichia, Hansenula, Schizosaccharomyces, Kluyveromyces, Yarrowia and Candida.
- yeast fungal species that can serve as host cells for expression of recombinant proteins are Saccharomyces cerevisiae, Hansenula polymorpha, Kluyveromyces lactis, Pichia pastoris, Schizosaccharomyces pombe and Yarrowia lipolytica.
- Preferred prokaryotic cells that can serve as host cells in the present invention include, without limitation, Escherichia coli, serovars Salmonella enterica, Shigella species, Wollinella succinogenes, Proteus vulgaris, Proteus mirabilis, Edwardsiella tarda, Citrobacter freundii, Pasteurella species, Haemophilus species, Pseudomonas species, Bacillus species, Staphyloccocus species and Streptococcus species.
- Suitable host cells for expression of the recombinant proteins of the present invention include protozoa, such as the trypanosomal host Leishmania tarentolae, and Caenorhaditis elegans nematode cells.
- protozoa such as the trypanosomal host Leishmania tarentolae, and Caenorhaditis elegans nematode cells.
- Various expression vectors are available for use in the cells mentioned above.
- Methods for “transferring nucleic acid sequence information” from one vector or other nucleic acid molecules to another are not limited in the present invention and include any of a number of genetic engineering or recombinant nucleic acid techniques known in the art. Particularly preferred transfer technologies include, but are not limited to, restriction digestion and ligation technologies, polymerase chain reaction (PCR) protocols (using specific or arbitrary primer sequences), homologous recombination technologies (using polynucleotide homology regions), and non-homologous recombination (e.g. random insertion) . Nucleic acid molecules containing a specific sequence can also be synthesized, for example, using an automated nucleic acid synthesizer, and the resulting product, nucleic acid, is then incorporated into another nucleic acid molecule of any of the above methods.
- PCR polymerase chain reaction
- a host cell may have (as determined by its genetic location) certain nutritional requirements, or a specific resistance or sensitivity to physical (e.g. temperature) and / or chemical (e.g. antibiotics) conditions.
- special culturing conditions may be necessary to regulate the expression of the desired gene (e.g., the use of inducible promoters), or to initiate a specific cell state (e.g., a mating or sporulating yeast cell).
- DHFR dihydrofolate reductase
- MTX metal-methotrexate
- Stability and “stable expression” refer to the ability of a cell culture to continue to express recombinant protein at an increased (increased) ) level when grown in the absence of methotrexate, i.e. in the absence of selective pressure for increased expression provided by the presence of methotrexate used in the amplification procedure.
- a stably transfected host cell can express a recombinant protein of interest in the presence or absence of methotrexate.
- “enhanced adaptation” or “improved adaptation” to the presence of methotrexate refers to higher survival and / or higher growth rate in the presence of methotrexate culture of host cells carrying expression vectors containing rEVE described herein compared to survival and / or growth rate in the presence of methotrexate culture of ho cells yaev carrying expression vectors that lack the rEVE.
- “Survival” of a host cell population refers to the ability of a host cell population to grow and reproduce in the presence of selective pressure (eg, methotrexate).
- homologous in this position for example, as used in the present description, the "homology" of amino acids or nucleic acids is equivalent to "identity "Amino acids or nucleic acid).
- Homology of nucleic acid sequences can be defined as the degree of identity between two sequences. Homology can be determined using computer programs known in the art, such as the GAP software provided in the GCG software package. See Needleman and Wunsch, J. Mol. Biol, 48: 443-453 (1970).
- isolated as used herein with respect to cells, proteins, and nucleic acids (e.g., DNA or RNA) can refer to molecules separated from other cells, proteins, or nucleic acids, respectively, that are present in the natural source of the macromolecule.
- isolated as used herein also can refer to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
- an "isolated nucleic acid” can refer to a nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state.
- isolated can also be used herein to refer to cells or polypeptides which are isolated from other cellular proteins or tissues. Isolated polypeptide can refer to both purified and recombinant polypeptides.
- the spermidine, the agent to increase AMD1 expression or activity or combination thereof can be administered in pharmaceutically or pharmacologically acceptable route.
- the spermidine, agent to increase AMD1 expression or activity, or a combination thereof can be administered as and/or with a pharmaceutically or pharmacologically acceptable carrier.
- compositions in a form appropriate for the intended application. Generally, this will entail preparing compositions that are essentially free of pyrogens, as well as other impurities that can be harmful to humans or animals. Non-limiting embodiments are described herein.
- phrases “pharmaceutically or pharmacologically acceptable” can refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
- pharmaceutically acceptable carrier can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients also can be incorporated into the compositions.
- compositions according to the present invention will be via any common route so long as the target tissue is available via that route.
- This includes, for example, oral administration and/or intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection.
- compositions can also be administered parenterally or intraperitoneally.
- Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form can be sterile and can be fluid to the extent that easy administration by a syringe is possible. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- a coating such as lecithin
- surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the spermidine of the present invention can be incorporated with excipients that can include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
- excipients can include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
- spermidine can be added to a liquid or a solid for a subject to ingest.
- spermidine can be added to the beverage of a subject to be ingested.
- the pharmaceutical combinations/formulation of the present invention comprise compounds configured to reduce the level putrescine described herein, compounds configured to increase the level of spermidine or AMD1 expression, or any other potential therapeutics in an admixture along with a pharmaceutically acceptable carrier prepared according to conventional pharmaceutical techniques.
- pharmaceutically acceptable carrier can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- Non-limiting examples of pharmaceutically acceptable carriers comprise solid or liquid fillers, diluents, and encapsulating substances, including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl benzoate, propyl benzoate, talc, magnesium stearate, and mineral oil.
- the amount of the carrier employed in conjunction with the combination is sufficient to provide a practical quantity of material per unit dose of the formulation.
- compositions of the present invention can be formulated in a neutral or salt form.
- Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
- Pharmaceutically acceptable carriers for oral administration comprise sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen- free water.
- Pharmaceutically acceptable carriers for parenteral administration comprise isotonic saline, propylene glycol, ethyl oleate, pyrrolidone, aqueous ethanol, sesame oil, corn oil, and combinations thereof.
- Various oral dosages forms can be employed, non-limiting examples of which comprise solid forms such as tablets, capsules, granules, suppositories and/or powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
- Liquid oral dosage forms comprise aqueous solutions, emulsions, suspensions, syrups, aerosols and/or reconstituted solutions and/or suspensions. The composition can alternatively be formulated for external topical application, or in the form of a sterile injectable solution.
- the dosage can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion.
- a therapeutically effective dose can depend upon a number of factors known to those of ordinary skill in the art.
- the dose(s) can vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires. These amounts can be readily determined by the skilled artisan.
- Single unit dosage forms of the disclosure are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal (e.g., cream, lotion, or dermal spray) or transcutaneous administration to a subject.
- mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
- parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
- topical e.g., eye drops or other ophthalmic preparations
- transdermal e.g., cream, lotion, or dermal spray
- transcutaneous administration e.g., cream, lotion, or dermal spray
- dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions or solutions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms for parenteral administration to a subject.
- suspensions e.g., aqueous or non-aqueous liquid suspensions or solutions, oil-in-
- composition, shape, and type of dosage forms of the disclosure will typically vary depending on their use. Further, the dosage can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion.
- a dosage form used in the acute treatment of a disease can contain larger amounts of one or more of the active agents it comprises than a dosage form used in the chronic treatment of the same disease.
- a parenteral dosage form can contain smaller amounts of one or more of the active agents it comprises than an oral dosage form used to treat the same disease.
- a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
- routes of administration are described herein, and comprise parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, nasal, and rectal administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- pharmaceutical combinations of the invention can be administered orally, either in the form of tablets containing excipients such as starch or lactose, or in capsules, either alone or mixed with excipients, or in the form of syrups or suspensions containing coloring or flavoring agents. They can also be injected parenterally, for example intramuscularly, intravenously or subcutaneously. In parenteral administration, they can be used in the form of a sterile aqueous solution which can contain other solutes, such as, for example, any salt or glucose in order to make the solution isotonic.
- the formulations can be administered to a subject for the treatment of a metabolic disorder, for example orally, either covered in gelatin capsules or compressed in lozenges.
- said compounds can be mixed with excipients and used in the form of lozenges, tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
- These preparations can contain at least 0.5% of active compound, but can vary depending on each form, in particular between 4% and 75% approximately of the weight of each unit.
- the amount of active compound in such compositions should be that which is necessary for obtaining the corresponding dosage.
- compositions and preparations as described herein can be prepared in such a way that each oral dosage unit can contain between 0.1 mg and 1g of the active compound.
- the active compounds of this invention can be incorporated in a solution or suspension.
- Such preparations can contain at least 0.1% of the active compound, but can vary between 0.5% and 50% approximately of the weight of the preparation.
- such preparations comprise about 0.1%, 0.5%, 1%, 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, 50%, of the weight of the preparation.
- the amount of active compound in such compositions should be that which is necessary for obtaining the corresponding dosage.
- compositions and preparations as described herein can be prepared in such a way that each parenteral dosage unit can contain between .01 mg and 1000 mg, for example between about 0.5mg and 100 mg of the active compound, for example.
- intramuscular administration can be given in a single dose or divided into up to multiple doses, such as three doses
- intravenous administration can include a drip device for giving the dose by venoclysis.
- Parenteral administration can be performed by means of ampoules, disposable syringes or multiple-dose vials made of glass or plastic.
- compositions or formulations suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- suitable carriers can include physiological saline, bacteriostatic water, Cremophor EMTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the composition can be sterile and should be fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyethylene glycol, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal.
- Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated herein.
- examples of useful preparation methods are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
- compositions can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
- a lubricant such as magnesium stearate or sterotes
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
- the pharmaceutical formulations and compositions can be administered to a subject in a single dose for the treatment of a condition, or as multiple doses over a period of time. Further, the formulation can be administered at intervals of about 4 hours, 8 hours, 12 hours, 24 hours, or longer. In embodiments, the formulation can be administered continuously over a period of time, such as for 4 hours, 8 hours, 12 hours, 24 hours, or longer.
- compositions described herein can be formulated as controlled- release pharmaceutical products, which have a goal of improving drug therapy over that achieved by their non-controlled counterparts.
- the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
- Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
- controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
- Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
- drug active ingredient
- Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds
- kits suitable for the treatment of a metabolic disease.
- the kit can comprise printed instructions for administering a formulation or composition as described herein to a subject in need thereof; a pharmaceutical composition as described herein, and/or a pharmaceutically acceptable carrier.
- a “kit” or “medical kit” of the disclosure comprises a dosage form of a formulation of the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof.
- a kit can also include two or more compounds as described herein, either in combination, such as in a single tablet, or provided separately, such as in two or more tablets.
- Kits can further comprise additional active agents, examples of which are described herein.
- Kits of the disclosure can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. Kits can also comprise printed instructions for administering the formulation to a subject.
- Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
- the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
- Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
- water-miscible vehicles such as, but not limited to, ethyl alcohol
- Such a diagnostic kit can comprise a substrate for collecting a sample from the patient; and means for measuring the biomarker disclosed or discussed herein.
- Exemplary, albeit non-limiting, means for measuring biomarker levels comprises Western blot; ELISA (enzyme linked immunosorbent assay); radioimmunoassay analysis (RIA); radial immunodiffusion; Ouchterlony immunodiffusion; rocket immunoelectrophoresis; tissue immunohistochemistry; immunoprecipitation assays; complement fixation assays; flow cytometry; protein chip (protein microarray); capillary western blot; protein MS; Protein sequencing; HPLC; and gas chromatography, among those described herein.
- ELISA enzyme linked immunosorbent assay
- RIA radioimmunoassay analysis
- radial immunodiffusion Ouchterlony immunodiffusion
- rocket immunoelectrophoresis tissue immunohistochemistry
- immunoprecipitation assays complement fixation assays
- flow cytometry protein chip (protein microarray); capillary western blot; protein MS; Protein sequencing; HPLC; and gas chromatography, among those described here
- Non-alcoholic fatty liver disease is a liver disease that can be a spectrum of pathologies, including non-alcoholic steatohepatitis (NASH).
- NASH non-alcoholic steatohepatitis
- NASH is linked to cardiovascular risk, and importantly there is no therapy currently available to treat NASH.
- NAFLD and NASH are reaching global epidemic proportions, clear diagnosis, primarily limited to liver biopsy is one of the major hurdles of an effective treatment.
- advances in non-invasive diagnostic tools are paramount.
- Our work shows that homeostasis of polyamines, small linear polycations that participate in multiple cellular functions, becomes imbalanced and displays consistent differences during NASH.
- spermidine:putrescine ratios (a metric of polyamine homeostasis) being used in the clinic as a routine evaluation for NASH risk, akin to how plasma cholesterol is assessed as a risk for cardiovascular disease.
- the result from this disclosure is the establishment of evaluating plasma spermidine:putrescine ratio as a metric in the clinic as a biomarker for NASH risk.
- Polyamine levels become imbalanced during Non-Alcoholic Steatohepatitis (NASH) and negatively correlate with key indices of disease.
- Polyamines comprised of putrescine, spermidine, and spermine, are a family of low-molecular-mass, highly charged molecules that direct proliferation, gene transcription, mRNA stability, and protein translation. Putrescine, spermidine, and spermine have all been shown to have protective effects in chronic, inflammatory diseases by restraining macrophage polarization towards a proinflammatory phenotype, lowering oxidative DNA damage, and promoting the production of anti-inflammatory cytokines.
- Non-alcoholic fatty liver disease represents a spectrum of liver pathologies ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which is emerging as the leading cause of liver disease.
- NASH leads to hepatocellular carcinoma and exacerbates heart and kidney disease. Therefore, there has been interest in identifying strategies to lower NASH. Remarkably, however, there are no drugs to treat NASH. Moreover, there are no circulating biomarkers to date that can diagnose NASH. These gaps provide an opportunity to make new discoveries in NASH pathophysiology and identify new therapeutic targets. Described herein, we reveal an unexpected role for the impairment in polyamine homeostasis during NASH.
- polyamine homeostasis is impaired in mice with diet-induced NASH aligned with hepatic downregulation of adenosylmethionine decarboxylase 1 (AMD1), the rate-limiting enzyme that governs polyamine homeostasis.
- AMD1 adenosylmethionine decarboxylase 1
- this impairment in polyamine homeostasis negatively correlated with key indices of NASH, suggesting that restoring the balance of polyamines can be a suitable therapeutic strategy. Described herein, we address the described gaps by 1) validating the role of polyamines in an experimental model of NASH, and 2) determining polyamine homeostasis in longitudinal studies in individuals with NASH.
- Aim 1 To Characterize the Role of Impaired Polyamine Homeostasis in NASH Progression. Without wishing to be bound by theory, balancing polyamine homeostasis will be achieved by restoring AMD1 expression in the liver and will lower NASH progression. Without wishing to be bound by theory, we can overexpress AMD1 in the hepatocytes of mice using AAV8-TBG-AMD1 and evaluate NASH in mice fed a high-fat, high-fructose, and cholesterol - enriched diet for 24 weeks. Furthermore, we can supplement the drinking water of mice with spermidine to raise the spermidine:putrescine ratio and assess NASH progression.
- Aim 2 To Determine the Predictive Value of Using thespermidine:Putrescine ratio as a Biomarker for NASH.
- NAFLD can present as a spectrum of liver pathologies ranging from simple hepatic steatosis to NASH, which is characterized by hepatocyte ballooning, lobular inflammation, and hepatic fibrosis 4 .
- Unmitigated progression of NASH leads to cirrhosis and end-stage liver disease with an increased risk of developing hepatocellular carcinoma 5 .
- NASH is associated with cardiometabolic comorbidities such as obesity, atherogenic dyslipidemia, and type 2 diabetes (T2D).
- T2D type 2 diabetes
- NASH is becoming the most common cause of chronic liver disease worldwide 1,6 .
- mice from NASH 2 Raising glycine levels by increasing its biosynthesis protected mice from NASH 2 .
- dietary arginine or leucine supplementation in mice reduced hepatic steatosis, improved glucose tolerance, and protected mice from liver injury 8 ' 10 .
- Various mouse models of NASH involve amino acid-deficient or modified diets, including the methionine and choline-deficient diet and the choline-deficient amino acid-defined (CDAA) diet, either of which causes hepatic steatosis, immune cell recruitment, and fibrosis 11 . While dysfunctions in amino acid metabolism during NASH have been observed, the mechanisms regulating these impairments and their downstream consequences have not been revealed.
- CDAA choline-deficient amino acid-defined
- SRM spermidine synthase
- SMS spermine synthase
- Essential to SRM and SMS activity is decarboxylated S-adenosyl-L- methionine (S-adeno met-DC), synthesized by adenosylmethionine decarboxylase (AMD1), which donates an n-propylamine residue for spermidine and spermine.
- Dysregulation in the expression of polyamine biosynthetic genes leads to imbalances in polyamine homeostasis, causing overexuberant inflammatory responses in macrophages, an inability to resolve inflammation, and unchecked proliferation and migration of tumor cells 3 12 .
- deletion of ODC1 in myeloid cells worsens ulcerative colitis by reprogramming the epigenetic landscape 13 .
- Loss of ARG1 or ODC1 in myeloid cells also impairs the clearance of dead cells by macrophages, dampens production of the anti-inflammatory cytokine IL- 10, and prevents atherosclerosis regression 14 15 .
- spermine has been shown to mitigate acute liver injury by inhibiting proinflammatory responses in liver-resident macrophages through AT G5 -dependent autophagy 16 . Furthermore, oral administration of spermidine and spermine alleviates ischemia-reperfusion injury in the liver and promotes liver regeneration 17 . In the carbon tetrachloride model of hepatotoxicity, treating rats with anti-inflammatory anthocyanins raised polyamine levels 18 . Spermidine treatment lowered hepatosteatosis in diet-induced obese mice, yet features of NASH, such as immune cell recruitment and fibrosis, were not assessed 19 . Furthermore, spermidine was more than 2-fold lower in individuals with advanced NASH compared to early NASH 20 . However, the role of impaired polyamine homeostasis in NASH has yet to be explored.
- NASH is emerging as the leading cause of liver disease, but incomplete understandings of its pathophysiology have led to a paucity of treatment options for individuals with this disease.
- polyamines as a new biomarker for NASH risk
- AMD1 rate-limiting polyamine biosynthetic enzyme
- we provide evidence for using polyamines as a new biomarker for NASH risk reveal that the rate-limiting polyamine biosynthetic enzyme AMD1 decreases as NASH progresses, and discover polyamine- based treatment that can enhance hepatic fatty acid disposal, reduce steatohepatitis, and lower fibrosis.
- these studies can (1) define the mechanisms regulating polyamine dysfunction during NASH, (2) evaluate the role of AMD1 overexpression in NASH, and (3) provide the first assessment of spermidine treatment in NASH in vivo. Furthermore, we can provide the first assessment of using polyamines as a clinically relevant biomarker for NASH diagnosis and progression in an observational study. Herein, we put forth a new paradigm for how NASH progresses in a manner that can be diagnosed and targeted therapeutically. [00191] Non-Limiting Experimental Design and Methods
- Polyamine levels become imbalanced during NASH and the ratio of spermidine to putrescine negatively correlates with key indices of disease.
- Poly amines comprised of putrescine, spermidine, and spermine, are a family of low-molecular-mass, highly charged molecules that direct proliferation, gene transcription, mRNA stability, and protein translation, and the circulating levels of these three polyamines are known to decrease in several chronic, inflammatory diseases 3, 15, 20 .
- Non-Limiting, Exemplary Aim 1 To characterize the role of impaired polyamine homeostasis in NASH progression. Rationale'. Our data indicate that polyamine homeostasis, for example in the balance between spermidine and putrescine, becomes dysregulated during NASH and that this impairment in maintaining polyamine homeostasis negatively correlates with key indices of NASH. We will evaluate the role of impaired polyamine homeostasis in NASH by correcting the expression of AMD1 using AAV8-mediated gene delivery and raising the level of spermidine in mice with NASH by orally supplementing exogenous spermidine in their drinking water.
- HepG2 hepatoma cell line to determine the mechanisms that impair polyamine biosynthesis in a culture setting where cells are challenged with both palmitate, a fatty acid that contributes to NASH progression, and the proinflammatory cytokines TNFa and IL-ip.
- mice for the AAV8-TBG-GFP group and 8 mice for the AAV8-TBG-AMD1 group.
- Mouse weight will be monitored weekly, and blood will be collected at the time of euthanasia from the inferior vena cava for biochemical, cytokine, biomarker, and polyamine analysis by LC-MS/MS. Liver weight will be assessed and then processed for biomolecular and histopathological analysis.
- We will analyze the state of steatohepatitis, hepatocyte ballooning, and bridging fibrosis.
- Liver steatosis Oleosis
- fibrosis Paneosis
- Trichrome fibrosis
- F4/80 and Mac2 for macrophages will be evaluated and graded by a blinded hepatobiliary anatomical pathologist, and inflammation will be assessed by immunofluorescence histochemistry (F4/80 and Mac2 for macrophages).
- Mitochondria dysfunction and subsequent ER stress are critical mediators of lipotoxicity in steatosis, particularly in the context of additional stressors, and a few studies suggest that polyamines can impact glucose utilization and mitochondria function 24 ' 26 .
- AMD1 protects hepatocytes from lipotoxicity
- LDH lactate dehydrogenase
- mice For controls, we will maintain mice on normal water throughout the 24-weekNASH diet feeding (Figure 9). Based on our experience using power calculations for NASH studies 2 , we will use 8 mice for the control group and 8 mice for the spermidine intervention group. Mouse weight will be monitored weekly, and blood will be collected at the time of euthanasia from the inferior vena cava for biochemical, cytokine, biomarker, and polyamine analysis by LC-MS/MS. Hepatocyte ballooning, fibrosis, hepatosteatosis, and inflammation will be evaluated as mentioned in Aim 1.1.
- Non-Limiting, Exemplary Aim 1 results and alternative strategies: We anticipate that AMD1 overexpression in hepatocytes will restore the S:P ratio and lower NASH progression, including a significant inhibition of fibrosis formation, a key feature of advanced NASH. Without wishing to be bound by theory, AMD1 overexpression can or cannot be insufficient to restore the balance in S:P ratios as this requires the upstream substrate putrescine levels to be metabolized into spermidine. However, we observed that putrescine levels are elevated, indicating that restoration of AMD1 can be sufficient to restore polyamine homeostasis. We can also consider a dual expression platform to overexpress both ODC1 and AMD1 simultaneously.
- spermidine supplementation will bypass the genetic loss of AMD1 to raise the S:P ratio. This is a direct approach to test the role of impaired polyamine homeostasis in NASH progression. Because spermidine supplementation has been shown in to raise systemic spermidine levels, without wishing to be bound by theory, homeostasis will be restored. In a mouse model of atherosclerosis, we have shown that putrescine supplementation increases fibrous cap thickening by enhancing collagen deposition 15 . Therefore, the enhanced putrescine levels we observed during NASH can contribute to fibrosis and its progression. An alternative approach is lowering putrescine levels and re-evaluate NASH progression.
- Non-Limiting, Exemplary Aim 2 To determine the predictive value of the spermidine: putrescine ratio as a biomarker for NASH. Rationale'.
- putrescine ratio as a biomarker for NASH. Rationale'.
- mRNA expression of AMUR the rate-limiting enzyme that controls polyamine balance
- the goal of this aim is to evaluate a direct link between the S:P ratio and decreased AMD1 protein expression in hepatocytes with NASH incidence and progression.
- a new or existing diagnosis of NAFLD will be defined as (1) hepatic steatosis confirmed by imaging using US/CT/MRI, (2) elevated transaminases, or by FibroScan without significant alcohol consumption (defined as > 21 standard drinks in men and > 14 standard drinks for women per week over a two-year period preceding diagnosis based on patient reported consumption as part of the standard hepatology visit) excluding other causes of hepatic steatosis or co-existing etiology of chronic liver disease.
- the 6- and 12- month follow-up plasma samples will be obtained in conjunction with standard of care hepatology and serology labs.
- the S:P ratio analysis will be performed as outlined in Aim 1 with clinical data extraction as outlined in Aim 2.1.
- n indicates an independent biological variable.
- the sample size for all animal experiments is calculated to achieve a ⁇ 0.05 and P > 0.80.
- the expected differences between means and variances are derived from published literature from multiple groups. Statistical analysis will be performed in consultation with biostatistician support, with specific attention paid to sample sizes, confounding factors, and data distribution. Images will be analyzed by at least two independent, blinded parties.
- Biological Variables All animal experiments will use age-matched male mice as female mice are resistant to diet-induced NASH 36, 37 . We used Russ Lenth’s power and sample size calculator to determine the number of mice required for studies in this application to ensure proper power.
- Multifactorial approaches using combinations of different stimuli and rescue experiments will ensure the validity of the findings. All experiments will be repeated at least four times. The experimenter will be blinded until after data analysis. Data will be tested for Normality (Shapiro-Wilk test) and significance using GraphPad Prism software. Data passing the Normality assumption will be analyzed using Student’s T-test or one-way or two-way ANOVA with LSD post-tests. We will use the Mann- Whitney U test and the Kruskal Wallis test with post hoc analysis to analyze data failing the Normality assumption. Differences will be considered significant at P ⁇ 0.05.
- the data generated herein can allows for a more mechanistic analysis of polyamine homeostasis in NASH in vitro and in vivo (e.g. data from Aim 1) and evaluate AMD1 expression in livers and circulating S:P ratios in humans with NASH (e.g. data from Aim 2).
- ODC Ornithine Decarboxylase
- MerTK Mertyrosine-Protein Kinase
- Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2016;24:848-862.
- Kirsch RE and Hall Pde L Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol. 2003;18: 1272-82.
- Example 3 Impairments in Polyamine Homeostasis as a Common Link in Cardiovascular Disease and Non-Alcoholic Steatohepatitis
- CVD cardiovascular disease
- NAFLD non-alcoholic steatohepatitis
- S-adeno met- DC decarboxylated S-adenosyl-L-methionine
- ALD1 adenosylmethionine decarboxylase
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Abstract
L'invention concerne des biomarqueurs pour une maladie métabolique et des procédés de traitement de ceux-ci.
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US20040162353A1 (en) * | 2000-08-24 | 2004-08-19 | Meyskens Frank L. | Alpha-difluoromethylornithine(DFMO) suppresses polyamine levels in the human prostate |
WO2012007531A2 (fr) * | 2010-07-13 | 2012-01-19 | Frank Madeo | Procédés et compositions de diagnostic d'états médicaux |
US20130345526A1 (en) * | 2012-06-25 | 2013-12-26 | Flint Hills Scientific, Llc | Automated Prevention and Control of Epileptic Seizures Using Biochemical And/or Electrical Signal Markers |
US20200054579A1 (en) * | 2016-11-14 | 2020-02-20 | Tll Longevity Labs Gmbh | Use of spermidine for the enhancement of mitochondrial respiration |
US20210077549A1 (en) * | 2019-09-18 | 2021-03-18 | Research Development Foundation | Methods and probiotic compositions for the treatment of metabolic diseases and disorders |
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US20040162353A1 (en) * | 2000-08-24 | 2004-08-19 | Meyskens Frank L. | Alpha-difluoromethylornithine(DFMO) suppresses polyamine levels in the human prostate |
WO2012007531A2 (fr) * | 2010-07-13 | 2012-01-19 | Frank Madeo | Procédés et compositions de diagnostic d'états médicaux |
US20130345526A1 (en) * | 2012-06-25 | 2013-12-26 | Flint Hills Scientific, Llc | Automated Prevention and Control of Epileptic Seizures Using Biochemical And/or Electrical Signal Markers |
US20200054579A1 (en) * | 2016-11-14 | 2020-02-20 | Tll Longevity Labs Gmbh | Use of spermidine for the enhancement of mitochondrial respiration |
US20210077549A1 (en) * | 2019-09-18 | 2021-03-18 | Research Development Foundation | Methods and probiotic compositions for the treatment of metabolic diseases and disorders |
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GAO MINGYUE, ZHAO WEI, LI CHUNMEI, XIE XIANGHONG, LI MEIXIA, BI YALAN, FANG FUDE, DU YUNFENG, LIU XIAOJUN: "Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 505, no. 1, 20 October 2018 (2018-10-20), Amsterdam NL , pages 93 - 98, XP093048028, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2018.09.078 * |
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