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WO2025059104A1 - Méthodes et compositions pour traiter une maladie neurodégénérative liée à l'âge associée à une dysbiose - Google Patents

Méthodes et compositions pour traiter une maladie neurodégénérative liée à l'âge associée à une dysbiose Download PDF

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Publication number
WO2025059104A1
WO2025059104A1 PCT/US2024/046084 US2024046084W WO2025059104A1 WO 2025059104 A1 WO2025059104 A1 WO 2025059104A1 US 2024046084 W US2024046084 W US 2024046084W WO 2025059104 A1 WO2025059104 A1 WO 2025059104A1
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Prior art keywords
patient
lacto
disease
treatment
human milk
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Inventor
Alexander Martinez
Emil CHUANG
Nicholas TALLEY
Jason FERRONE
Dustin CRAWFORD
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The University of Newcastle
Newcastle University of Upon Tyne
Intrinsic Medicine Inc
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The University of Newcastle
Newcastle University of Upon Tyne
Intrinsic Medicine Inc
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Publication of WO2025059104A1 publication Critical patent/WO2025059104A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • GI gastrointestinal
  • the invention includes a method of treating a patient suffering from a genetic or idiopathic neurodegenerative disease comprising, administering to said patient a composition consisting of at least one human milk oligosaccharide (HMO).
  • HMO human milk oligosaccharide
  • the neurodegenerative diseases include Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and age-related dementia.
  • the patient is a PD patient; for example, the patient is diagnosed with PD in accordance with a diagnostic criteria selected from UK Parkinson’s Disease Society Brain Bank Diagnostic Criteria, Movement Disorder Society Criteria for Parkinson’s Disease.
  • the patient is diagnosed with Alzheimer’s Disease.
  • the invention also includes a method of treating Parkinson’s Disease (PD) in a patient in need thereof, the method comprising administering to said patient an effective amount of 2 -FL, or a composition thereof.
  • PD Parkinson’s Disease
  • the PD is idiopathic PD.
  • the PD is genetic PD.
  • the patient exhibits one or more of bradykinesia, rest tremor, rigidity, postural or gait impairment, apathy, anxiety, mood disorders, depression, hallucinations, illusions, delusions, cognitive deterioration, orthostatic hypotension, constipation, urinary dysfunction, sexual dysfunction, excessive swelling, seborrhea, sialorrhea, insomnia, REM behavior disorder, restless leg disorder, periodic movements in sleep, excessive daytime sleepiness, hyposmia, and decreased visual contrast.
  • the treatment improves one or more of the following: gut microbiome diversity; gastrointestinal symptoms associated with gut dysbiosis; gut microbiome dysbiosis; weekly complete spontaneous bowel movements or weekly worst abdominal pain (WAP); nasal dysbiosis; oral dysbiosis; olfactory dysfunction, gustatory dysfunction; and inflammatory symptoms associated with dysbiosis.
  • a patient at risk of developing PD is a patient that has one or more risk factors associated with the development of PD including, but not limited to, advanced age (e.g., 50 years or older, 55 years or older; 60 years or older; 65 years or older; or 70 years or older); males; family history of PD; genetic mutation associated with PD; autoimmune rhematic disease such as rheumatoid arthritis; past traumatic brain injury; past exposure to environmental toxins; gut dysbiosis; ulcerative colitis; and Crohn’s disease.
  • composition to be administered comprises an effective amount of the one or more human milk oligosaccharides.
  • the composition comprises one or more HMDs selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N- hexaose (LNH), lacto-N-neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3 ’FL), lacto-difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N- fucopentaose I (LNFP I), lacto-N-difuco-hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), difucosyl-
  • the composition can comprise a mixture of two, three, four or five human milk oligosaccharides.
  • Exemplary mixtures include: 2’FL and LNT; 2’FL and LNnT; 2’FL, 3 ’FL, 3’SL, 6’SL and LNT; 3’SL and 6’SL; and 6’SL and LNT.
  • the HMO is 2-FL.
  • the 2-FL can be administered with one or more additional HMOs either as part of the same composition or as part of different compositions.
  • additional HMOs are selected from the group consisting lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N-neohexaose (LNnH), 3’fucosyllacose (3 ’FL), lacto-difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N-fucopentaose I (LNFP I), lacto-N-difuco-hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), d
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • Each component must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • compositions described herein can include a pharmaceutically acceptable carrier.
  • a composition comprising an HMO can include the HMO and a pharmaceutically acceptable carrier.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like.
  • a mammalian subject can refer to a human patient.
  • the subject is a human patient.
  • a patient in need of treatment can include a patient who exhibits symptoms of the disease, condition or disorder, including a patient that exhibits early symptoms of the disease, condition or disorder.
  • a patient in need of treatment can also include (depending on the context) a patient who does not yet show symptoms of the disease, condition or disorder but has an increased risk of developing the disease, condition or disorder.
  • a patient in need of treatment can include a patient who exhibits symptoms of PD (for example, tremor, muscle stiffness, slowness of movement and impaired balance and coordination), including a patient that exhibits an early symptom of PD, as well as a patient with an increased risk of PD.
  • the patient in need of treatment is a patient diagnosed with a neurodegenerative disease such as PD or AD.
  • release controlling excipient refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • non-release controlling excipient refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • substantially pure as used herein in reference to a given oligosaccharide means that the oligosaccharide is substantially free from other biological macromolecules.
  • the substantially pure oligosaccharide is at least 75% (e.g., at least 80, 85, 95, or 99%) pure by dry weight. Purity can be measured by any appropriate standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
  • treat refers to ameliorating one or more symptoms associated with a disease, condition, or disorder (e.g., one or more symptoms of age-related neurodegeneration) including inhibiting the progress of the disease or disorder (e.g., one or more symptoms of Age-related neurodegeneration, AD, or PD), reducing the rate of progression of disease or disorder, reducing the severity of the disease or disorder (e.g., one or more symptoms of Age-related neurodegeneration, AD, or PD) or a symptom thereof, and/or lessening the severity or frequency of symptoms of the disease, condition, or disorder.
  • a disease, condition, or disorder e.g., one or more symptoms of age-related neurodegeneration
  • the amelioration of one or more symptoms, inhibition of the progress of the disease or disorder, reduction of the severity of the disease, disorder or symptom, reduction in the rate of progression of the disease or disorder, lessening of the severity or frequency of symptoms is compared to that prior to the initiation of the treatment (e.g., prior to the administration of the HMO or composition thereof) and/or compared to what would be expected or predicted in the absence of the treatment (the administration of the HMO or composition thereof).
  • the present invention encompasses co-administration of the composition comprising one or more human milk oligosaccharide and an additional active agent.
  • co-administration means administration of at least two therapeutically active drugs or compositions (e.g., administration of the human milk oligosaccharide and an additional active agent, such as an additional therapeutic agent or nutritional supplement, or pharmaceutical compositions thereof), at different times or simultaneously or substantially simultaneously in either separate formulation or the same formulation/composition.
  • additional active agent such as an additional therapeutic agent or nutritional supplement, or pharmaceutical compositions thereof
  • an “effective amount” or a “therapeutically effective amount” of an agent refers to an amount of the active agent, alone or in combination with another active agent, that is sufficient to achieve a specific effect or result, and/or treats the disease or condition and/or the symptoms therefore, for example, alleviating, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • an “effective amount” of a human milk oligosaccharide encompasses an amount that, alone or in combination with another human milk oligosaccharide, is effective to reduce or ameliorate a sign or symptom of Age-related neurodegeneration.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenecity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • active agent refers to an agent administered as part of a method of treatment, alone or in combination with one or more pharmaceutically acceptable excipients and/or carriers, to a subj ect for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • active agent includes, but are not limited to, human milk oligosaccharides.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disease,” “syndrome” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • disease a disease, disorder, condition, and/or a syndrome.
  • the invention encompasses methods of treating age-related neurodegeneration in a subject in need thereof comprising administering to said subject a composition comprising an effective amount of one or more human milk oligosaccharide.
  • Nonlimiting examples of neurodegeneration including AD and PD.
  • the invention also encompasses a method of treating Parkinson’s disease in a subject in need thereof comprising administering to the subject a composition comprising an effective amount of one or more human milk oligosaccharide.
  • PD is a specific example of a disorder of the gut (brain) immune axis.
  • GI dysbiosis is characterized by increased putative pro-inflammatory microbes, belonging to the phylum Proteobacteria, and a reduction in putative beneficial short chain fatty acids (SCFAs)-producing bacteria (e.g., Blautia, Roseburia, and Faecalibacterium) [10]
  • SCFAs putative beneficial short chain fatty acids
  • SCFAs have been shown to have anti-inflammatory and neuroprotective effects and have been linked to improved cognitive function [11, 12]
  • the promotion of a pro-inflammatory GI microbiota profile has also been reported by others [13] and as a result an adverse response by the immune system has been documented and as a result affecting the production of key neurotransmitters (neuroinflammation).
  • the nasal cavity may be a secondary site (in addition to the GIT) triggering neuroinflammation in PD. It is hypothesized that this serves as another route of pathogen/toxin exposure, and originally termed the “dual-hit hypothesis” [15], Like the GI the nasal cavity has a unique microbiota that plays a critical role in olfactory development and smell [16], it has also been associated with pro-inflammatory disease states.
  • HMOs Human milk oligosaccharides
  • Human milk contains three major HMO types: neutral, neutral N-containing, and acid.
  • Neutral fucosylated HMOs such as 2 fucosyllactose (2’FL) represent 35% to 50% of the total HMO in human milk [19], and due to reported benefits, 2’FL is routinely added to many infant formulae to simulate human breast milk.
  • 2’FL can selectively promote the growth of beneficial bacteria in the gut, such as Bifidobacteria and Lactobacilli (SCFA producers), while reducing the growth of potentially harmful bacteria [20], 2’FL has been identified as a potential treatment for PD due to its roles in promoting GI health and its effects on the host immune system.
  • 2’FL has been shown to support the growth of beneficial microbiota, such as Bifidobacterium, and to induce the production of SCFAs, which serve as an energy substrate for colonic epithelial cells [21, 22].
  • beneficial microbiota such as Bifidobacterium
  • SCFAs which serve as an energy substrate for colonic epithelial cells
  • HMOs are considered safe, with synthetically produced 2’FL granted the Generally Regarded As Safe (GRAS) designation by FDA in 2018 for the inclusion in infant and toddler nutritional products and TGA approval in 2021 in 5 g increment doses, which are provided over the counter to promote gut health in adults (GRN 749; TGA 2021).
  • GRAS Generally Regarded As Safe
  • the invention is directed to the administration of 2’FL in a patient in need thereof.
  • the administration of 2’FL improves the GI microbiota, cognition, and/or GI symptoms in a PD patient.
  • the invention encompasses methods of treating age-related neurodegeneration in a subject in need thereof comprising administering to said subject a composition comprising an effective amount of one or more human milk oligosaccharide. For example, such treatment reduces or improves at least one sign or symptom of age-related neurodegeneration.
  • Signs or symptoms of age-related neurodegeneration include, but are not limited to, brain fog or other neurological signs and symptoms (including, but not limited, memory loss, attention disorder, and delirium); depression, anxiety, or other neuropsychiatric signs and symptoms (including, but not limited to, obsessive compulsive disorder, post-traumatic stress disorder, psychosis, and paranoia); fatigue; muscle weakness; dyspnea, cough, or other respiratory symptom (including, for example, sore throat); insomnia or sleep disturbance (including, but not limited to, sleep disorder or sleep apnea); headache; paresthesias; dysautonomia; dizziness; pain; weight loss; hypertension; olfactory or gustatory dysfunction (including, for example, anosmia or ageusia); hair loss or other dermatologic symptom; palpitations/tachy cardia, chest pain, or other cardiac symptom; arthral gia/j oint pain; rhinitis; Sicca/Sjogren syndrome; fever;
  • the methods described herein reduce fatigue.
  • the reduction of fatigue can be measured, for example, by visual analogue scale, Samn-Perelli seven point fatigue scale, Karolinska Sleepiness Scale, or Psychomotor Vigilance Task.
  • the methods described herein reduce muscle weakness as measured by a test selected from the group consisting of lower handgrip muscle strength, short physical performance battery (SPPB) score, Timed Up and Go test (TUGT), walking speed (WS), and/or grip strength (GS).
  • SPPB short physical performance battery
  • TUGT Timed Up and Go test
  • WS walking speed
  • GS grip strength
  • the method comprising administration of at least one HMO reduces or improves brain fog.
  • the reduction or improvement in brain fog can be measured by cognitive battery score, for example.
  • the method reduces or improves memory impairment.
  • the reduction or improvement in memory impairment can, for example, be measured by a test selected from Short Test of Mental Status, the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE), or by an assessment of symptoms by a physician (see, for example, mayoclinic.org/diseases-conditions/mild-cognitive- impairment/diagnosis-treatment/drc-20354583; the contents of which are expressly incorporated by reference herein).
  • the methods described herein can additionally reduce dyspnea, for example, as measured by a clinical scale selected from the group consisting of the Medical Research Council (MRC) scale, the Baseline Dyspnea Index (BDI), and Transitional Dyspnea Index (TDI), or a combination thereof (see, for example, Crisafulli et al. (2010), Mutidiscip Respir Med 5(3): 202-210; the contents of which are expressly incorporated by reference herein).
  • MRC Medical Research Council
  • BDI Baseline Dyspnea Index
  • TDI Transitional Dyspnea Index
  • the method of the present invention improves insomnia and/or sleep disturbance.
  • the improvement in insomnia and/or sleep disturbance can, for example, be measured by the Karolinska Sleep Scale (KSS) or the Sleepiness Symptoms Questionnaire (SSQ).
  • KSS Karolinska Sleep Scale
  • SSQ Sleepiness Symptoms Questionnaire
  • the method described herein improves gut microbiome dysbiosis or persistent dysbiosis.
  • Dysbiosis is defined by the loss or gain of bacteria that promotes health or disease (see, for example, Wilkins et al. (2019), Defining Dysbiosis for a Cluster of Chronic Diseases, Nature Briefing 9: 12918; the contents of which are expressly incorporated by reference herein).
  • the dysbiosis is determined by fecal microbiome analysis such as 16S ribosomal RNA sequencing. In yet other aspects, the dysbiosis is determined or diagnosis by measuring an increased level of salivary cortisol, plasma IL-6, plasma IL-ip, plasma TNF-a, plasma c-reactive protein, MCP-1, MIPl-a, fecal calprotectin in the subject.
  • the administration of the HMO as described herein can improve gastrointestinal symptoms associated with the dysbiosis. Additionally, the methods described herein can improve neurological, respiratory, or inflammatory symptoms associated with dysbiosis.
  • the sign or symptom of age-related neurodegeneration is a neurob ehavioral abnormality associated with dysbiosis (see, for example, Maguire et al. (2016), oral, nasal or gut dysbiosis, leaky gut, and intestinal epithelial proliferation in neurological disorders: towards the development of a new therapeutic using amino acids, prebiotics, probiotics, and postbiotics, Reviews in the Neurosciences, 30(2); the contents of which are expressly incorporated by reference herein.
  • the neurob ehavioral abnormality can be an anxiety disorder, depression, brain fog, stress, and negatively impacted cognitive performance.
  • the method can entail administering a neurob ehavioral test to a subject and determining if neurob ehavioral function is impacted and the subject is in need of treatment.
  • the method comprises using a neurob ehavioral test to monitor the effectiveness of the treatment.
  • the patient has been diagnosed with age-related neurodegeneration.
  • a diagnosis of age-related neurodegeneration can comprise utilization of the Work Productivity and Activity Impairment (WPAI) Questionnaire.
  • the method reduces and/or improves at least one sign or symptom of age-related neurodegeneration as assessed by a method comprising use of the Work Productivity and Activity Impairment (WPAI) Questionnaire.
  • the invention comprises administration of an effective amount of one or more HMOs.
  • the HMDs can be co-administered, including administration of at least two compositions comprising the HMOs or as one composition comprising the HMOs.
  • the one or more HMO is administered in amount from about 1 to about 15 g (total HMOs) once or twice a day for one or more days, for one or more weeks, for one or more months.
  • the one or more HMO is administered in an amount from about 1.5 to about 7.5 g twice a day, once or twice a day for one or more days, for one or more weeks, for one or more months.
  • oligosaccharide is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).
  • a “human milk oligosaccharide” or an “HMO” is an oligosaccharide found in human milk.
  • human milk oligosaccharide includes natural or native oligosaccharides found in human milk, as well as pharmaceutically acceptable salts, derivatives, prodrugs, and solvates thereof.
  • natural human milk oligosaccharide” or “natural HMO” refers to human milk oligosaccharides naturally found in human milk.
  • Natural human milk oligosaccharides are separated into different classes including, for example, sialylated human milk oligosaccharides and fucosylated oligosaccharides.
  • HMOs include natural sialylated human milk oligosaccharides and fucosylated oligosaccharides, as well as non-naturally occurring derivatives thereof.
  • Natural human milk oligosaccharides are separated into different classes including, for example, sialylated human milk oligosaccharides (which include sialyllactoses; sialyllactoses are sialylated oligosaccharides that comprise a lactose) and fucosylated oligosaccharides (which include “fucosy llactoses”; fucosyllactoses are fucosylated oligosaccharides that comprise a lactose).
  • HMOs include natural sialylated human milk oligosaccharides and fucosylated oligosaccharides, as well as non-naturally occurring derivatives thereof.
  • Non-limiting examples of sialyllactoses are 3’-SL and 6’-SL.
  • a non-limiting example of a Fucosyllactose is 2’ -FL.
  • the oligosaccharides, human milk oligosaccharides or natural human milk oligosaccharides of the present invention are not isolated from human milk.
  • the oligosaccharides of the present invention are optionally synthesized chemically, enzymatically or with synthetic biology technology, i.e. genetically engineered microorganism.
  • Sialyllactose is a class of human milk oligosaccharides (HMOs) that appear in two different forms in human milk. These two forms are 3 ’-sialyllactose (3’-SL) and 6’- sialyllactose (6’-SL):
  • 3’-SL and “3’SL” are used interchangeably herein.
  • 6’-SL and “6’SL” are used interchangeably herein.
  • Sialyllactoses have been shown to modulate acute and chronic immune responses in both murine and human derived macrophages stimulated with LPS and various pro-inflammatory cytokines.
  • Both 3’SL and 6’SL have shown reductions in interleukin (IL)-ip, IL-2, IL-4, IL-6, IL- 12, interferon (IFN) y or TNF-a in vitro, with 3’-SL exhibiting more significant reductions.
  • IL interleukin
  • IFN interferon
  • 3’SL has been shown to reduce other key target proteins, including PDL1, COX2 and select chemokines, such as CCL2 (also known as monocyte chemoattractant protein 1 (MCP1)) and CCL5.
  • CCL2 also known as monocyte chemoattractant protein 1 (MCP1)
  • MCP1 monocyte chemoattractant protein 1
  • Fucosylated oligosaccharides are a class of human milk oligosaccharides (HMDs) that have been associated with the production of anti-inflammatory short-chain fatty acids.
  • Fucosylated oligosaccharides include, for example, 2'-fucosyllactose, 3-fucosyllactose, difucosyllactose, lacto-N-fucopentaoses (that is to say lacto-N-fucopentaose I, lacto-N- fucopentaose II, lacto-N-fucopentaose III and lacto-N-fucopentaose V), lacto-N- difucohexaose I, fucosyllacto-N-hexaose, Difucosyllacto-N-hexaose I and Difucosyllacto-N- neohexaose II.
  • a “fucosylated oligosaccharide” is an oligosaccharide having the three sugar unit backbone, wherein each of the sugar units (fucose (Fuc), galactose (Gal), and glucose (Glc)) can be independently either in its native form or in a modified form.
  • the modified form of a sugar unit can be a sugar unit, in which at least one or more (e.g., 1, 2, 3, or more) of the hydroxyl groups is replaced with hydrogen, alkyl or a functional group; such as, for example, hydrogen, substituted or unsubstituted C1-C6 alkyl (e.g., methyl, ethyl), or substituted or unsubstituted amine group.
  • at least one or more (e.g., 1, 2, 3, or more) of the hydroxyl groups is replaced with hydrogen, alkyl or a functional group; such as, for example, hydrogen, substituted or unsubstituted C1-C6 alkyl (e.g., methyl, ethyl), or substituted or unsubstituted amine group.
  • a fucose unit is linked to a galactose unit of a lactose molecule via an alpha 1,2 linkage (2'-fucosyllactose, 2'-FL) or via an alpha 1,3 linkage to the glucose unit of a lactose (3 -Fucosyllactose, 3-FL).
  • 2-'FL has the chemical structure shown below:
  • 2’ -fucosyllactose or “2’ -FL” and “2’FL” are used interchangeably herein.
  • 2 ’-fucosyllactose has been granted generally regarded as safe (GRAS) status in the U.S. and is regarded by the Europe Food Safety Authority as safe for infant and follow-on formula.
  • 2’ -FL has been shown to have many beneficial properties, such as improving gut health through modulation of the gut microbiome as well as reduction of local gut inflammation in models of necrotizing enterocolitis and other inflammatory bowel diseases.
  • 2’- FL has been shown to have positive effects on gut epithelial barrier function and also independent anti-inflammatory effects through the reduction in TNFa and IL-8.
  • Derivatives of natural HMOs can be chemically modified as compared to the natural HMO.
  • the derivative of the natural HMO retains at least 50%, at least 60%, at least 70% or more (including, e.g., at least 80%, at least 90%, at least 95%, at least 98%, at least 99% and up to 100%) of the biological functions of a natural HMO.
  • HMOs include, but are not limited to, compounds having a structure of a formula shown below (e.g., Formula I, Formula I(a)-I(e), Formula (II), Formula 11(a), Formula 111(a), Formula 111(b)):
  • R is absent or a (Ci-Cs)alkyl
  • R' is independently selected from H, D, an unsubstituted or substituted (Ci-Ce) alkyl, an unsubstituted or substituted (Ci-C6)heteroalkyl, an unsubstituted or substituted (C2-C6) alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-Ce)alkynyl, an un substituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl; and
  • R 29 is an unsubstituted or substituted (Ci-C6)alkyl.
  • the HMO has the Formula Illb:
  • R 19 -R 28 are each independently selected from the group consisting of hydrogen, an unsubstituted or substituted Ci-Ce alkyl (including, but not limited to, methyl and ethyl) and N(R’)2 (wherein R’ is as defined above), the remainder or R19-R28 are - OH, and R 29 is substituted or unsubstituted C1-C 6 alkyl; or one, two or three of R 19 -R 29 are each independently selected from NHC(O)R”, wherein R” is unsubstituted or substituted (Ci-Ce) alkyl (including, but not limited to, methyl), the remainder or R19-R28 are -OH, and R 29 is substituted or unsubstituted C1-C 6 alkyl.
  • R 26 is NHC(0)CH3 and R 19 -R 25 and R 27 -R 28 are -OH, and R 29 is methyl.
  • alkyl refers to an organic group that is comprised of carbon and hydrogen atoms that contains single covalent bonds between carbons.
  • an "alkyl” as used in this disclosure refers to an organic group that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of the foregoing values.
  • the carbons may be connected in a linear manner, or alternatively if there are more than 2 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, or quaternary carbons.
  • An alkyl may be substituted or un substituted, unless stated otherwise.
  • alkenyl refers to an organic group that is comprised of carbon and hydrogen atoms that contains at least one double covalent bond between two carbons.
  • an "alkenyl” as used in this disclosure refers to organic group that contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of the foregoing values. While a C2-alkenyl can form a double bond to a carbon of a parent chain, an alkenyl group of three or more carbons can contain more than one double bond.
  • the alkenyl group will be conjugated, in other cases an alkenyl group will not be conjugated, and yet other cases the alkenyl group may have stretches of conjugation and stretches of non-conjugation. Additionally, if there is more than 2 carbons, the carbons may be connected in a linear manner, or alternatively if there are more than 3 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, or quaternary carbons. An alkenyl may be substituted or un substituted, unless stated otherwise.
  • alkynyl refers to an organic group that is comprised of carbon and hydrogen atoms that contains a triple covalent bond between two carbons.
  • an "alkynyl” as used in this disclosure refers to organic group that contains that contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of the foregoing values. While a C2-alkynyl can form a triple bond to a carbon of a parent chain, an alkynyl group of three or more carbons can contain more than one triple bond.
  • the carbons may be connected in a linear manner, or alternatively if there are more than 4 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, or quaternary carbons.
  • An alkynyl may be substituted or un substituted, unless stated otherwise.
  • aryl refers to a conjugated planar ring system with delocalized pi electron clouds that contain only carbon as ring atoms.
  • An "aryl” for the purposes of this disclosure encompass from 1 to 4 aryl rings wherein when the aryl is greater than 1 ring the aryl rings are joined so that they are linked, fused, or a combination thereof.
  • An aryl may be substituted or unsubstituted, or in the case of more than one aryl ring, one or more rings may be unsubstituted, one or more rings may be substituted, or a combination thereof.
  • cycloalkyl refers to an alkyl that contains at least 3 carbon atoms but no more than 12 carbon atoms connected so that it forms a ring.
  • a "cycloalkyl” for the purposes of this disclosure encompasses from 1 to 4 cycloalkyl rings, wherein when the cycloalkyl is greater than 1 ring, then the cycloalkyl rings are joined so that they are linked, fused, or a combination thereof.
  • a cycloalkyl may be substituted or un substituted, or in the case of more than one cycloalkyl ring, one or more rings may be un substituted, one or more rings may be substituted, or a combination thereof.
  • hetero- when used as a prefix, such as, hetero-alkyl, hetero-alkenyl, hetero-alkynyl, or hetero-hydrocarbon, for the purpose of this disclosure refers to the specified hydrocarbon having one or more carbon atoms replaced by non-carbon atoms as part of the parent chain.
  • non-carbon atoms include, but are not limited to, N, O, S, Si, Al, B, and P. If there is more than one non-carbon atom in the hetero-based parent chain then this atom may be the same element or may be a combination of different elements, such as N and O.
  • a "hetero"-hydrocarbon refers to a hydrocarbon that has from 1 to 3 C, N and/or S atoms as part of the parent chain.
  • heterocycle refers to ring structures that contain at least 1 noncarbon ring atom.
  • a “heterocycle” for the purposes of this disclosure encompass from 1 to 4 heterocycle rings, wherein when the heterocycle is greater than 1 ring the heterocycle rings are joined so that they are linked, fused, or a combination thereof.
  • a heterocycle may be aromatic or nonaromatic, or in the case of more than one heterocycle ring, one or more rings may be nonaromatic, one or more rings may be aromatic, or a combination thereof.
  • a heterocycle may be substituted or unsubstituted, or in the case of more than one heterocycle ring one or more rings may be unsubstituted, one or more rings may be substituted, or a combination thereof.
  • the noncarbon ring atom is N, O, S, Si, Al, B, or P.
  • these noncarbon ring atoms can either be the same element, or combination of different elements, such as N and O.
  • heterocycles include, but are not limited to: a monocyclic heterocycle such as, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3- dihydrofuran, 2, 5 -dihydrofuran tetrahydrofuran, thiophane, piperidine, 1, 2,3,6- tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3- dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-di oxane, 1,3 -di oxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-aze
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7- oxabicyclo[2.2. l]heptane.
  • heterocyclic group refers to a heterocycle that has had one or more hydrogens removed there from.
  • hydrocarbons refers to groups of atoms that contain only carbon and hydrogen. Examples of hydrocarbons that can be used in this disclosure include, but are not limited to, alkanes, alkenes, alkynes, arenes, and benzyls.
  • optionally substituted means independent replacement of one or more hydrogen atoms with a substituent.
  • optionally substituted also refers to a functional group, typically a hydrocarbon or heterocycle, where one or more hydrogen atoms may be replaced with a substituent.
  • optionally substituted refers to a functional group that is substituted, in that one or more hydrogen atoms are replaced with a substituent, or unsubstituted, in that the hydrogen atoms are not replaced with a substituent.
  • an optionally substituted hydrocarbon group refers to an unsubstituted hydrocarbon group or a substituted hydrocarbon group.
  • the subject is administered a composition comprising one or more human milk oligosaccharides.
  • the composition can comprise 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharide.
  • the composition is not human milk. In additional aspects, the composition is not derived from human milk.
  • the one or more human milk oligosaccharides are selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N- neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3 ’FL), lacto-difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N-fucopentaose I (LNFP I), lacto- N-difuco-hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), difucosyl-para- lacto-N-neohexaose (DF
  • the oligosaccharides disclosed herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, a racemic mixture, or a diastereomeric mixture.
  • administration of an oligosaccharide in its (R) form is equivalent, for oligosaccharides that undergo epimerization in vivo, to administration of the oligosaccharide in its (S) form.
  • oligosaccharide disclosed herein contains an acidic or basic moiety, it may also be disclosed as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- glucamine, hydrabamine, IH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)- morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-
  • the oligosaccharide as disclosed herein may also be designed as a prodrug, which is a functional derivative of the oligosaccharide as disclosed herein and is readily convertible into the parent oligosaccharide in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent oligosaccharide. They may, for instance, be bioavailable by oral administration whereas the parent oligosaccharide is not.
  • the oligosaccharides disclosed herein can be produced in high yields in aqueous media by fermentation of genetically modified bacteria, yeasts or other microorganisms. See, for example, W0200104341; W02007101862, W02010070104; W02010142305; WO2012112777; Priem et al., Glycobiology 12:235 (2002); Drouillard et al., Angew. Chem. Int. Ed. 45: 1778 (2006); Han et al., Biotechnol. Adv. 30: 1268 (2012); Lee et al., Microb. Cell Fact. 11:48 (2012); Baumgartner et al., Microb. Cell Fact. 12:40 (2013); and WO 2014135167A1.
  • oligosaccharides of the disclosure can be synthesized based upon methods described in WO2011100980A1; W02012007588A1;
  • oligosaccharides can be made as described in WO 2012/127410.
  • WO 2001/04341 and WO 2007/101862 describe how to make oligosaccharides optionally substituted by fucose using genetically modified E. colt.
  • the oligosaccharides disclosed herein can be produced in high yields in aqueous media by fermentation of genetically modified bacteria, yeasts or other microorganisms.
  • oligosaccharides of the disclosure can be synthesized based upon methods described in WO2011100980A1; W02012007588A1;
  • WO 2001/04341 and WO 2007/101862 describe how to make oligosaccharides optionally substituted by fucose or sialic acid using genetically modified E. coli.
  • the composition described herein can further comprise one or more foodgrade agents.
  • foodgrade agents that can be used with the oligosaccharides disclosed herein, include, but are not limited to, milk (e.g., cow's milk, almond milk, soy milk), yogurt, maltodextrin, milk protein concentrate, Sucromalt, glycerine, cocoa powder, soy protein isolate, fructose, vegetable or animal oils (e.g, high oleic safflower oil, soy oil, canola oil), plant sterol esters, HMSs/HMOs, soy lecithin, carrageenan, taurine, L-camitine, vitamins and/or minerals (e.g, sodium ascorbate, potassium citrate, sodium phosphate, calcium citrate, choline chloride, potassium chloride, sodium citrate, magnesium oxide, alpha-tocopheryl acetate, zinc sulfate, ferrous sulfate, niacinamide, calcium pan
  • milk e
  • compositions comprising one or more oligosaccharides described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as an active ingredient, combined with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof; in combination with one or more pharmaceutically acceptable excipients or carriers.
  • compositions in modified release dosage forms which comprise one or more oligosaccharides of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers as described herein.
  • Suitable modifiedrelease dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water- soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof.
  • compositions may also comprise non-release controlling excipients or carriers.
  • compositions in enteric coated dosage forms which comprise one or more human milk oligosaccharides as disclosed herein, ora pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers for use in an enteric coated dosage form.
  • the pharmaceutical compositions may also comprise non-release controlling excipients or carriers.
  • compositions in effervescent dosage forms which comprise one or more human milk oligosaccharides as disclosed herein in substantially pure form (e. ., lacking other oligosaccharides found in milk), or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers for use in an effervescent dosage form.
  • the pharmaceutical compositions may also comprise non-release controlling excipients or carriers.
  • compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of one or more human milk oligosaccharides disclosed herein in the form of at least two consecutive pulses separated in time (e. , separated in time from 0.1 up to 24 hours or a few days).
  • the pharmaceutical compositions comprise an oligosaccharide as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling and nonrelease controlling excipients or carriers, such as those excipients or carriers suitable for a disruptable semi-permeable membrane and as swellable substances.
  • compositions in a dosage form for oral administration to a subject which comprise one or more as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.
  • compositions that comprise about 0.1 to about 1000 mg or up to 2000 mg or up to 3000 mg (or any value between 0.1 - 3000 mg), in the form of immediate release tablets for oral administration.
  • the pharmaceutical compositions further comprise inactive ingredients such as flavoring agents, copovidone, ethylcellulose, magnesium stearate, mannitol, and silicon dioxide.
  • compositions that comprise about 0. 1 to about 1000 mg or up to 2000 mg or up to 3000 mg (or any value there between), about 500 to about 1000 mg, about 500 to about 2000 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg in the form of extended release tablets for oral administration.
  • the pharmaceutical compositions further comprise inactive ingredients such as ethylcellulose, dibutyl sebacate, polyvinyl pyrroliodone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinyl alcohol.
  • compositions disclosed herein may be disclosed in unit-dosage forms or multiple-dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the oligosaccharide sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged to capsules. Unit-dosage forms may be administered in fractions or multiples thereof.
  • the oligosaccharides as disclosed herein may be administered alone, or in combination with one or more other oligosaccharides disclosed herein, and/or one or more other active ingredients.
  • the pharmaceutical compositions that comprise an oligosaccharide disclosed herein may be formulated in various dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002;
  • compositions disclosed herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence ofsymptoms.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastimes, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as com starch, potato starch, and pre-gelatinized starch (e.
  • gelatin such as sucrose, glucose, dextrose, molasses, and lactose
  • natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum
  • celluloses such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH- 101, AVICEL-PH- 103, AVICELRC-581, AVICEL-PH- 101, AVICE
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions disclosed herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such asmannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross- linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of disintegrant in the pharmaceutical compositions disclosed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions disclosed herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • compositions disclosed herein may be formulated as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar- coated, or film-coated tablets.
  • the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets andlozenges.
  • the pharmaceutical compositions disclosed herein may be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated in a capsule.
  • suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides.
  • Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the activeingredient.
  • compositions disclosed herein may be formulated in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) disclosed herein, and a dialkylated mono- or polyalkylene glycol.
  • compositions disclosed herein for oral administration may be also formulated in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions disclosed herein may be formulated as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • compositions disclosed herein can be formulated as an oral nutritional composition.
  • An oral nutritional composition can contain sources of protein, lipids and/or digestible carbohydrates and can be in solid, powdered or liquid forms.
  • the composition can be designed to be the sole source of nutrition or a nutritional supplement.
  • Suitable protein sources include intact, hydrolyzed, and partially hydrolyzed protein, which can be derived from any suitable source such as milk (e. ., easin, whey), animal (e. , meat, fish), cereal (e.g, rice, com), and vegetable (e.g, soy, potato, pea), insect (e.g, locust) and combinations of these sources.
  • Examples of the source of protein include whey protein concentrates, whey protein isolate, whey protein hydrolysates, and acid.
  • compositions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed- release forms.
  • compositions disclosed herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action.
  • compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • compositions disclosed herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • compositions disclosed herein may be formulated for single or multiple dosage administration.
  • the single dosage formulations are packaged in an ampule, a vial, or a syringe.
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions may be formulated as a suspension, solid, semisolid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Pharmaceutically acceptable carriersand excipients suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • the pharmaceutical compositions disclosed herein may be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions may be formulated in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1, 1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1, 1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the pharmaceutical compositions may also be formulated as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder may comprise a bioadhesive agent, including chitosan or cyclodextr
  • modified release refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • the pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion- exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
  • compositions disclosed herein in a modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.
  • the amount of an oligosaccharide disclosed herein required to be administered to the person can vary depending upon factors such as the risk and condition severity, the age of the person, the form of the composition, and other medications being administered to the person. It would be expected that an oligosaccharide described herein should be well tolerated irrespective of the age and condition of the subject.
  • the dosage of oligosaccharide to be administered can readily be set by a medical practitioner and would generally be in the range from about 100 mg to about 20 g per day, in certain embodiments from about 100 mg to about 15 g per day, from about 500 mg to about 15 g per day, in certain embodiments from about 500 mg to about 10 g per day, in certain embodiments from about 1 g to about 7.5 g per day.
  • An appropriate dose can be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the condition, being treated, other ailments and/or diseases of the person, the incidence and/or severity of side effects and the manner of administration. Appropriate dose ranges can be determined by methods known to those skilled in the art.
  • the dosing can be higher (for example 200 mg to 20 g per day, preferably 500 mg to 15 g per day, more preferably 1 g to 10 g per day, in certain embodiments 2.5 g to 7.5 g per day).
  • the dosing can be reduced (for example, 10 mg to 10 g per day, preferably 100 mg to 7.5 g per day, more preferably 500 mg to 5 g per day, in certain embodiments 1 g to 2.5 g per day).
  • the dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day.
  • the dose or sub-doses can be administered in the form of dosage units containing from about 0.01 to about 2 grams, from about 0.05 to about 1 gram, or from about 10 to about 500 milligrams active ingredient(s) per dosage unit.
  • an appropriate dosage level is about 0.01 to about 5 g/kg patient body weight per day (mg/kg per day), about 0.01 to about 1 g/kg per day, about 0.01 to about .5 g/kg per day, or about 0.1 to about 500 mg/kg per day, which may be administered in single ormultiple doses.
  • a suitable dosage level may be about 0.1 to about 500 mg/kg per day, about 0.1 to about 250 mg/kg per day, or about 0.1 to about 100 mg/kg per day. Within this range the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 100 mg/kg per day.
  • the oligosaccharides disclosed herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of a condition as described herein.
  • the therapeutic effectiveness of one of the oligosaccharides described herein may be enhanced by administration of an adjuvant (z.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with an oligosaccharide as disclosed herein.
  • an oligosaccharide as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to an oligosaccharide disclosed herein may be utilized but is not required.
  • compositions disclosed herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to an oligosaccharide disclosedherein.
  • Parkinsons’ s disease (PD) patients suffer from both cognitive impairment as well as GI symptoms (including, for example, constipation).
  • Prebiotic supplementation with 2’FL has been reported to modulate the GI microbiota, reduce host inflammation, and promote the production of neuromodulators that promote cognitive function. Therefore, it is hypothesized that supplementation with OM002 (2-FL) will improve cognitive function and reduce GI symptom severity in patients diagnosed with PD.
  • OM002 is a synthetic oligosaccharide that is identical to the HMO 2’FL, for the treatment of signs and symptoms of PD.
  • the aim of the study is to determine whether OM002 alters the immune profile, oral, nasal, and GI microbiota in people with PD, as well as changes in cognitive function using standardized neuropsychological tests.
  • GI symptoms will be assessed using validated questionnaires. Specifically, the effect of OM002 on PD patients’ disease progression (including, cognitive decline) will be assessed in a controlled randomized trial. Shotgun metagenomic sequencing will be used to identify distinct oral, nasal and stool profiles and key microbes related to OM002 and PD symptom reduction.
  • immune phenotyping of the inflammatory profile of PD patients will be performed and the effects of OM002 will be determined. Correlative analyses will be conducted to identify positive association between the immune and microbiota profile with OM002 and symptom alleviation.
  • OM002 has the potential to address the underlying pathophysiology of PD constipation and address unmet clinical needs in these patients.
  • This study is being conducted to assess the safety and efficacy of OM002 in patients with PD.
  • the data collected from this double-blind, randomized, placebo-controlled study will be used in combination with available open-label data to guide late-stage development of OM002 in subjects with PD.
  • OM002 is expected to improve stool frequency and consistency.
  • An improvement in cognitive function based on the GI microbiota modulation capabilities of 2’FL.
  • OM002 OM002
  • the doses of OM002 chosen for this study are based on prior experience with 2’FL in PD patients which has studied a dose of up to 20.0 g per day.
  • a dose of 5.0 g twice daily will be used in this study since this was shown previously in an IBS study to have no dose limiting drug toxicity.
  • Primary outcomes to be investigated are reduction of constipation and improvement in motor function in PD patients. Secondary outcomes to be investigated is Mean reduction in Parkinson’s Disease cognitive decline as measured with cognitive battery routinely used.
  • PD inclusion criteria include the following: 1. Males and females; 2. Adults aged > 18 years of age; 3. A clinical diagnosis of idiopathic PD according to the UK Parkinson's Disease Society Brain Bank Diagnostic Criteria; and 4. Being managed by a specialist neurologist.
  • PD Exclusion criteria are as follows: 1. Secondary Parkinsonism; 2. Tube feeding; 3. Medical or surgical disorders preventing completion of questionnaires and significant cognitive impairment demonstrated by an incapacity to provide consent; 4. Pregnancy; 5. Smoker; and 6. Antibiotics in the last 3 months. ii. Clinical work up
  • DHWS Digestive Health and Wellbeing Survey
  • FFQ food frequency questionnaire
  • CNAQ Comprehensive Nutrition Assessment Questionnaire
  • a medical interview including a detailed medical history (to include allergies) and other pathologies, medication usage, surgical history, family medical history and demographics.
  • Cognitive function assessment will be completed following a published battery [30], this includes: QoL assessed by the PDQ-39 [31] and the Short Form Health Survey (SF-36) [32], Mood assessed by the Beck Depression Inventory (BDI) [33], cognitive function by the Montreal Cognitive Assessment (MoCA) [34], whilst chronic pain severity was assessed by the Visual Analogue Scale [35] and physical activity by the International Physical Activity Questionnaire (IPAQ) [36], Non-motor symptoms evaluated by the Non-Motor Symptoms Scale (NMSS) [37], Clinical motor assessments using the Movement Disorder Society — Unified Parkinson’s Disease Rating Scale — Part III (MDS-UPDRS III) criteria [38] performed by a neurologist.
  • PD medication will be calculated as daily levodopa equivalent dose (LED) [39], iii. Sample collection and processing
  • Buccal (cheek) swab, saliva, nasal swab, stool, blood, and urine samples will be collected.
  • Next generation sequencing (16S rRNA amplicon gene (16S) and metagenomic shotgun sequencing (MGS)) will be used to characterize the microbial profile from saliva (16S), nasal (16S), and stool (MGS).
  • Detailed lifestyle information will be obtained from patients using the Digestive Health and Wellbeing Surveys used by the University of Newcastle Centre for Research Excellence (CRE) Digestive Health Biobank.
  • CRE Committee for Research Excellence
  • Buccal Swab/DNA collection and analysis Cells from inside of the participant’s cheek will be collected using a standard buccal swab supplied by IsohelixTM.
  • Buccal swabs are a relatively non-invasive way to collect DNA samples for testing. Self-collected samples will be placed into a biological ziplock plastic pouch and submitted to project researcher. The research team will store all buccal swabs (labelled with deidentified participant-specific alpha-numeric codes) in a -80°C freezer until shipment to HMRI. QuickExtract DNA solution (Illumina, VIC, Australia) will be used to extract DNA from the buccal swabs.
  • Genotyping for specific pro- and antiinflammatory polymorphisms will be performed using the TaqMan allelic discrimination assay (Life Technologies, VIC, Australia). DNA sequencing will be performed and may be undertaken by third party service providers. All samples will be de-identified with participant-specific alpha-numeric codes to ensure the privacy of participants is protected and that samples are unbiasedly analyzed. Any remaining DNA samples will be stored in de-identified, coded tubes in a laboratory freezer at the site of collection (NeuRA or HMRI) for at least 5 years after the publication of the initial findings, unless all material is utilized prior to this time.
  • Saliva and nasal DNA extraction for microbiota sequencing Total DNA will be extracted from saliva and nasal samples through a combination of bead-beating homogenization and automated DNA recovery system Maxwell (Promega) available at University of Newcastle’s (UON) labs.
  • Bacterial and fungal targeted gene sequencing Due to the host DNA contamination inherent in saliva and nasal samples sequencing will be employed through targeted gene amplification of the 16S rRNA to amplify the bacterial community and in addition specific primers designed to target the internal transcribed spacer (ITS) region between the 18S and 28 S gene will be used to specifically amplify the fungal community. This will be performed out of house with ACE with Illumina MiSeq platform.
  • ITS internal transcribed spacer
  • Total DNA will be extracted from patient stool through a combination of bead-beating homogenization and column nucleic acid purification system, this will ensure adequate lysis of the microbial community and standardized DNA recovery for all samples.
  • MGS will be performed out of house with Microba Life Sciences. Short/long read metagenomic sequencing will be completed on either the Illumina NovoSeq6000 or Nanopore PromethlON. MGS will provide microbiome taxonomic composition as well as functional data, with strain level resolution.
  • MGS analysis Bioinformatics workflow will be applied to resulting MGS data, briefly bioinformatics packages (such as HUManN2) will be used to identify taxonomical and functional changes between groups, while R software (i.e., phyloseq and vegan) will be used to determine diversity metrics (both alpha, beta) and investigate correlations between the microbiome, immune responses, diet, and intervention outcomes.
  • bioinformatics packages such as HUManN2
  • R software i.e., phyloseq and vegan
  • PBMCs Peripheral blood mononuclear cells
  • Flow cytometry will phenotype the T cells populations, using a surface marker staining approach established by Professor Keely’s lab.
  • CD4+a4+b7+CCR9+ we are also able to determine if there are differences in the proportions of activated (CD4+CD45RA+CCR7-) and memory (CD4+CD45RO+CCR7+/-) T cells.
  • T cell subsets such as Thl/Th2/Thl7 phenotypes can also be determined by surface staining (CCR6, CC44, CXCR3) and cytokine production (e.g., IFN-g, IL-5, IL-17a) profiles to provide insights into the phenotypes of PD gastrointestinal inflammation.
  • Inflammatory markers can be assayed using multiplex methodology. All survey and microbiome data can then be correlated with immune profiles to identify links between the gastrointestinal immune axis and PD. iv. Trial design
  • the data collected from this double-blind, randomized, placebo-controlled study trial with 2 arms will be used to assess the effect of OM002 treatment for Parkinson's disease patients.
  • Biological samples and surveys will be sampled at 6 timepoints (baseline, mid treatment, completion of first arm (13 weeks), mid open label treatment, and at the end of the open label treatment period (13 weeks)). Once participants have reached the open-label phase of the trial researchers will be un-blinded to facilitate analysis of data (FIG. 1).
  • HMOs are considered safe, with synthetically produced 2’FL granted the Generally Regarded As Safe (GRAS) designation by FDA in 2018 for the inclusion in infant and toddler nutritional products and TGA approval in 2021 in 5 g increment doses, which are provided over the counter to promote gut health in adults (GRN 749; TGA 2021). All other safety issues relate to routine care, with the study contributing no additional risk.
  • GRAS Generally Regarded As Safe

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Abstract

L'invention concerne des méthodes de traitement d'une maladie neurodégénérative, telle qu'une maladie neurodégénérative liée à l'âge chez un patient dont l'état le nécessite, comprenant l'administration d'une composition contenant une quantité thérapeutiquement efficace d'au moins un oligosaccharide de lait humain (HMO). L'invention concerne également des méthodes de traitement de la maladie de Parkinson (MP) chez un patient dont l'état le nécessite, comprenant l'administration audit patient d'une quantité efficace d'un HMO.
PCT/US2024/046084 2023-09-11 2024-09-11 Méthodes et compositions pour traiter une maladie neurodégénérative liée à l'âge associée à une dysbiose Pending WO2025059104A1 (fr)

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