Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis

Abstract

Described are methods of treating a neurodegenerative disease, such as an age- related neurodegenerative disease in a patient in need thereof, comprising administering a composition comprising a therapeutically effective amount of at least one human milk oligosaccharide (HMO). Also described are methods of treating Parkinson's Disease (PD) in a patient in need thereof comprising administering to said patient an effective amount of an HMO.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING AGE-RELATED NEURODEGENERATIVE DISEASE ASSOCIATED WITH DYSBIOSIS

[0002] RELATED APPLICATION

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 537,725, filed on September 11, 2023. The entire teachings of the above application are incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The disclosure provides for oligosaccharides, and therapeutic uses thereof for the treatment of neurodegenerative disease.

[0006] BACKGROUND OF THE INVENTION

[0007] Neurodegeneration, including age-related neurodegenerative disorders, has a major emotional, physical, economic, and health system impact in today’s modem aging population. While most diseases of neurodegeneration, including Parkinson’s, Alzheimer’s, ALS, and age-related dementia occurs in patients at 50 years or older, many of these same disease symptoms have begun to appear in patients of younger ages which has spurred research into other potential environmental and microbial origins of these diseases. Some studies have shown an increase in risk of developing many of these neurodegenerative diseases with gut dysbiosis and other idiopathic, inflammatory gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis (UC), irritable bowel syndrome (IBS) and general gut dysbiosis. Each of these conditions has an impact on the gut lining which protects the body from various products of pathogenic bacteria in the gut. The microbiome is an emerging area of research which has compartmentalized various important microbiome environments of the human body, including the oral, nasal and GI, have been shown to be connected wherein an oral dysbiosis in a patient can lead to gut dysbiosis, which can lead to profound systemic inflammatory conditions that can be linked to many of the most devastating diseases associated with aging. One such hypothesis that has been confirmed by in vitro, in vivo and clinical evidence, is the Braak’s hypothesis where nasal dysbiosis leads to gut dysbiosis and then leads to Lewy body pathogenesis from both nasal and dysbiosis

[0042] , To date, there have been several unsuccessful attempts (including traditional pharmaceutical approaches, fecal matter transplants (FMTs) and isolated consortium of isolated beneficial bacteria) at restoring health microbiome environments to prevent or treat many of diseases related to aging and inflammation linked to dysbiosis. Several billion dollars have been invested into these approaches to no avail with most of these companies folding. Therefore, there still exists a long-felt need to identify compounds and methods to address microbiome dysbiosis which have an impact on many diseases, including neurodegenerative diseases.

[0008] A specific example of a neurodegenerative disease that has been associated with changes in the microbiota is Parkinson’s disease (PD). A recent meta-analysis suggests that changes in the gut microbiome are consistently observed in PD patients

[0013] , Specifically, the depletion of certain bacteria that play a key role in maintaining gut health is widespread in Parkinson’s disease (PD) across populations

[0013] , This loss in beneficial bacteria is similar to the dysbiosis observed in other gastrointestinal dysfunctions (e.g., IBD). In addition, several studies have indicated that patients with IBD, such as ulcerative colitis and Crohn’s disease, have a higher overall risk of developing PD

[0013] ,

[0009] PD is a progressive neurodegenerative disorder characterized by the loss of dopamine- producing neurons in the substantia nigra region of the brain. PD increases with age and affects approximately 1% of the population over the age of 60 [1], The pathophysiology of PD is complex and involves the accumulation of alpha-synuclein protein in the brain, which forms Lewy bodies and leads to the death of dopamine-producing cells [2], This loss of neurons leads to the development of movement problems, including tremors, stiffness, slow movement, impaired balance and coordination, and cognitive decline. Additionally, as discussed above, many patients with PD may also experience non-motor symptoms such as gastrointestinal (GI) symptoms, including constipation, dysphagia, and gastroparesis, and other symptoms like sleep and mood disorders, and fatigue [3-5], The current standard of care for PD includes dopamine replacement therapy and other medications that aim to improve motor symptoms. There is an unmet medical need for treatments that can slow or halt disease progression and address non-motor symptoms such as GI symptoms.

[0010] Modification of the microbiota also plays a role in Alzheimer’s disease (AD)

[0041] , This effect is at least partially mediated by astrocytes and microglia that are altered by changes in the microbiome

[0041] , Activated astrocytes (Al astrocytes) are responsible for expressing and secreting cytokines and these cytokine in turn can affect the permeability of the blood brain barrier (BBB). Changes in the permeability of the BBB have been observed in patients with mild cognitive impairment and is considered an early step in AD pathogenesis. In addition, astrocytes undergo morphological and functional changes during aging, a process called clasmatodendrosis. Clasmatodendrosis impairs the ability of astrocytes to clear Ap from neurons and increases fibrillar Ap deposition. In mouse models of AD, the impairment of Ap clearance increases neurodegeneration.

[0011] Thus there is a need in the art for treatments that address microbiome dysbiosis, which has an impact on many diseases, including neurodegenerative diseases. There also remains a need in the art for therapies to treat neurodegenerative diseases including PD and AD.

[0012] SUMMARY OF THE INVENTION

[0013] The invention provides methods of treating a neurodegenerative disease, such as an age-related neurodegenerative disease, in a patient in need thereof, comprising administering to said patient a composition comprising a therapeutically effective amount of at least one human milk oligosaccharide (HMO), wherein such treatment reduces or improves at least one sign or symptom of age-related neurodegeneration.

[0014] 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). Non-limiting examples of the neurodegenerative diseases include Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and age-related dementia. In certain specific aspects, 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. In yet further aspects, the patient is diagnosed with Alzheimer’s Disease.

[0015] 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. In certain aspects, the PD is idiopathic PD. In additional embodiments, the PD is genetic PD.

[0016] In additional embodiments, the patient exhibits manifestations or biomarkers of nasal, oral or gut dysbiosis and / or gut permeability. In additional aspects, the patient exhibits symptoms of Crohn’s disease, ulcerative colitis, chronic idiopathic constipation, gastroparesis, dysphagia, dyspepsia, or irritable bowel syndrome.

[0017] In yet additional aspects, the patient exhibits one or more early signs of Parkinson’ s Disease selected from tremor, small handwriting, loss of smell, trouble sleeping, bradykinesias, constipation, soft or low voice, less expressive face, dizziness or fainting, or stooped posture.

[0018] In further aspects, 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.

[0019] In certain embodiments, 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.

[0020] In additional aspects, the treatment improves a cognitive battery score.

[0021] In further aspects, the treatment reduces a neurological sign or symptom, wherein the neurological sign or symptom is memory impairment as 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.

[0022] In certain additional embodiments, the treatment improves a neuropsychiatric symptom; for example, reduces depression and / or anxiety.

[0023] In certain aspects, the treatment slows or stops cognitive decline.

[0024] In some embodiments, the treatment improves one or more of the following in a PD patient: PD-associated gastrointestinal symptoms (e.g., constipation, dysphagia, and gastroparesis); cognitive function; neuroinflammation (e.g, reduced neuroinflammation as measured by biomarkers and / or reduced T-cell infiltration in the brain); motor function; gastrointestinal, nasal and / or oral microbiome diversity (e.g., a decrease in proinflammatory microbes such as microbes belonging to the phylum Proteobacteria and / or an increase in short-chain fatty acid (SCFA) producing bacteria such as Blautia, Roseburia, and Faecalibacterium) ; Lewy body pathogenesis; and accumulation of synuclein aggregates. Also encompassed are methods of reducing the risk of developing Parkinson’s disease in a patient in need thereof, the method comprising administering to said patient an effective amount of 2-FL or a composition thereof. 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.

[0025] The composition to be administered comprises an effective amount of the one or more human milk oligosaccharides. In certain aspects, 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-para-lacto-N-neohexaose (DFpLNnH), difucosyllacto-N- hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS -tetrasaccharide a (LSTa), LS -tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N- acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or disialyllacto-N- tetraose (DSLNT), or a combination of any of thereof. In yet other aspects, the one or more HMDs is selected from 2’FL, 3 ’FL, 3’SL, 6’SL, LNT, or LNnT, or a combination of any of thereof.

[0026] In yet further aspects, 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.

[0027] In certain specific aspects, the HMO is 2-FL. In certain additional aspects, 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. Such 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), difucosyl- para-lacto-N-neohexaose (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS- tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT), or a combination of any of thereof. In yet further aspects, the one or more HMOs is selected from 3 ’FL, 3’SL, 6’SL, LNT, or LNnT, or a combination of any of thereof.

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an oligosaccharide" or “an HMO” includes a plurality of such oligosaccharides and reference to "a therapeutic agent" includes reference to one or more therapeutic agents and equivalents thereof known to those skilled in the art, and so forth.

[0030] Also, the use of "or" means "and / or" unless stated otherwise. Similarly, "comprise, ""comprises," "comprising" "include," "includes," and "including" are interchangeable and not intended to be limiting.

[0031] It is to be further understood that where descriptions of various embodiments use the term "comprising," those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language "consisting essentially of or "consisting of."

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0033] Although many methods and reagents are similar or equivalent to those described herein, the exemplary methods and materials are disclosedherein. All publications mentioned herein are incorporated herein by reference in full for the purpose of describing and disclosing the methodologies, which might be used in connection with the description herein. Moreover, for terms expressly definedin this disclosure, the definition of the term as expressly provided in this disclosure will control in all respects, even if the term has been given a different meaning in a publication, dictionary, treatise, and the like.

[0034] The term “about” as used herein, in reference to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, within 5%, or within 4%, or within 2% of the value or range.

[0035] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" as used herein, refers to a pharmaceutically-acceptable material, composition, or vehicle, 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. Examples of "pharmaceutically acceptable carriers" and "pharmaceutically acceptable excipients" can be found in the following, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe etal.. Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004. The compositions described herein can include a pharmaceutically acceptable carrier. For example, a composition comprising an HMO can include the HMO and a pharmaceutically acceptable carrier.

[0036] The term "subject" as used herein, 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. The terms "subject" and "patient" are used interchangeably herein. For example, a mammalian subject can refer to a human patient. In preferred aspects, the subject is a human patient.

[0037] 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. For example, 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. In certain aspects, the patient in need of treatment is a patient diagnosed with a neurodegenerative disease such as PD or AD.

[0038] The term "release controlling excipient" as used herein, 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. The term "non-release controlling excipient" as used herein, 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.

[0039] The term "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.

[0040] The terms "treat", "treating" and "treatment," as used herein, 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. In certain aspects, 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).

[0041] The present invention encompasses co-administration of the composition comprising one or more human milk oligosaccharide and an additional active agent. As used here “coadministration” 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. When at least two therapeutic agents are administered at different times, their administration can be separated by minutes, hours, days, weeks, or months, and / or be administered as part of the same treatment regimen.

[0042] An “effective amount” or a “therapeutically effective amount” of an agent (e.g., one or more HMOs or additional active agent) as described herein 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. For example, an “effective amount” of a human milk oligosaccharide, as described herein, 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.

[0043] The term "therapeutically 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.

[0044] The terms “active agent,” “drug,” “therapeutic agent,” are used interchangeably herein and refer 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. The terms “active agent,” “therapeutic agent,” and “drug” as used herein includes, but are not limited to, human milk oligosaccharides.

[0045] The term “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. For example, age-related neurodegeneration can be considered a disease, disorder, condition, and / or a syndrome.

[0046] 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. There is an increasing body of evidence to suggest that alterations in the GI microbiome may be associated with the development and progression of PD [6-8], For example, studies have shown that people with PD have different patterns of GI microbiota compared to healthy individuals [9], PD 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)

[0010] , 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

[0013] 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). In addition, the loss of loss of olfaction that has been associated with pre-motor PD in 75-95% of early cases

[0014] , 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”

[0015] , Like the GI the nasal cavity has a unique microbiota that plays a critical role in olfactory development and smell

[0016] , it has also been associated with pro-inflammatory disease states. Much like the GI microbiota, studies have examined the PD nasal microbiota community and hypothesize that an altered deep nasal microbiota, characterized by a putative pro- inflammatory microbial community, could trigger neuroinflammation in PD

[0017] ,

[0047] Human milk oligosaccharides (HMOs) are naturally occurring prebiotics

[0018] , 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

[0019] , and due to reported benefits, 2’FL is routinely added to many infant formulae to simulate human breast milk. Studies have shown that 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

[0020] , 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. In nonclinical studies, 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], Roles in GI motility, barrier function, and lining inflammation have also been reported, as 2’FL reduces the frequency and velocity of gut contractions, blocks potentially harmful bacterial strains from adhering to host cell receptors, and has anti-inflammatory effects

[0023] , In addition, HMOs affect gene expression in intestinal epithelial cells, influencing their differentiation, survival, and surface glycan expression

[0024] , Further to improving GI barrier function 2’FL has also been reported to directly reduce inflammation via T-cell regulation

[0025] ,

[0048] 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). In a recently published study, patients with IBS (n = 317; all subtypes) were treated with a mixture of HMOs containing 4 g 2’FL and 1 g lacto-N-neotetraose for 12 weeks

[0026] , The results showed that irrespective of IBS subtype, patients had statistically significant improvements in bowel function, pain, and quality of life following treatment, suggesting a potential therapeutic role of 2’FL in IBS. As PD suffer from similar GI symptoms (i.e., constipation) in addition to increased inflammation, we postulate that 2’FL could offer the same alleviation of symptoms as seen for IBS sufferers through the promotion of a “good bacterium” that produce SCFA which will improve cognitive function and reduce neuroinflammation. Further to this animal models have demonstrated cognitive function during 2’FL feeding, specifically improved memory and learning in adult animals

[0027] , Further animal work attributes this improved cognitive function to the increased expression of different molecules involved in the storage of newly acquired memories, such as the postsynaptic density protein 95, phosphorylated calcium / calmodulin-dependent kinase II and brain-derived neurotrophic factor in cortical and subcortical structures

[0028] , Therefore, in certain embodiments, the invention is directed to the administration of 2’FL in a patient in need thereof. In certain aspects, the administration of 2’FL improves the GI microbiota, cognition, and / or GI symptoms in a PD patient.

[0049] 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; gastroenterological symptom (including, but not limited to, abdominal pain and diarrhea); gut microbiome dysbiosis; or a combination of any of thereof. In certain aspects, 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. In other aspects, 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).

[0050] In additional aspects, 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.

[0051] In further aspects, 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).

[0052] 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).

[0053] In additional aspects, 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). In further aspects, 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). In certain aspects, 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.

[0054] In certain aspects, the sign or symptom of age-related neurodegeneration is a neurob ehavioral abnormality associated with dysbiosis (see, for example, Maguire et al. (2018), 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. Alternatively, or in addition, the method comprises using a neurob ehavioral test to monitor the effectiveness of the treatment.

[0055] In certain aspects, 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. In additional embodiments, 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.

[0056] 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. In specific examples, 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. In another example, 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.

[0057] An "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. As used herein, the term “human milk oligosaccharide” includes natural or native oligosaccharides found in human milk, as well as pharmaceutically acceptable salts, derivatives, prodrugs, and solvates thereof. The term “natural human milk oligosaccharide” or “natural HMO” refers to human milk oligosaccharides naturally found in human milk. Natural human milk oligosaccharides (HMOs) 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 (HMOs) 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. In certain aspects, 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.

[0058] 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):

[0059] 2,3 Sialyllactose (3'-SL) 2,6 Sialyllactose (6'-SL)

[0060] The terms “3’-SL” and “3’SL” are used interchangeably herein. Similarly, the terms “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. In addition, 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. In vivo data in mouse models of rheumatoid arthritis, which include an LPS challenge, sialyllactose has shown benefit in clinical assessments of disease when administered orally.

[0061] 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. In certain aspects, the fucosylated non-digestible oligosaccharide is 2’- fucosyllactose (2’-FL). In certain aspects, the fucosylated oligosaccharide is 2'- fucosyllactose (2'-FL), 3-fucosyllactose (3 ’-FL), difucosyllactose (DFL). In yet further aspects, the fucosylated oligosaccharide is 2’ -FL. As used herein, 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. For example, 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.

[0062] Fucosyllactose (FL) is a fucosylated non-digestible oligosaccharide present in human milk but not in cow milk. The primary fucosylated HMO is 2’-fuscosyllactose or 2’FL. It consists of three monosaccharide units, fucose, galactose and glucose linked together. Lactose is a galactose unit linked to a glucose unit via a beta 1,4 linkage. 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:

[0063] The terms 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. In addition, 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.

[0064] Derivatives of natural HMOs can be chemically modified as compared to the natural HMO. In certain aspects, 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)):

[0065] Formula 1(a);

[0066]

[0067] Formula 1(c);

[0068]

[0069] Formula 1(d);

[0070]

[0071] Formula 1(e);

[0072]

[0073] Formula 11(a);

[0074]

[0075] Formula Illa or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: 1 18

[0076] R -R are each independently selected from H, D, a halo, an unsubstituted or substituted (Ci-Ce)alkyl, an unsubstituted or substituted (Ci-C6)heteroalkyl, an unsubstituted or substituted (C2- Ce)alkenyl, an unsubstituted or substituted (C2- C6)heteroalkenyl, an unsubstituted or substituted (C3-Ce)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR', - RN(R')2, -RS SR', -SH, - RSOR', -RSO2R', -RSO2H, -RSO3H, -RC(=S)-R', -ROH, - RC(=O)R', -RNO2, -RSR', -RCN, -RNC, -RNNR', -RC(=O)OR', -ROC(=O)R', - RC(=O)H, -RC(=O)OH, -RC(=O)N(R')2, -RN3, -ROCN, -RNCO, -RONO2, -RNO, - ROP(=O)(OH)2, and -RB(OH)2;

[0077] R is absent or a (Ci-Cs)alkyl;

[0078] 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

[0079] R29is an unsubstituted or substituted (Ci-C6)alkyl.

[0080] In yet additional aspects, the HMO has the Formula Illb:

[0081]

[0082] Formula Illb wherein: one, two or three of R19-R28are 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 R29is substituted or unsubstituted C1-C6alkyl; or one, two or three of R19-R29are 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 R29is substituted or unsubstituted C1-C6alkyl. In certain aspects, R26is NHC(0)CH3 and R19-R25and R27-R28are -OH, and R29is methyl.

[0083] The term “alkyl” refers to an organic group that is comprised of carbon and hydrogen atoms that contains single covalent bonds between carbons. Typically, 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. Where if there is more than 1 carbon, 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.

[0084] The term “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. Typically, 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. In certain instances, 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.

[0085] The term "alkynyl", refers to an organic group that is comprised of carbon and hydrogen atoms that contains a triple covalent bond between two carbons. Typically, 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.

[0086] Where if there is more than 3 carbons, 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.

[0087] The term "aryl", as used in this disclosure, 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.

[0088] The term "cycloalkyl", as used in this disclosure, 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.

[0089] The term "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. Examples of such 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. In a particular embodiment, a "hetero"-hydrocarbon (e.g., alkyl, alkenyl, alkynyl) refers to a hydrocarbon that has from 1 to 3 C, N and / or S atoms as part of the parent chain.

[0090] The term "heterocycle," as used herein, 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. Typically, the noncarbon ring atom is N, O, S, Si, Al, B, or P. In the case where there is more than one noncarbon ring atom, these noncarbon ring atoms can either be the same element, or combination of different elements, such as N and O.

[0091] Examples of 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-azepine homopiperazine, 1,3- dioxepane, 4,7- dihydro-l,3-dioxepin, and hexamethylene oxide; and polycyclic heterocycles such as, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3- dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, 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. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7- oxabicyclo[2.2. l]heptane.

[0092] The terms "heterocyclic group", "heterocyclic moiety", "heterocyclic", or "heterocyclo" used alone or as a suffix or prefix, refers to a heterocycle that has had one or more hydrogens removed there from.

[0093] The term "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.

[0094] The term “optionally substituted” means independent replacement of one or more hydrogen atoms with a substituent. The term "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. Accordingly, "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. For example, an optionally substituted hydrocarbon group refers to an unsubstituted hydrocarbon group or a substituted hydrocarbon group.

[0095] As described herein, 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. In certain aspects, the composition is not human milk. In additional aspects, the composition is not derived from human milk.

[0096] In certain aspects, 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 (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS-tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N- acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT), or a combination of any of thereof. In yet other aspects, the one or more human milk oligosaccharides are selected from 2’FL, 3 ’FL, 3’SL, 6’SL, LNT, or LNnT, or a combination of any of thereof.

[0097] The composition administered to the subject can comprise one HMO or can comprise a mixture of two, three, four, five or more HMOs. In certain aspects, the composition comprises one HMO and the HMO is selected from the group consisting of 2’FL, 3 ’FL, 3’SL, 6’SL, LNT, or LNnT.

[0098] In further aspects, the composition comprises a mixture of 2’FL and at least one other HMO. In certain aspects, the composition comprises 2’FL and LNT; 2’FL and LNnT; 2’FL, 3 ’FL, 3’SL, 6’SL and LNT. The composition comprising 2’FL and LNT includes a 4: 1 mixture of 2’FL and LNT; such a composition is GRAS (generally regarded as safe) and is available from Glycom, Lyngby, Denmark. A composition comprising 2’FL, 3 ’FL, 3’SL, 6’SL and LNT is sold by Jennewein Biotechnologie and is GRAS.

[0099] In further aspects, the composition comprises a mixture of one neutral core and one neutral fucosylated human milk oligosaccharide. In additional embodiments, the composition comprises a mixture of one neutral and one acidic human milk oligosaccharide.

[0100] The composition can be administered orally. The composition can be formulated as a liquid formulation (e.g., aqueous solutions), a powder, a nutritional additive, protein bar, as well as a tablet and capsule.

[0101] The HMO can be co-administered with an additional active agent. The additional active agent can be part of the same composition comprising the HMO, or the additional active agent and the HMO can be administered as part of different compositions. A nonlimiting example of an additional active agent is a prebiotic agent and / or a probiotic agent. A specific prebiotic that can be co-administered with an HMO is a fructan, such as inulin. Inulin includes a beta-2- 1 -linked chain of fructose molecules, this chain having at its end an alphaD-glucose unit at the reducing end. Inulin occurs in various plants such as, for example, chicory roots, dahlia tubers, Jerusalem artichokes and artichokes. The average chain lengths of the various inulins and their physico-chemical properties differ in different plant species. In certain aspects, the inulin is administered as a gel-based in inulin formulation such as that described in WO2021061789, the contents of which are expressly incorporated by reference herein. In some embodiments, the agent is a gel-based inulin formulation having an average degree of polymerization between 20 and 47. In certain specific aspects, the gel-based inulin formulation having an average degree of polymerization of 23 to 33, or 28.

[0102] The invention also encompasses methods of treating a neurodegenerative disease, such as an age-related neurodegenerative disease, in a patient in need thereof, comprising administering to said patient a composition comprising a therapeutically effective amount of inulin, wherein such treatment reduces or improves at least one sign or symptom of age- related neurodegeneration. The invention additionally includes a method of treating a patient suffering from a genetic or idiopathic neurodegenerative disease comprising, administering to said patient a composition consisting of inulin. In certain aspects, the inulin is administered as a gel -based in inulin formulation such as that described in WO2021061789, the contents of which are expressly incorporated by reference herein. In some embodiments, the agent is a gel-based inulin formulation having an average degree of polymerization between 20 and 47. In certain specific aspects, the gel-based inulin formulation having an average degree of polymerization of 23 to 33, or 28.

[0103] The oligosaccharides described herein can be synthesized chemically, enzymatically or with synthetic biology technology, i.e. genetically engineered microorganism. Human milk oligosaccharides, including 2’-fucosyllactose, 3’sialyllactose, and 6’sialyllactose, can, for example, be readily prepared with well-established synthetic biology methods.

[0104] In some embodiments, the composition comprises at least 9% (e.g. , 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%; or any value between any of the foregoing) of the total human milk oligosaccharides in the composition.

[0105] In certain aspects, the pharmaceutical composition one or more human milk oligosaccharides, and optionally a pharmaceutically acceptable carrier or excipient.

[0106] The oligosaccharide can be administered in an amount from about 1 g to about 20 g, about 1 to about 15 g, or about 2.5 to 7.5 g per day or per dose. The oligosaccharide can be administered at various intervals, for example, once a day, twice a day, three times a day, once a week, twice a week, or as needed.

[0107] In further aspects, the methods additionally provide an improvement in the subject’s microbiota (gut and / or oral) composition. Improvement in, or avoidance of, gastrointestinal symptoms, such as constipation, diarrhea, stool consistency, stool smell, flatulence and abdominal pain is desirable, such as, for example, at weeks 8 and 16 of the beginning of treatment.

[0108] Oral administration of the oligosaccharides of the disclosure provide for systemic circulation of the oligosaccharides both in infantsand adults. Unlike other drug products approved by the FDA, the oligosaccharides described herein can not only be administered to treat a disease or disorder in an adult subj ect, but can also be administered to pregnant females, infants, and subjects who have impaired organ function (c. ., liver disfunction, kidney failure). Due to the oligosaccharides of the disclosure having little to no adverse effects in humans, this form of therapy could be used as a preventive, as a first line therapy option, or as an adjunct to existing therapies that would be well tolerated by patients of either sex.

[0109] In a further embodiment, said oligosaccharide is substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)- enantiomer and about 10% or less by weight of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

[0110] 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. As such, one of skill in the art will recognize that 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. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0111] When the 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).

[0112] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL- mandelic acid, methanesulfonic acid, naphthal ene-2-sulfonic acid, naphthal ene- 1,5- disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0113] 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- hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D- glucamine, 2- amino-2-(hydroxy methyl)- 1,3 -propanediol, and tromethamine.

[0114] 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.

[0115] The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent oligosaccharide. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in “Design of Biopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671- 696; Asgharnejad in “Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875- 877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409- 421; Nathwani and Wood, Drugs 1993, 45, 866-94;

[0116] Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

[0117] The oligosaccharide may be produced by biotechnological means using enzymebased fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures and / or mixed cultures may be used. Alternatively, the oligosaccharides may be produced by chemical synthesis from lactose and other substrates. Biotechnological approaches have made it possible for the large scale, cost- efficient production of target oligosaccharides.

[0118] Precisely, 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.

[0119] Alternatively, the oligosaccharides of the disclosure can be synthesized based upon methods described in WO2011100980A1; W02012007588A1;

[0120] W02012127410A1; WO2012155916A1; WO2013044928A1; and US9102966B2. 2'-FL can be made as described in WO 2010 / 115934 and WO 2010 / 115935, 3-FL can be made as described in WO 2013 / 139344. Fucosylated oligosaccharides can be made as described in WO 2012 / 127410. With regard to biotechnological methods, 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. See, for example, W0200104341; W02007 101862, WO2010070104; WO2010142305; WO2012112777; Priem et al. , Glycobiology 12:235 (2002); Drouillard etal., 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., Micro b. CellFact. 12:40 (2013); and WO 2014135167A1.

[0121] Alternatively, the oligosaccharides of the disclosure can be synthesized based upon methods described in WO2011100980A1; W02012007588A1;

[0122] W02012127410Al;W02012155916Al;W02013044928Al;and US9102966B2. 2'-FL can be made as described in WO 2010 / 115934 and WO 2010 / 115935, 3-FL can be made as described in WO 2013 / 139344, 6'-SL and salts thereof can be made as described in WO 2010 / 100979, sialylated oligosaccharides can be made as describedin WO 2012 / 113404 and mixtures of human milk oligosaccharides can be made as described in WO 2012 / 113405. As examplesof enzymatic production, sialylated oligosaccharides can be made as described in WO 2012 / 007588, fucosylated oligosaccharides can be made as described in WO 2012 / 127410.

[0123] With regards to biotechnological methods, WO 2001 / 04341 and WO 2007 / 101862 describe how to make oligosaccharides optionally substituted by fucose or sialic acid using genetically modified E. coli.

[0124] In a certain embodiment, the composition described herein can further comprise one or more foodgrade agents. Examples of 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 pantothenate, vitamin A palmitate, citric acid, manganese sulfate, pyridoxine hydrochloride, vitamin D3, copper sulfate, thiamine mononitrate, riboflavin, beta carotene, folic acid, biotin, potassium iodide, chromium chloride, sodium selenate, sodium molybdate, phytonadione, vitamin B12, magnesium chloride, calcium phosphate).

[0125] Disclosed herein are methods of treatment comprising administering pharmaceutical 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.

[0126] Disclosed herein are pharmaceutical 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.

[0127] The pharmaceutical compositionsmay also comprise non-release controlling excipients or carriers.

[0128] Further disclosed herein are pharmaceutical 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.

[0129] Further disclosed herein are pharmaceutical 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.

[0130] Additionally, disclosed are pharmaceutical 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.

[0131] Disclosed herein also are pharmaceutical 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.

[0132] Described herein are pharmaceutical 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.

[0133] Described herein are pharmaceutical 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.

[0134] The pharmaceutical compositions disclosed herein may be disclosed in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, 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. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple- dosage forms include vials, bottles of tablets or capsules, or bottles of pints orgallons.

[0135] 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.

[0136] These 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;

[0137] Vol. 126).

[0138] The pharmaceutical 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.

[0139] Once improvement of the patient's condition has occurred, 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.

[0140] The pharmaceutical compositions disclosed herein may be formulated in solid, semisolid, or liquid dosage forms for oral administration. As used herein, 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. In addition to the oligosaccharides, 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.

[0141] 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. , STARCH 1500); gelatin; sugars, 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-105(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. 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.

[0142] 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.

[0143] 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.

[0144] It should be understood that many carriers and excipients may serve several functions, even within the same formulation. The pharmaceutical 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.

[0145] 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.

[0146] 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), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. 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. The 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.

[0147] The pharmaceutical 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.

[0148] 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. For a liquid dosage form, for example, 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.

[0149] Other useful 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.

[0150] The pharmaceutical 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.

[0151] The pharmaceutical 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.

[0152] The pharmaceutical 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.

[0153] Examples of the source of protein include whey protein concentrates, whey protein isolate, whey protein hydrolysates, and acid.

[0154] The pharmaceutical compositions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed- release forms.

[0155] The pharmaceutical 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.

[0156] The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0157] The pharmaceutical 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. Such 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).

[0158] The pharmaceutical 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.

[0159] The pharmaceutical 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.

[0160] The pharmaceutical compositions may be formulated as a suspension, solid, semisolid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, 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.

[0161] 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.

[0162] 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. 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. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

[0163] The pharmaceutical compositions disclosed herein may be formulated as a modified release dosage form. As used herein, the term “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.

[0164] 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).

[0165] The pharmaceutical 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.

[0166] Generally, 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. During an initial treatment phase, 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). During a maintenance phase, 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).

[0167] Depending on the disorder to be treated and the inj ection in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0168] 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.

[0169] In certain embodiments, 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.

[0170] 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. Or, by way of example only, 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).

[0171] 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. When 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.

[0172] Accordingly, the pharmaceutical compositions disclosed herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to an oligosaccharide disclosedherein.

[0173] The invention is illustrated by the following non-limiting examples.

[0174] Example 1: Effect of 2-FL on symptom alleviation on Parkinson’s Disease

[0175] 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.

[0176] 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. In addition, 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.

[0177] The development of 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. For patients 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.

[0178] Briefly, in this interventional randomized double-bind trial, patients will ingest OM002 once a day for 26 weeks. 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.

[0179] It is hypothesized that one or more of the following outcomes will be observed after OM002 treatment: reduction of constipation, slowing of cognitive decline, and improvement of motor function.

[0180] Research plan and methodology i. Patient recruitment

[0181] Patients will be recruited into this study primarily through Neuroscience Research Australia (NeuRA), Randwick, New South Wales, with community recruitment via social media as a secondary recruitment strategy. We aim to recruit 180 PD cases who will participate in the supplement trial. 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

[0182] Clinical details will be recorded for all patients using:

[0183] 1. The validated Digestive Health and Wellbeing Survey (DHWS) to assess gastrointestinal symptoms, anxiety and depression, sleep, smoking and alcohol intake.

[0184] 2. The food frequency questionnaire (FFQ) to measure baseline diet and intervention diet compliance. Comprehensive Nutrition Assessment Questionnaire (CNAQ) was developed in Australia and validated in a group of healthy Australian adults in 2010

[0029] , to assess intake of macronutrients, vitamins, minerals, sugars, and fermentable carbohydrates (dietary history).

[0185] 3. A medical interview, including a detailed medical history (to include allergies) and other pathologies, medication usage, surgical history, family medical history and demographics.

[0186] 4. Cognitive function assessment will be completed following a published battery

[0030] , this includes: QoL assessed by the PDQ-39

[0031] and the Short Form Health Survey (SF-36)

[0032] , Mood assessed by the Beck Depression Inventory (BDI)

[0033] , cognitive function by the Montreal Cognitive Assessment (MoCA)

[0034] , whilst chronic pain severity was assessed by the Visual Analogue Scale

[0035] and physical activity by the International Physical Activity Questionnaire (IPAQ)

[0036] , Non-motor symptoms evaluated by the Non-Motor Symptoms Scale (NMSS)

[0037] , Clinical motor assessments using the Movement Disorder Society — Unified Parkinson’s Disease Rating Scale — Part III (MDS-UPDRS III) criteria

[0038] performed by a neurologist. PD medication will be calculated as daily levodopa equivalent dose (LED)

[0039] , iii. Sample collection and processing

[0187] Buccal (cheek) swab, saliva, nasal swab, stool, blood, and urine samples will be collected.

[0188] 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. Statistical analysis will assess correlations between disease progression, intervention, and microbiota to identify specific microbial factors modulated by OM002 and reduction of symptom severity.

[0189] 1. Buccal Swab / DNA collection and analysis: Cells from inside of the participant’s cheek will be collected using a standard buccal swab supplied by Isohelix™. 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.

[0190] 2. 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.

[0191] 3. 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.

[0192] 4. 16S and ITS analysis; Data will be processed with QIIME2 and DADA2. Taxonomic assignment performed in R with DADA2 against SILVA SSU reference database for 16S reads and the fungal ITS data annotated against the DAnlEL database

[0040] , Analysis of microbiota diversity will be performed in R, using packages phyloseq, breakaway, ampvis2, and microbiome. Alpha diversity was analyzed for significant difference through Wilcoxon test, Bonferroni correction was used for post-hoc comparisons. Adonis2 (PERMANOVA) was used to test statistical significance of beta diversity plots. Data will be normalized with total sum scaling (TSS) and subsequently transformed using centre log ratio (CLR) for rank sum testing.

[0193] 5. Stool DNA extraction and MGS; 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.

[0194] 6. 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.

[0195] 7. Immune phenotyping: Peripheral blood mononuclear cells (PBMCs) will be isolated from blood samples by density gradient centrifugation. Flow cytometry will phenotype the T cells populations, using a surface marker staining approach established by Professor Keely’s lab. In addition to identifying the total gut-homing populations in PD patients (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

[0196] 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. The trial will consist of 2 groups (n=80 / each) who will receive either OM002 or placebo for 13 weeks in addition to the standard of care. Following this period both groups will receive an open label for an additional 13 weeks. 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).

[0197] To achieve statistical power 0.8 at the 0.05 level of statistical significance (two- tailed) requires n=160 subjects in total randomized equally into active and control conditions. We will aim to recruit 180 to control for study drop out.

[0198] Participants in this study will continue to be provided with routine medical care and treatment throughout the trial. 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.

[0199] This study may result in the reduction of symptom severity and disease progression for PD. Characterization of PD immune profile, the oral, nasal, and GI microbiota in parallel with specific OM002 intervention may identify microbes associated with symptom reduction and disease progression. Such microbe(s) can then be isolated the microbe and assessed for its capacity for pro- or synbiotic development. REFERENCES

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[0240] 2017; 8: 37.

[0241] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[0242] All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED:

1. 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.

2. The method of claim 1, wherein the genetic or idiopathic neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and age-related dementia.

3. The method of any one of claims 1 or 2, wherein the patient also exhibits manifestations or biomarkers of nasal, oral or gut dysbiosis and / or gut permeability.

4. The method of claim 3, wherein the patient also exhibits symptoms of Crohn’s disease, ulcerative colitis, chronic idiopathic constipation, gastroparesis, dysphagia, dyspepsia, or irritable bowel syndrome.

5. The method of any one of claims 2-4, wherein the patient exhibits one or more early signs of Parkinson’s Disease selected from tremor, small handwriting, loss of smell, trouble sleeping, bradykinesias, constipation, soft or low voice, less expressive face, dizziness or fainting, or stooped posture.

6. The method of any one of claims 1-4, wherein 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 disfunction, sexual dysfunction, excessive swelling, seborrhea, sialorrhea, insomnia, REM behavior disorder, restless leg disorder, periodic movements in sleep, excessive daytime sleepiness, hyposmia, decreased visual contrast.

7. The method of any one of claims 2-4, wherein the patient is diagnosed with Parkinson’s disease 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.

8. The method of any one of claims 2-4, wherein the patient is diagnosed with Alzheimer’s Disease.

9. The method of any one of the preceding claims, wherein the diagnosis comprises use of the Work Productivity and Activity Impairment (WPAI) Questionnaire.

10. The method of any one of claims 1-4, wherein the at least one human milk oligosaccharide is selected from the group consisting of 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-fucopentaose 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 (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS- tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT).

11. The method of claim 10, wherein the one or more human milk oligosaccharide selected from 2’FL, 3 ’FL, 3’SL, 6’SL, LNT, or LNnT.

12. The method of claim 1, wherein the composition comprises one or more human milk oligosaccharides contains a mixture of two, three, four or five human milk oligosaccharides.

13. The method of claim 12, wherein the composition comprises a mixture selected from: i. 2’FL and LNT; ii. 2’FL and LNnT; iii. 2’FL and 3’SL; iv. 2’FL, 3 ’FL, 3 ’ SL, 6’ SL and LNT; v. 2’FL, 3 ’FL, 3 ’ SL, 6’ SL and LNnT; vi. 2’FL and 6’SL; vii. 3’SL and 6’SL; viii. 6'SL and LNnT; or ix. 6’SL and LNT.

14. The method of any of claims 1 - 4, wherein the composition comprises a mixture of one neutral core and one neutral fucosylated human milk oligosaccharide.

15. The method of any of claims 1 - 4, wherein the composition comprises a mixture of one neutral and one acidic human milk oligosaccharide.

16. The method of claim 10, wherein the one or more human milk oligosaccharides is selected from 2’FL, 3’SL or 6’SL.

17. The method of any of claims 1 - 4, wherein the composition comprises a mixture of one neutral fucosylated and one acidic human milk oligosaccharide.

18. The method of claim 1, wherein the composition is not a mammalian milk.

19. The method of claim 1, wherein the composition is not derived from mammalian milk.

20. The method of claim 1, wherein the composition comprises 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharides.

21. The method of any one of the preceding claims, wherein the treatment improves gut microbiome diversity.

22. The method of any one of the preceding claims, wherein the treatment improves gastrointestinal symptoms associated with gut dysbiosis.

23. The method of any one of the preceding claims, wherein the treatment improves weekly complete spontaneous bowel movements or weekly worst abdominal pain (WAP).

24. The method of any one of the preceding claims, wherein the treatment improves the cognitive battery score.

25. The method of any one of the preceding claims, wherein the treatment reduces a neurological sign or symptom, wherein the neurological sign or symptom is memory impairment as 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.

26. The method of any one of the preceding claims, wherein the treatment reduces depression and / or anxiety and / or other neuropsychiatric symptoms.

27. The method of any one of the preceding claims, wherein the treatment improves olfactory dysfunction or gustatory dysfunction.

28. The method of any one of the preceding claims, wherein the treatment improves nasal or oral dysbiosis.

29. The method of any one of the preceding claims, wherein the method improves gut microbiome dysbiosis.

30. The method of claim 29, wherein the method improves gastrointestinal symptoms associated with gut microbiome dysbiosis.

31. The method of any one of claims 28 - 30, wherein the method improves inflammatory symptoms associated with the dysbiosis.

32. The method of any one of the preceding claims, wherein the patient is 55 years old or less.

33. The method of any one of the preceding claims, wherein the patient is 50 years old or less.

34. The method of any one of claims 1 to 31, wherein the patient is 55 years or older.

35. The method of claim 34, wherein the patient is 60 years or older.

36. The method of claim 35, wherein the patient is 70 years or older.

37. The method of any one of the preceding claims, wherein the patient is female.

38. The method of any one of claims 1 to 36, wherein the patient is male.

39. The method of any one of the preceding claims, wherein the patient has a body mass index (BMI) greater than or equal to 30.

40. The method of any one of the preceding claims, wherein the treatment slows or stops cognitive decline.

41. The method of any one of the preceding claims, wherein the treatment improves oral, nasal or gut microbiome diversity.

42. The method of any one of the preceding claims, wherein the treatment improves biomarkers of systemic inflammation.

43. The method of any one of the preceding claims, wherein the treatment improves motor function.

44. The method of any one of the preceding claims, wherein the treatment decreases Lewy body pathogenesis in the patient.

45. The method of any one of the preceding claims, wherein the treatment slows or stops the accumulation of synuclein aggregates in the brain of the patient.

46. 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.

47. The method of claim 46, wherein PD-associated gastrointestinal symptoms are improved after initiation of the treatment.

48. The method of claim 47, wherein PD-associated constipation is improved after initiation of the treatment.

49. The method of claim 46, wherein cognitive function of the patient is improved after initiation of the treatment.

50. The method of claim 46, wherein neuroinflammation is decreased after initiation of the treatment.

51. The method of claim 46, wherein motor function is improved after initiation of the treatment.

52. The method of claim 46, wherein gastrointestinal microbiome diversity is improved after initiation of the treatment.

53. The method of claim 52, wherein there is a decrease in pro-inflammatory microbes and / or an increase in short-chain fatty acid (SCFA) producing bacteria.

54. The method of claim 46, wherein the nasal microbiome diversity is improved after initiation of the treatment.

55. The method of claim 54, wherein there is a decrease in pro-inflammatory microbes and / or a decrease in short-chain fatty acid producing bacteria.

56. The method of claim 46, wherein oral microbiome diversity is improved after initiation of the treatment.

57. The method of claim 46, wherein the treatment decreases Lewy body pathogenesis in the patient.

58. The method of claim 46, wherein the treatment slows or stops the accumulation of synuclein aggregates in the brain of the patient.

59. The method of any one of claims 46 to 58, wherein 2-FL is co-administered with one or more additional HMOs.

60. The method of claim 59, wherein the one or more additional HMOs are selected from the group consisting of 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-fucopentaose 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 (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS-tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or di si aly 11 acto-N -tetraose (D SLNT) .

61. The method of claim 46, wherein the 2-FL is administered in a composition that is not a mammalian milk.

62. The method of claim 46, wherein the 2-FL is administered in a composition that is not derived from mammalian milk.

63. A method of reducing the risk of developing Parkinson’s disease in a patient at risk of developing PD, the method comprising administering to said patient an effective amount of 2-FL.

64. The method of claim 63, wherein the patient is 55 years or older.

65. The method of claim 64, wherein the patient is 60 years or older.

66. The method of claim 65, wherein the patient is 70 years or older.

67. The method of claim 63, wherein the patient is wherein the patient is 55 years old or less.

68. The method of any one of claims 63 to 67, wherein the patient is male.

69. The method of any one of 63 to 67, wherein the patient is female.

70. The method of claim 63, wherein the patient has a gene mutation associated with PD.

71. The method of claim 63, wherein the patient has a family history of PD.

72. The method of claim 63, wherein the patient has been diagnosed with an autoimmune rheumatic disease.

73. The method of claim 63, wherein the patient has suffered past traumatic brain injury.

74. The method of claim 63, wherein the patient has suffered past exposure to environmental toxins associated with increased risk of PD.

75. The method of claim 63, wherein the patient suffers from gut dysbiosis.

76. The method of claim 63, wherein the patient suffers from ulcerative colitis or Crohn’s disease.

77. The method of any one of claims 63 to 76, wherein 2-FL is co-administered with one or more additional HMOs.

78. The method of claim 77, wherein the one or more additional HMOs is selected from the group consisting of 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-fucopentaose 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 (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS -tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or di si aly 11 acto-N -tetraose (D SLNT) .

79. The method of claim 63, wherein the 2-FL is administered in a composition that is not a mammalian milk.

80. The method of claim 63, wherein the 2-FL is administered in a composition that is not derived from mammalian milk.

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