WO2023076144A1 - Méthodes et compositions destinées à améliorer la production et la sécrétion d'insuline - Google Patents

Méthodes et compositions destinées à améliorer la production et la sécrétion d'insuline Download PDF

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Publication number
WO2023076144A1
WO2023076144A1 PCT/US2022/047541 US2022047541W WO2023076144A1 WO 2023076144 A1 WO2023076144 A1 WO 2023076144A1 US 2022047541 W US2022047541 W US 2022047541W WO 2023076144 A1 WO2023076144 A1 WO 2023076144A1
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Prior art keywords
exosome
nutritional composition
enriched product
bovine milk
protein
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PCT/US2022/047541
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English (en)
Inventor
José María LÓPEZ PEDROSA
Ricardo Rueda Cabrera
Jorge GARCÍA MARTÍNEZ
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Abbott Laboratories
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Publication of WO2023076144A1 publication Critical patent/WO2023076144A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to methods of improving insulin production in a subject suffering from impaired p-cell function, to methods of restoring and/or preserving p-cell mass in a subject suffering from reduced insulin production, and to methods of delaying the progression of diabetes in a subject suffering from reduced insulin production.
  • Pancreatic p-cells produce and secrete insulin, which is the hormone that regulates blood glucose concentration by promoting absorption of glucose from the blood into liver, fat and skeletal muscle cells, p-cells must be able to produce, store, and secrete insulin in sufficient concentrations to maintain normal levels of glucose in the blood, i.e., euglycemia.
  • euglycemia is governed by the balance between peripheral insulin sensitivity, which is how readily body cells in the periphery tissue can absorb glucose, and insulin secretion: when insulin sensitivity is reduced, insulin secretion is increased. Since p-cells are very sensitive to blood glucose concentrations, changes in the body’s ability to maintain equilibrium in blood glucose concentration greatly influences p-cell function.
  • Insulin resistance and p-cell dysfunction have important roles in the pathogenesis and evolution of diabetes.
  • Insulin resistance often present years before diabetes is diagnosed, reflects a diminished response to insulin in key target tissues, such as muscle, liver and adipose tissue, and has been shown to predict the development of the disease, p-cell function is already reduced in subjects with impaired glucose tolerance (e.g., prediabetic patients) and is even more reduced in subjects with type 2 diabetes mellitus (T2DM), often referred to simply as type 2 diabetes.
  • impaired glucose tolerance e.g., prediabetic patients
  • T2DM type 2 diabetes mellitus
  • antidiabetic medication is widespread.
  • Available pharmaceutical therapies for treating diabetes have been developed as “symptomatic” medications since they primarily act to reduce elevated blood glucose levels.
  • monotherapy with antidiabetic medications e.g., metformin, rosiglitazone, and glyburide
  • monotherapy with antidiabetic medications fails over time, albeit with differences in the rates of decline.
  • current therapies do not completely abolish the progressive loss of p-cell function, and their use is also associated with hypoglycemia and weight gain.
  • treatment should also stop p-cell dysfunction and promote the restoration of fully functional P-cell mass, independently of reducing hyperglycemia. Management of T2DM should ideally involve early and simultaneous treatment of insulin resistance and p-cell dysfunction.
  • methods of improving insulin production and methods for restoring and/or preserving p-cell mass and/or p-cell functional mass are desirable, particularly for patients suffering from metabolic syndrome, prediabetes, and diabetes. It is also desirable to provide methods of improving insulin production, restoring p-cell mass and/or functional p-cell mass, and/or preserving p-cell mass and/or functional p-cell mass in order to help delay progression of, prevent, or reverse diabetes.
  • a nutritional intervention that can help address the above limitations associated with existing diabetes treatments is also desirable.
  • the invention is directed to a method of improving insulin production in a subject suffering from impaired p-cell function, comprising administering an exosome- enriched product comprising intact bovine milk-derived exosomes to the subject.
  • the present invention is directed to a method of restoring and/or preserving p-cell mass in a subject suffering from impaired insulin production, comprising administering an exosome-enriched product comprising intact bovine milk-derived exosomes to the subject.
  • the present invention is directed to a method of delaying diabetes progression in a subject suffering from impaired insulin production, comprising administering an exosome-enriched product comprising intact bovine milk-derived exosomes to the subject.
  • the methods of improving insulin production, restoring and/or preserving p-cell mass, and delaying diabetes progression are advantageous in that they may contribute to improved regulation of blood glucose concentration, reduced p-cell deterioration and/or improved p-cell functionality.
  • the methods of the invention can thus help delay or prevent the onset of diabetes, delay or prevent diabetes progression, provide treatment, and/or promote remission.
  • FIG. 1 illustrates p-cell proliferation and viability in INS-1 cells incubated with palmitate for 24 hours and 48 hours in the presence, or absence of, respectively, (1) an exosome-enriched product comprising intact bovine milk-derived exosomes, and (2) an exosome-enriched product comprising sonicated bovine milk-derived exosomes, as described in Example 2.
  • FIG. 2 illustrates the acute response of insulin secretion to extracellular glucose concentration in INS-1 cells incubated for 2 hours with, or in the absence of, respectively, (1) an exosome-enriched product comprising intact bovine milk-derived exosomes, and (2) an exosome- enriched product comprising sonicated bovine milk-derived exosomes, as described in Example
  • FIG. 3 illustrates the effects on insulin production of INS-1 cells incubated for 24 hours with, or in the absence of, respectively, (1) an exosome-enriched product comprising intact bovine milk-derived exosomes, and (2) an exosome-enriched product comprising sonicated bovine milk- derived exosomes, followed by 2 hours of incubation with 10 mM glucose, as described in Example 3.
  • FIG. 4 illustrates the effects on insulin secretion and insulin production of INS-1 cells incubated for 24 hours with, or in the absence of, respectively, (1) an exosome-enriched product comprising intact bovine milk-derived exosomes, and (2) an exosome-enriched product comprising sonicated bovine milk-derived exosomes, and subsequently lysed, as described in Example 3.
  • compositions described in the present disclosure can comprise, consist of, or consist essentially of any of the elements and steps as described herein.
  • T2DM is a chronic condition that affects the way the body metabolizes sugar. In patients with T2DM, the body either resists the effects of insulin, resulting in reduced glucose uptake by cells, or does not produce enough insulin to maintain normal glucose levels. T2DM often starts as insulin resistance, meaning that the body is not capable of using insulin efficiently.
  • Gestational diabetes occurs only during pregnancy and is a result of insulin-blocking hormones that are produced during pregnancy. Patients diagnosed with gestational diabetes are at a higher risk of developing diabetes after pregnancy.
  • prediabetes refers to a condition wherein a patient has a higher than normal blood sugar level, but this higher blood sugar level is not yet high enough to be considered diabetes. More specifically, patients suffering from prediabetes typically have impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A prediabetic patient will normally have a fasting blood glucose level of 100 to 125 mg/dL, a blood glucose level of 140-199 mg/dL following a glucose tolerance test, and an HbA1c value of 5.7-6.4%. A prediabetic patient is considered to be at an elevated risk for developing diabetes.
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • the methods of the present invention employ an exosome-enriched product comprising intact bovine milk-derived exosomes.
  • an exosome-enriched product comprising intact bovine milk-derived exosomes increases insulin production, restores and/or preserves - cell mass and/or p-cell functional mass, and can be used to delay diabetes progression.
  • Bovine milk contains exosomes which are extracellular membrane vesicles of approximately 20-200 nm in diameter. These nanosized structures contain several bioactive agents, including, but not limited to, enzymatic and non-enzymatic proteins (e.g., CD9, CD63, MHC-class II, lactadherin, TSG101 and Hsc70), nucleic acids (including high amounts of microRNA (miRNA) and messenger RNA (mRNA)) and lipids (e.g., phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine and sphingomyelin).
  • enzymatic and non-enzymatic proteins e.g., CD9, CD63, MHC-class II, lactadherin, TSG101 and Hsc70
  • nucleic acids including high amounts of microRNA (miRNA) and messenger RNA (mRNA)
  • lipids e.g., phosphatidylethanolamine
  • bovine milk exosomes can be isolated from the milk whey fraction or from other dairy streams, such as a cheese whey fraction.
  • Procedures for the isolation of bovine milk exosomes include physical methods (e.g., ultracentrifugation at increasing speeds, membrane ultrafiltration or size exclusion chromatography) and chemical methods (e.g., the use of polymers to precipitate bovine milk exosomes by an incubation step). Remarkably, most of these procedures tend to co-purify exosomes and other dairy constituents (i.e., caseins and other whey proteins).
  • the isolation methods yield a fraction enriched in bovine milk exosomes that may undergo further processing to produce a powder suitable for its end use application.
  • exosome-enriched product comprising intact bovine milk-derived exosomes refers to a product in which intact exosomes have been substantially separated from other bovine milk components such as lipids, cells, and debris, and are concentrated in an amount higher than that found in bovine milk. Exosomes are small, extracellular vesicles and account for a minor percentage of milk’s total content.
  • the exosome-enriched product is provided in a liquid form or a powdered form and also contains co-isolated milk solids.
  • intact exosomes refers to exosomes in which the vesicle membrane is not ruptured and/or otherwise degraded and the endogenous cargo, i.e. , the bioactive agents, therapeutics (e.g. miRNA), and/or other biomolecules which are inherently present in a bovine milk-derived exosome, are retained therein in active form.
  • the endogenous cargo i.e. , the bioactive agents, therapeutics (e.g. miRNA), and/or other biomolecules which are inherently present in a bovine milk-derived exosome, are retained therein in active form.
  • P-cell dysfunction refers to an impaired ability of the pancreatic p-cells to produce and/or secrete insulin.
  • diabetes progression refers to the gradual worsening of p-cell function and/or p-cell mass. Diabetes progression may be categorized into stages, with each stage being defined by various physiological changes within the body, e.g., changes in p-cell mass, phenotype, and function.
  • stage 1 is normally defined as insulin resistance.
  • the pancreatic p-cells are able to compensate for insulin resistance by producing more insulin, thereby maintaining normal blood sugar levels.
  • stage 2 which is often referred to as prediabetes, insulin resistance increases and the production of extra insulin is not enough to maintain euglycemia.
  • fasting blood glucose levels reach around 100 to 125 mg/dL
  • blood glucose levels are around 140-199 mg/dL following a glucose tolerance test
  • HbA1c values are between 5.7-6.4%.
  • stage 3 a patient is diagnosed as diabetic, and will exhibit increased insulin resistance and/or further reduced p-cell mass and/or further impaired p-cell functional mass.
  • Blood sugar levels are abnormally high, i.e. , fasting blood sugar levels are above 126 mg/dL and blood sugar levels are above 200 mg/dL following a glucose tolerance test.
  • HbA1c values are typically 6.5% or higher.
  • Stage 4 normally coincides with “end-stage diabetes” and is linked to a number of diabetic complications, including albuminuria, chronic kidney disease, coronary artery disease, heart failure, peripheral neuropathy, and/or stroke. Fortunately, it is possible for some patients suffering from T2DM to improve their condition through appropriate medication and lifestyle modifications, including improved diet and exercise.
  • P-cell functional mass refers to the amount of pancreatic p-cells which are able to produce and/or secrete appropriate amounts of insulin. An assessment of p-cell functional mass is essential for the diagnosis and staging of diabetes.
  • P-cell mass refers to the number of existing pancreatic p-cells. p-cell mass is determined as the sum of replication, neogenesis and hypertrophy minus the rate of apoptosis.
  • insulin production refers to the process wherein insulin is synthesized by pancreatic p-cells. Insulin is responsible for regulating the level of glucose in the blood. Insulin production involves the biologically inactive precursor, preproinsulin, being cleaved by signal peptidase to form proinsulin. Proinsulin is then converted to insulin by removal of C-peptide by a specialized set of endoproteases and a carboxypeptidase activity. Preproinsulin, proinsulin, and insulin are synthesized in the p-cells of the pancreas.
  • insulin secretion refers to the process wherein insulin is released by pancreatic p-cells. Insulin secretion is primarily regulated by the glucose level in the extracellular fluid surrounding the p-cells, although insulin secretion is also stimulated by, inter alia, growth hormone, cortisol, prolactin, melatonin, estrogen, leptin, and glucagon.
  • a method of improving insulin production in a subject suffering from impaired p-cell function comprises administering an exosome- enriched product comprising intact bovine milk-derived exosomes to the subject.
  • a method of restoring and/or preserving p-cell mass in a subject suffering from impaired insulin production is provided.
  • the method comprises administering an exosome-enriched product comprising intact bovine milk-derived exosomes to the subject.
  • a method of delaying diabetes progression in a subject suffering from impaired insulin production is provided.
  • the method comprises administering an exosome-enriched product comprising intact bovine milk-derived exosomes to the subject.
  • the subject is suffering from diabetes.
  • the subject is suffering from metabolic syndrome or prediabetes.
  • metabolic syndrome refers to a combination of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. This grouping of conditions increase the risk of heart disease, stroke and T2DM.
  • NEP National Cholesterol Education Program
  • metabolic syndrome is present if three or more of the following five criteria are met: waist circumference over 40 inches (men) or 35 inches (women), blood pressure over 130/85 mmHg, fasting triglyceride (TG) level over 150 mg/dl, fasting high-density lipoprotein (HDL) cholesterol level less than 40 mg/dl (men) or 50 mg/dl (women), and fasting blood sugar over 100 mg/dl.
  • TG triglyceride
  • HDL high-density lipoprotein
  • the exosome-enriched product comprises at least about 0.001 wt % exosomes. In other specific embodiments, the exosome-enriched product comprises at least about 0.01 wt %, 1 wt %, 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, or 50 wt % exosomes. In additional specific embodiments of the invention, the exosome-enriched product comprising intact bovine milk-derived exosomes comprises at least 10 wt % exosomes.
  • the exosome-enriched product comprises at least about 10 8 exosomes per gram of the exosome- enriched product as measured by a nanotracking procedure.
  • nanoparticle tracking analysis can be used to determine exosome diameter and concentration. The principle of NTA is based on the characteristic movement of nanosized particles in solution according to the Brownian motion. The trajectory of the particles in a defined volume is recorded by a camera that is used to capture the scatter light upon illumination of the particles with a laser. The Stokes-Einstein equation is used to determine the size of each tracked particle. In addition to particle size, this technique also allows determination of particle concentration.
  • the exosome-enriched product comprises from about 10 8 to about 10 14 exosomes per gram of the exosome-enriched product. In yet a more specific embodiment, the exosome-enriched product comprises from about 10 9 to about 10 13 exosomes per gram of the exosome-enriched product. In another specific embodiment, the exosome- enriched product contains at least about a three-fold increase in the number of exosomes, as compared to a raw whey-containing bovine milk fraction. In a more specific embodiment, the exosome-enriched product contains a 3-fold to 50-fold increase in the number of exosomes, as compared to a raw whey-containing bovine milk fraction, for example cheese whey.
  • At least about 50 wt % of the exosomes in the exosome-enriched product are intact. In further specific embodiments of the invention, at least about 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt % of the exosomes in the exosome-enriched product are intact.
  • the intact bovine milk-derived exosomes are sourced from a whey-containing bovine milk fraction.
  • the whey-containing bovine milk fraction is cheese whey.
  • the exosomes are obtained from a whey-containing bovine milk fraction using gentle procedures which do not disrupt the exosome vesicle membrane, thereby leaving the exosomes intact and active bioactive agents contained within the exosome structure.
  • Various methods may be employed to isolate exosomes with care being exercised to avoid disruption of the lipid membrane.
  • Fresh bovine milk, refrigerated bovine milk, thawed frozen bovine milk, or otherwise preserved bovine milk, or any bovine milk fraction containing exosomes, for example, cheese whey, may be employed as a source of exosomes.
  • Isolating the exosomes may comprise performing the isolation immediately upon obtaining milk from a bovine.
  • isolating the exosomes may comprise performing the isolation within about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days or about 6 days, or about 7 days from the time of obtaining the milk from a bovine.
  • the exosomes may be isolated within about 10 days, or within about 14 days from the time of obtaining milk from a bovine. Additionally, the bovine milk may be frozen and then thawed for processing for isolating exosomes, with the bovine milk preferably having been frozen within about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days or about 6 days, or about 7 days from the time of obtaining the milk from a bovine. Thawed milk is preferably processed immediately upon thawing.
  • the fresh bovine milk may be subjected to the processing within about 5 days of obtaining the milk from a bovine, or thawed bovine milk which is subjected to processing is thawed from bovine milk that was frozen within about 5 days of obtaining the milk from a bovine.
  • a whey-containing bovine milk fraction or, specifically, cheese whey may serve as a source of exosomes.
  • Cheese whey is the liquid by-product of milk after the formation of curd during the cheese-making or casein manufacturing process. Since cheese whey has already been separated from the casein fraction during the cheese manufacture process, cheese whey has very low casein content. Furthermore, cheese whey advantageously retains more than 50% of milk nutrients, including lactose, fat, proteins, mineral salts, and, surprisingly, a significant number of exosomes that were originally present in the milk in intact form.
  • cheese whey is less expensive than raw milk, and thus using cheese whey as a starting material significantly reduces costs for production of an exosome- enriched product.
  • cheese whey is a novel and promising source for isolating milk exosomes and producing exosome-enriched products.
  • the cheese whey is obtained by applying an enzyme or enzyme mixture, and more specifically a protease enzyme, for example chymosin, to milk to hydrolyze casein peptide bonds, thus allowing for enzymatic coagulation of casein in the milk.
  • a protease enzyme for example chymosin
  • the protease enzyme cleaves the protein, it causes the casein in the milk to coagulate and form a gel structure.
  • the casein protein gel network and milk fat then contract together and form curd.
  • the resulting liquid that is separated from the curd is often referred to as sweet whey or cheese whey, typically has a pH from about 6.0 to about 6.5, and comprises whey proteins, lactose, minerals, water, fat and other low level components.
  • the enzyme or enzyme mixture is capable of destabilizing the casein protein in the milk fraction by cleaving peptides which stabilize the casein protein in the milk. Therefore, any proteolytic enzyme suitable for this purpose may be used to obtain cheese whey.
  • the cheese whey is provided by adding rennet enzyme to bovine milk, resulting in enzymatic coagulation of casein.
  • Rennet enzyme is commonly used in the cheese making process and comprises a set of enzymes which are produced in the stomachs of ruminant mammals. These enzymes normally include chymosin, pepsin, and lipase.
  • the rennet enzyme mix destabilizes the casein protein in the bovine milk fraction by proteolytically cleaving peptides which stabilize the protein in the milk.
  • the casein in the milk coagulates and contracts with milk fat to form the cheese curd.
  • the remaining liquid i.e., the sweet cheese whey, comprises whey proteins, lactose, minerals, water, fat, and other low level components.
  • a gentle procedure of obtaining an exosome-enriched product containing intact bovine milk-derived exosomes may comprise physical methods and/or chemical methods.
  • an exosome-enriched product is obtained by cascade membrane filtration.
  • the exosome-enriched product is lactose-free.
  • sweet cheese whey which may be obtained as described in the preceding paragraph, is processed using tandem multiple ceramic filtration steps.
  • a multiple filtration process employs, successively, membranes with cut offs which gradually decrease in size.
  • the method of processing sweet cheese whey is subjected to microfiltration (MF), ultrafiltration (UF) and diafiltration (DF).
  • the process employs, successively, MF, UF and DF membranes with cut offs of about 1.4 pm, 0.14 pm and 10 kDa, respectively, to provide an exosome-enriched product.
  • a first MF step employs a first membrane with a molecular weight cut off of, for example, about 1.4 pm and yields a first retentate R1 and a first permeate P1.
  • the first permeate P1 is then subjected to a an UF step employing a second membrane with a molecular weight cut off of, for example, about 0.14 pm, which yields a second retentate R2 and second permeate P2.
  • the second retentate R2 may be re-suspended in water and again passed through the second membrane to remove additional lactose, minerals and the like, if desired. For example, in one embodiment, about 5 volumes of water may be added to one volume of the second retentate R2 and the resulting suspension is then passed through the 0.14 pm MF membrane. The resulting third retentate R3 is then subjected to a DF step using a 10 kDa membrane.
  • the third retentate is first diluted with an approximately equal volume of water and diafiltered to obtain a fourth retentate R4, and then the fourth retentate R4 is again diluted with water, for example with a volume of water five times that of the fourth retentate R4 and then diafiltered to yield a concentrated retentate R5.
  • This exosome- enriched product may be used in the form of the concentrated retentate R5, or the concentrated retentate R5 may be further processed.
  • the exosome-enriched product resulting from successive filtration steps may be pasteurized to provide storage stability.
  • the exosome- enriched product may be heated, for example, at about 70°C for about 15 seconds, to ensure microbiological stability in order to yield a pasteurized fraction, R6.
  • Other pasteurization conditions will be apparent to those skilled in the art and may be employed.
  • the exosome-enriched product may be used as is or subjected to additional processing steps to provide a desired physical form.
  • the exosome-enriched product optionally pasteurized, may be converted to a powder form.
  • the exosome-enriched product can be spray-dried, freeze dried, or otherwise converted to powder form.
  • the exosome-enriched product may be spray dried, for example, at 185°C/85°C, to obtain an exosome-enriched product in the form of a spray-dried powder (SP).
  • SP spray-dried powder
  • the exosome-enriched product Prior to spray drying, the exosome-enriched product may be subjected to an optional evaporation step to increase the solids content of the product and therefore reduce the time and/or energy demand for the spray drying process.
  • an optional evaporation step to increase the solids content of the product and therefore reduce the time and/or energy demand for the spray drying process.
  • Other spray drying conditions will be apparent to those skilled in the art and may be employed.
  • the exosome-enriched product may be freeze-dried, for example at -50°C and 0.5 mbar vacuum to obtain an exosome-enriched freeze-dried powder (FP).
  • FP exosome-enriched freeze-dried powder
  • Other freeze drying conditions will be apparent to those skilled in the art and may be employed.
  • the exosome-enriched product is administered in the form of an exosome-enriched powder.
  • the exosome-enriched product is administered in the form of an exosome- enriched liquid.
  • the exosome enriched product can be administered to the subject in either form.
  • the exosome-enriched product is an exosome-enriched powder comprising spray-dried intact exosomes.
  • the exosome-enriched product comprising intact bovine milk-derived exosomes is administered to the subject orally.
  • the exosome-enriched product comprising intact bovine milk- derived exosomes is provided in a nutritional composition, which can be administered to the subject orally.
  • the nutritional composition is in the form of a powder.
  • the nutritional composition is in the form of a liquid.
  • the nutritional compositions comprise water, and in more specific embodiments, comprise emulsions.
  • nutritional powder refers to nutritional powders that are generally flowable particulates and that are reconstitutable with an aqueous liquid, and which are suitable for oral administration to a human.
  • the methods described herein employ amounts of an exosome-enriched product comprising intact bovine milk-derived exosomes that are effective to improve insulin production, restore and/or preserve p-cell mass and/or p-cell functional mass, and/or delay diabetes progression.
  • the subject is administered a dose of about 0.01 to about 50 g, about 0.5 to about 40 g, about 1 to about 40 g, about 1 to about 30 g, about 1 to about 20 g, about 1 to about 10 g, or about 1 to about 5 g of the exosome-enriched product comprising intact bovine milk-derived exosomes per day.
  • the nutritional composition comprises about 0.001 to about 30 wt %, about 0.01 to about 30 wt %, about 0.01 to about 20 wt %, about 0.01 to about 10 wt %, about 0.01 to about 5 wt %, about 0.1 to about 30 wt %, about 0.1 to about 20 wt %, about 0.1 to about 10 wt %, about 0.1 to about 5 wt %, about 1 to about 30 wt %, about 1 to about 20 wt %, about 1 to about 10 wt %, or about 1 to about 5 wt % of the exosome-enriched product comprising intact bovine milk-derived exosomes, based on the weight of the nutritional composition.
  • the nutritional composition comprises about 0.01 to about 10 wt % of the exosome-enriched product comprising intact bovine milk-derived exosomes, based on the weight of the nutritional composition.
  • the nutritional composition further comprises protein, carbohydrate, and/or fat, in any amounts as desired.
  • protein, carbohydrate, and/or fat can be used in embodiments of nutritional compositions described herein.
  • the nutritional composition includes protein, carbohydrate and fat.
  • the protein in the nutritional composition comprises whey protein concentrate, whey protein isolate, whey protein hydrolysate, milk protein concentrate, milk protein isolate, milk protein hydrolysate, organic milk protein concentrate, soy protein concentrate, soy protein isolate, soy protein hydrolysate, pea protein concentrate, pea protein isolate, pea protein hydrolysate, acid casein, sodium caseinate, calcium caseinate, potassium caseinate, casein hydrolysate, nonfat dry milk, condensed skim milk, collagen protein, collagen protein isolate, L-Carnitine, taurine, lutein, rice protein concentrate, rice protein isolate, rice protein hydrolysate, fava bean protein concentrate, fava bean protein isolate, fava bean protein hydrolysate, meat protein, potato protein, chickpea protein, canola protein, mung protein, quinoa protein, amaranth protein, chia protein, hemp protein, flax seed protein, earthworm protein, insect protein, or combinations of two or more thereof.
  • the nutritional composition may comprise protein in an amount of about 0.01 wt % to about 90 wt % of the nutritional composition. More specifically, the protein may be present in an amount of about 1 wt% to about 80 wt %, including about 1 wt% to about 70 wt%, about 1 wt% to about 60 wt%, about 1 wt% to about 50 wt%, about 1 wt% to about 40 wt %, about 1 wt% to about 30 wt %, about 1 wt% to about 25 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 4 wt % to about 80 wt %, about 4 wt % to about 70 wt %, about 4 wt % to about 60 wt
  • the nutritional composition is a powder and the protein comprises about 10 wt % to about 90 wt %, about 10 wt % to about 70 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 30 wt %, about 20 wt % to about 80 wt %, about 30 wt % to about 80 wt %, about 40 wt % to about 80 wt %, about 50 wt % to about 80 wt % or about 60 wt % to about 75 wt %, of the nutritional composition.
  • the nutritional composition is a liquid and the protein comprises about 0.01 wt % to about 15 wt %, about 1 wt % to about 10 wt %, or about 2 wt % to about 6 wt %, of the nutritional composition.
  • the carbohydrate in the nutritional composition comprises fiber, human milk oligosaccharides (HMOs), maltodextrin, corn maltodextrin, corn syrup, organic corn starch, corn syrup, corn syrup solids, soluble corn fiber, sucralose, cellulose gel, cellulose gum, gellan gum, carrageenan, fructooligosaccharides (FOS), inositol, hydrolyzed starch, glucose polymers, rice-derived carbohydrates, sucrose, glucose, glycerin, lactose, honey, sugar alcohols, isomaltulose, sucromalt, pullulan, potato starch, galactooligosaccharides, oat fiber, soy fiber, corn fiber, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arab
  • HMOs human milk oli
  • the carbohydrate in the nutritional composition comprises a combination of two or more carbohydrates, wherein the carbohydrates have varying rates of absorption.
  • the carbohydrate that may be used in the nutritional composition of the invention comprises isomaltulose, sucromalt, resistant maltodextrin (e.g., Fibersol or Nutriose), FOS, inulin, oat fiber, soy fiber, or a combination of two or more thereof.
  • the nutritional composition may comprise carbohydrate in an amount of about 0.01 wt % to about 75 wt %, including about 0.01 wt % to about 60 wt %, about 0.01 wt % to about 50 wt %, about 0.01 wt % to about 40 wt %, about 0.01 to about 30 wt %, about 0.01 to about 20 wt %, about 0.01 to about 10 wt %, about 1 wt % to about 70 wt %, about 5 wt % to about 70 wt %, about 5 wt % to about 65 wt %, about 5 wt % to about 50 wt %, about 5 wt % to about 40 wt %, about 5 wt % to about 30 wt %, about 5 wt % to about 25 wt %, about 10 wt % to about 65 wt %, about
  • the carbohydrate may be present in an amount about 1 wt % to about 10 wt % of the nutritional composition, including about 1 wt % to about 9 wt %, about 1 wt % to about 8 wt %, about 1 wt % to about 7 wt %, about 1 wt % to about 6 wt %, about 2 wt % to about 10 wt %, about 2 wt % to about 9 wt %, about 2 wt % to about 8 wt %, about 2 wt % to about 7 wt %, or about 2 wt % to about 6 wt %, of the nutritional composition.
  • the nutritional composition is a powder and the carbohydrate comprises about 0.01 wt % to about 15 wt %, about 1 wt % to about 12 wt %, or about 8 wt % to about 10 wt %, of the nutritional composition.
  • the nutritional composition is a liquid and the carbohydrate comprises about 0.01 wt % to about 10 wt %, about 2 wt % to about 8 wt %, or about 4 wt % to about 7 wt %, of the nutritional composition.
  • the fat comprises coconut oil, fractionated coconut oil, soy oil, soy lecithin, corn oil, safflower oil sunflower oil, palm olein, canola oil monoglycerides, lecithin, canola oil, medium chain triglycerides, one or more fatty acids such as linoleic acid, alpha-linolenic acid, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, medium chain triglyceride oil (MCT oil), high gamma linolenic (GLA) safflower oil, palm oil, palm kernel oil, marine oil, fish oil, algal oil, borage oil, cottonseed oil, fungal oil, interesterified oil, transesterified oil, structured lipids, omega-3 fatty acid, or combinations of two or more thereof.
  • fatty acids such as linoleic acid, alpha-linolenic acid, fractionated coconut oil, soy oil, corn oil, olive oil,
  • the omega-3 fatty acid is selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid, and alpha-linolenic acid, and combinations of two or more thereof.
  • fat and oil as used herein, unless otherwise specified, are used interchangeably to refer to lipid materials derived or processed from plants or animals. These terms also include synthetic lipid materials so long as such synthetic materials are suitable for oral administration to humans.
  • the nutritional composition may comprise fat in an amount of about 0.01 wt % to about 30 wt % of the nutritional composition. More specifically, the fat may be present in an amount of about 1 wt % to about 30 wt%, including about 1 wt% to about 20 wt%, about 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 1 wt % to about 9 wt %, about 1 wt % to about 8 wt %, about 1 wt % to about 7 wt %, about 1 wt % to about 6 wt %, about 1 wt% to about 5 wt%, , about 2 wt % to about 10 wt %, about 2 wt % to about 9 wt %, about 2 wt % to about 8 wt %, about 2 wt % to about 7 wt %, about
  • the nutritional composition is a powder and the fat comprises about 0.01 wt % to about 15 wt %, about 1 wt % to about 10 wt %, about 1 wt % to about 5 wt %, or about 6 wt % to about 8.5 wt %, of the nutritional composition.
  • the nutritional composition is a liquid and the fat comprises about 0.01 wt % to about 10 wt %, about 1 wt % to about 5 wt %, or about 2 wt % to about 4 wt %, of the nutritional composition.
  • concentration and relative amounts of the sources of protein, carbohydrate, and fat in the exemplary nutritional compositions can vary considerably depending upon, for example, the specific dietary needs of the intended user.
  • the nutritional composition is a nutritional liquid composition and comprises about 0.01 to about 15 wt % of protein, about 0.01 to about 10 wt % fat, and about 0.01 to about 10 wt % carbohydrate, based on the weight of the nutritional composition.
  • the nutritional composition is a nutritional powder composition and comprises about 10 to about 90 wt % of protein, about 0.01 to about 15 wt % fat, and about 0.01 wt % to about 15 wt % carbohydrate, based on the weight of the nutritional composition.
  • the nutritional composition comprises at least one protein comprising milk protein concentrate and/or soy protein isolate, at least one fat comprising canola oil, corn oil, coconut oil and/or marine oil, and at least one carbohydrate comprising maltodextrin, digestion resistant maltodextrin, sucrose, and/or short-chain fructooligosaccharide.
  • the nutritional composition may also comprise one or more components to modify the physical, chemical, aesthetic, or processing characteristics of the nutritional composition or serve as additional nutritional components.
  • additional components include preservatives, emulsifying agents (e.g., lecithin), buffers, sweeteners including artificial sweeteners (e.g., saccharine, aspartame, acesulfame K, sucralose), colorants, flavorants, thickening agents, stabilizers, and so forth.
  • the nutritional composition has a neutral pH, i.e. , a pH of about 6 to 8 or, more specifically, about 6 to 7.5.
  • the nutritional composition has a pH of about 6.5 to 7.2 or, more specifically, about 6.8 to 7.1.
  • the nutritional composition may be formed using any techniques known in the art.
  • the nutritional composition may be formed by (a) preparing an aqueous solution comprising protein and carbohydrate; (b) preparing an oil blend comprising fat and oilsoluble components; and (c) mixing together the aqueous solution and the oil blend to form an emulsified liquid nutritional composition.
  • the exosome-enriched product can be added at any point in the formation of the nutritional composition.
  • the nutritional composition can be administered in the form of a powder or in the form of a liquid.
  • a serving size is about 10 g to about 70 g, about 20 g to about 45 g, or about 45 g to about 70 g, to be administered as a powder or to be reconstituted in about 1 mL to about 500 mL of liquid. In a specific embodiment, a serving size is about 31 g to be reconstituted in about 237 mL of liquid.
  • a serving ranges about 1 mL to about 500 mL, including about 230 mL to about 475 mL, about 230 mL to about 350 mL, about 230 mL to about 300 mL, about 290 mL to about 475 mL, about 290 mL to about 350 mL, about 290 mL to about 300 mL, about 300 mL to about 475 mL, about 300 mL to about 350 mL, and about 330 mL to about 475 mL.
  • the serving is about 237 mL, or about 296 mL, or about 330 mL, or about 473 mL.
  • the nutritional composition comprising an exosome-enriched product comprising intact bovine milk-derived exosomes is administered to a subject once or multiple times daily or weekly.
  • the nutritional composition is administered to the subject about 1 to about 6 times per day or per week, or about 1 to about 5 times per day or per week, or about 1 to about 4 times per day or per week, or about 1 to about 3 times per day or per week.
  • the nutritional composition is administered once or twice daily for a period of at least one week, at least two weeks, at least three weeks, or at least four weeks.
  • the nutritional composition comprises protein, carbohydrate, fat, and one or more nutrients selected from the group consisting of vitamins and minerals.
  • Specific embodiments of the nutritional composition may comprise vitamins and/or related nutrients, non-limiting examples of which include vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, niacin, folic acid, pantothenic acid, biotin, choline, inositol, and/or salts and derivatives thereof, and combinations thereof.
  • Specific embodiments of the nutritional composition comprise minerals, non-limiting examples of which include calcium, phosphorus, magnesium, zinc, manganese, sodium, potassium, molybdenum, chromium, iron, copper, iodine, selenium, chloride, and combinations thereof.
  • Example 1 Preparation and Characterization of Exosome-enriched Products
  • This example describes a method of preparing an exosome-enriched product from cheese whey.
  • the cheese whey was provided by adding rennet enzyme to bovine milk, resulting in enzymatic coagulation of casein and production of sweet cheese whey, as described above.
  • An exosome-enriched product containing from about 10 8 to about 10 14 intact bovine milk- derived exosomes per gram of the exosome-enriched product was prepared by cascade membrane filtration.
  • 1 ,000 L of sweet cheese whey was processed using tandem multiple ceramic filtration steps.
  • the first microfiltration MF step employed a membrane with a molecular weight cut off of 1.4 pm, which yielded a first retentate R1 and a first permeate P1.
  • the first permeate P1 was then subjected to a ultrafiltration step UF with a molecular weight cut off of 0.14 pm, which yielded a second retentate R2 and second permeate P2.
  • UF ultrafiltration step
  • About 5 volumes of water was added to one volume of the second retentate R2, and the diluted retentate was then passed through the 0.14 pm UF membrane again to remove at least part of the lactose and minerals.
  • the resulting retentate R3 was then combined with an equal volume of water and diafiltered using a 10 kDa membrane to produce a fourth retentate R4.
  • the retentate R4 was diluted with a volume of water five times that of the fourth retentate R4 and diafiltered a second time using the 10 kDa membrane to yield a concentrated retentate, R5.
  • the lactose-free exosome-enriched product R5 was pasteurized at 70°C for 15 seconds to ensure microbiological stability in order to yield a pasteurized exosome-enriched product R6.
  • the pasteurized exosome-enriched product R6 was subjected to evaporation at about 65°C to increase the solids content up to 17-18% and then spray-dried at 185°C/85°C to obtain a exosome-enriched spray-dried product, SP.
  • Example 2 MTT Assay for p-cell Proliferation and Viability
  • This example demonstrates that a spray-dried exosome-enriched product comprising intact bovine milk-derived exosomes (SDEx) increased p-cell proliferation of pancreatic p-cells subjected to prolonged exposure (24 hours and 48 hours) of palmitate, as compared to an exosome-enriched product comprising sonicated bovine milk-derived exosomes (SDEx-S), and as compared to the absence of an exosome-enriched product comprising bovine milk-derived exosomes (C). This was shown by evaluating p-cell proliferation through MTT assay of the rat INS-1 cell line (clone 832/13).
  • MTT assay is a colorimetric method which measures the reduction of a yellow tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) to formazan, an insoluble crystalline product with a deep purple color. Only metabolically active cells are able to convert MTT to formazan. The resulting intracellular purple formazan can be solubilized and quantified by spectrophotometric means. Absorbance values greater than the control indicate cell proliferation and increased viability, while lower values suggest cell death or inhibition of proliferation.
  • MTT yellow tetrazolium salt
  • the rat INS-1 cell line is a cell line capable of insulin release in response to glucose stimulation and is therefore used as a p-cell model for diabetes research.
  • the cells were maintained in RPMI 1640 medium with 11.1 mmol/L D-glucose supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 pg/mL streptomycin, 10 mmol/L HEPES, 2mmol/L glutamine, 1 mmol/L sodium pyruvate, and 50 pmol/L p-mercaptoethanol at 37°C/5% CO2 in a humidified atmosphere.
  • pancreatic cells Pre-confluent pancreatic cells were employed.
  • the cells were treated with palmitate at a concentration of 250 pM for 24 hours in complete medium in order to induce pancreatic p-cell lipotoxicity.
  • Lipotoxicity which is defined as the accumulation of excess lipids in non-adipose tissues, has roles in both insulin resistance and pancreatic beta cell dysfunction.
  • Saturated fatty acids, such as palmitate are known to promote insulin resistance in peripheral tissues and prolonged exposure to palmitate induces changes in p-cell protein lysine acetylation, thereby resulting in p-cell damage.
  • the cells were not treated with palmitate.
  • the MTT solution (0.5 mg/mL) was added for 30 minutes. The supernatant was removed, 100 pl MTT solvent was added to each well, and the culture plate was shaken for 10 minutes before the optical density (OD) values were recorded at 570 nm.
  • a two-way ANOVA test was used to analyze the statistical significance between groups, with (*) representing palmitate treated cells vs untreated cells (p ⁇ 0.05), (&) representing untreated cells vs an exosome-enriched product comprising intact bovine milk-derived exosomes (p ⁇ 0.05), and (#) representing palmitate treated cells vs an exosome-enriched product comprising intact bovine milk-derived exosomes (p ⁇ 0.05).
  • non-palmitate treated INS-1 cells incubated with the exosome- enriched product comprising intact bovine milk-derived exosomes increased p-cell proliferation at 24 and 48 hours by almost 31% and 30%, respectively, as compared to non-palmitate treated Control.
  • Palmitate-treated INS-1 cells incubated with the exosome-enriched product comprising intact bovine milk-derived exosomes increased p-cell proliferation at 24 and 48 hours by almost 42% and 140%, respectively, as compared to palmitate-treated Control.
  • non-palmitate treated INS-1 cells incubated with the exosome-enriched product comprising intact bovine milk-derived exosomes increased p-cell proliferation at 24 and 48 hours by almost 42% and 33%, respectively, as compared to non-palmitate treated INS-1 cells incubated with the exosome-enriched product comprising sonicated intact bovine milk-derived exosomes.
  • Palmitate-treated INS-1 cells incubated with the exosome-enriched product comprising intact bovine milk-derived exosomes increased p-cell proliferation at 24 and 48 hours by almost 35% and 32%, respectively, as compared to palmitate-treated INS-1 cells incubated with the exosome-enriched product comprising sonicated intact bovine milk-derived exosomes.
  • exosome-enriched product comprising intact bovine milk-derived exosomes (SDEx) increased both insulin secretion and insulin production of pancreatic p-cells exposed to extracellular glucose concentration, as compared to an exosome- enriched product comprising sonicated bovine milk-derived exosomes (SDEx-S), or the absence of any exosome-enriched product comprising bovine milk-derived exosomes (C).
  • SDEx-S exosome-enriched product comprising intact bovine milk-derived exosomes
  • C bovine milk-derived exosomes
  • INS-1 cells were maintained in RPMI 1640 medium with 11.1 mmol/L D- glucose supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 pg/mL streptomycin, 10 mmol/L HEPES, 2 mmol/L glutamine, 1 mmol/L sodium pyruvate, and 50 pmol/L P-mercaptoethanol at 37°C/5% CO2 in a humidified atmosphere.
  • the cells were washed twice with 300 pL glucose-free Krebs-Ringer Bicarbonate buffer (KRB) (116 mM NaCI, 1.8 mM CaCl2'2(H2O), 0.8 Mm MgSO 4 '7(H 2 O), 5.4 mM KCI, 1 mM NaH 2 PO4-2(H 2 O), 26 mM NaHCO 3 , and 0.5% BSA, pH 7.4), followed by pre-incubation for 1 hour at 37°C in 200 pL 2 mM glucose KRB.
  • KRB glucose-free Krebs-Ringer Bicarbonate buffer
  • INS-1 cells incubated with an exosome-enriched product comprising intact bovine milk-derived exosomes (20 pg/mL) increased insulin secretion of pancreatic p-cells.
  • the acute response (2 hour incubation) of insulin secretion to extracellular glucose concentration in the presence of an exosome-enriched product comprising intact bovine milk-derived exosomes showed a significant difference (*p ⁇ 0.05 vs untreated cells (C) and #p ⁇ 0.05 vs SDEx-S treated cells).
  • no effects on insulin secretion were observed with the exosome enriched product comprising sonicated bovine milk- derived exosomes.
  • the cells were washed twice with 300 pL glucose-free Krebs-Ringer Bicarbonate buffer (KRB) (116 mM NaCI, 1.8 mM CaCl2'2(H2O), 0.8 Mm MgSO4'7(H2O), 5.4 mM KCI, 1 mM NaH2PO4'2(H2O), 26 mM NaHCO 3 , and 0.5% BSA, pH 7.4), followed by pre-incubation for 1 hour at 37°C in 200 pL 2 mM glucose KRB.
  • KRB glucose-free Krebs-Ringer Bicarbonate buffer
  • INS-1 cells were maintained in RPMI 1640 medium with 11.1 mmol/L D-glucose supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 pg/mL streptomycin, 10 mmol/L HEPES, 2mmol/L glutamine, 1 mmol/L sodium pyruvate, and 50 pmol/L - mercaptoethanol at 37°C/5% CO2 in a humidified atmosphere.
  • an exosome-enriched product comprising intact bovine milk-derived exosomes increases insulin secretion, insulin production, and p-cell proliferation and viability.
  • the increased insulin secretion, insulin production, and p-cell proliferation and viability leads to improved p-cell functionality, which has a significant application in the prevention or treatment of diabetes.

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Abstract

Méthode d'amélioration de la production d'insuline chez un sujet souffrant d'une fonction β-cellulaire altérée, qui comprend l'administration au sujet d'un produit enrichi en exosomes comprenant des exosomes dérivés de lait bovin intacts. Une méthode de restauration et/ou de préservation de la masse de cellules β chez un sujet souffrant d'une diminution de la production d'insuline comprend l'administration d'un produit enrichi en exosomes comprenant des exosomes dérivés de lait bovin intacts. Une méthode permettant de retarder la progression du diabète chez un sujet souffrant d'une diminution de la production d'insuline, comprend l'administration au sujet d'un produit enrichi en exosomes comprenant des exosomes dérivés de lait bovin intacts.
PCT/US2022/047541 2021-10-29 2022-10-24 Méthodes et compositions destinées à améliorer la production et la sécrétion d'insuline WO2023076144A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170296627A1 (en) * 2014-09-05 2017-10-19 Exerkine Corporation Exersomes, methods of producing and method of using
WO2021092209A1 (fr) * 2019-11-08 2021-05-14 Abbott Laboratories Exosomes en poudre isolés à partir de lait de vache, compositions nutritionnelles et procédés
WO2021202824A1 (fr) * 2020-04-03 2021-10-07 Abbott Laboratories Produits à base d'exosomes de lait bovin et procédés, compositions nutritionnelles et procédés thérapeutiques associés
WO2021216420A1 (fr) * 2020-04-20 2021-10-28 Abbott Laboratories Méthodes de diminution de l'atrophie musculaire et/ou de promotion de la régénération musculaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170296627A1 (en) * 2014-09-05 2017-10-19 Exerkine Corporation Exersomes, methods of producing and method of using
WO2021092209A1 (fr) * 2019-11-08 2021-05-14 Abbott Laboratories Exosomes en poudre isolés à partir de lait de vache, compositions nutritionnelles et procédés
WO2021202824A1 (fr) * 2020-04-03 2021-10-07 Abbott Laboratories Produits à base d'exosomes de lait bovin et procédés, compositions nutritionnelles et procédés thérapeutiques associés
WO2021216420A1 (fr) * 2020-04-20 2021-10-28 Abbott Laboratories Méthodes de diminution de l'atrophie musculaire et/ou de promotion de la régénération musculaire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BR MED J, vol. 317, 1998, pages 703 - 713
GE QIAN ET AL: "Exosome-Like Vesicles as New Mediators and Therapeutic Targets for Treating Insulin Resistance and β -Cell Mass Failure in Type 2 Diabetes Mellitus", JOURNAL OF DIABETES RESEARCH, vol. 2019, 12 March 2019 (2019-03-12), pages 1 - 7, XP055773001, ISSN: 2314-6745, Retrieved from the Internet <URL:http://downloads.hindawi.com/journals/jdr/2019/3256060.xml> DOI: 10.1155/2019/3256060 *
LANCET, vol. 352, 1998, pages 837 - 853

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