WO2011070565A1

WO2011070565A1 - Glucans for treating or preventing food sensitivity

Info

Publication number: WO2011070565A1
Application number: PCT/IL2010/001004
Authority: WO
Inventors: Oded Shoseyov; Nir Shani; Ziv Shani
Original assignee: Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd.
Priority date: 2009-12-07
Filing date: 2010-12-01
Publication date: 2011-06-16

Abstract

Disclosed are pharmaceutical compositions comprising glucan and uses of glucans for the treatment and/or prophylaxis of conditions associated with or mediated by food sensitivity.

Description

GLUCANS FOR TREATING OR PREVENTING FOOD SENSITIVITY

FIELD OF THE INVENTION

This invention relates to methods and compositions for the treatment and/or prevention of food sensitivity and diseases and disorders associated therewith.

BACKGROUND OF THE INVENTION

Food sensitivity, resulting in adverse reactions to food, can be roughly categorized into food intolerance and food allergy. Food intolerance (or non-allergic food hypersensitivity) is a digestive system response rather than an immune system response. It occurs when something in a food irritates a person's digestive system or when a person is unable to properly digest or breakdown the food. Intolerance to lactose, which is found in milk and other dairy products, is the most common food intolerance.

On the other hand, food allergy (FA) is characterized by an abnormal immunologic reactivity to food proteins. The gastro-intestinal (GI) tract serves not only a nutritive function but is also a major immunologic organ. Although previously thought to be triggered primarily by an IgE-mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA. The clinical manifestations of FA, expressed in affected target organs, are possibly the result of immunologic injury mediated by interaction of food antigens with contiguous elements of mucosal associated lymphoid tissue. These appear to be modulated by relative imbalances of the Thl/Th2 paradigm, which may be the ultimate determinant governing the expression of FA as IgE-mediated, non-IgE- mediated, or mixed forms of IgE/non-IgE mechanisms of FA. Thus, food allergy may be defined as a complex of clinical syndromes resulting from the sensitization of the patient to one or more foods, in which symptoms manifest locally in the gastrointestinal (GI) tract or in remote organs as a result of an immunologic reaction.

Unlike other food related enteropathies, celiac disease, a disorder induced by gluten (a protein found in wheat, rye and barley), cannot be distinctly characterized as either food intolerance or FA. On the one hand celiac can be categorized as a food intolerance since gluten is, by itself, toxic to the intestine and since unique peptides that are formed by its ineffective digestion are involved in the disease progression. On the other hand, gluten or gluten peptides that are formed by gluten's partial digestion, induces a Thl immune reaction that causes an inflammation of the intestine and thus can be categorized as a food allergy (FA is characterized by an abnormal immunologic reactivity to food proteins). In order to simplify discussion, celiac disease is arbitrarily classified as food intolerance in this application. Celiac disease (gluten intolerance) affects between 0.5 and 1 percent of people in the United States and its only known effective treatment is a lifelong gluten-free diet.

Food allergies can range from merely irritating to life-threatening. Approximately 30,000 Americans go to the emergency room each year to be treated for severe food allergies, according to the Food Allergy and Anaphylaxis Network (FAAN). It is estimated that 150 to 200 Americans die each year because of allergic reactions to food. Food allergy may coexist with eating disorders, metabolic problems, diabetes and other disease states.

The most common inducers of food allergies in young children are cow's milk, egg, peanut, wheat, soy, tree nuts, fish and shellfish (such as shrimp, lobster and crab). Most of the early childhood allergies to milk, egg, soy and wheat are resolved by school age while peanut, tree nut and seafood allergies generally persist throughout life. The only efficient treatment of food allergic individuals is food allergen avoidance by avoiding causal food or foods.

The clinical manifestations of food allergy are many and include symptoms in the digestion system, skin, respiratory system and a systematic anaphylactic shock. Symptoms in the digestive system include allergic eosinophilic infiltration of the esophagus, stomach and intestine that can result in vomiting, abdominal pain and diarrhea, blood loss in the stools, iron deficiency anemia and weight loss. The most common skin disorders that are provoked by food allergy are acute urticaria and angioedema; however, there is also a strong link between ingestion of food allergens and exacerbations in the cutaneous manifestations of atopic dermatitis.

Food allergies induced anaphylaxis accounts to one third to half of the reported cases of anaphylaxis and peanuts and tree nuts (such as walnuts) are responsible for the majority of the more serious events. Anaphylaxis, which is an IgE dependent acute systemic allergic reaction, causes systemic vasodilation that can result in a sudden drop in blood pressure, edema of bronchial mucosa resulting in bronchoconstriction and breathing difficulties and in severe cases cardiovascular symptoms, including hypotension, vascular collapse, and cardiac dysrhythmias. When left untreated, anaphylaxis can lead to death due to heart failure and blockage of the airways.

It has recently been demonstrated that the major grass allergens from group I and groups II/III (β-expansin and expansin like proteins respectively) contain a hypothetical carbohydrate binding module (CBM) [1,2]. Furthermore, a close structural relationship was demonstrated between the CBM and allergenic properties [2]. Furthermore, it was shown that oxidized cellulose (OC), a biocompatible and biodegradable derivative of cellulose [3,4], possesses an impressive binding capacity of rye grass pollen allergens which was far superior to the allergen binding capacity of a variety of other carbohydrates that were tested including cellulose [5].

Additionally, it was determined that particles, e.g., micro or nano in size, of glucans may be employed to prevent and/or treat allergic non-food reactions [5].

REFERENCES

[1] Shoseyov, O., Z. Shani, and I. Levy, Carbohydrate binding modules: biochemical properties and novel applications. Microbiol Mol Biol Rev, 2006. 70(2): p. 283-95.

[2] Barre, A. and P. Rouge, Homology modeling of the cellulose-binding domain of a pollen allergen from rye grass: structural basis for the cellulose recognition and associated allergenic properties. Biochem Biophys Res Commun, 2002. 296(5): p. 1346-51.

[3] Dimitrijevich, S.D., et al., Biodegradation of oxidized regenerated cellulose. Carbohydr Res, 1990. 195(2): p. 247-56.

[4] Dimitrijevich, S.D., et al., In vivo degradation of oxidized, regenerated cellulose. Carbohydr Res, 1990. 198(2): p. 331-41.

[5] WO07/113835.

SUMMARY OF THE INVENTION

The inventors of the present invention have found that food allergens such as ovalbumin (OVA), a major egg allergen, bind to oxidized cellulose (OC). In contrast to other allergens, such as grass allergens, that have also been shown to bind OC, OVA does not contain the known carbohydrate binding molecule (CBM). Since OC is a biocompatible derivative of cellulose it may be added to various allergen-containing food products as a food additive in order to prevent the allergic potential of food allergens, either during food production of food products containing allergens or after consumption of such products inside the body.

Thus, in its broadest scope, the present invention relates to the use of at least one glucan, such as oxidized cellulose, for preparing medicaments for therapeutic treatment and/or prophylaxis of conditions mediated by or associated with food sensitivity (i.e. food allergy and/or food intolerance), to pharmaceutical compositions comprising said glucan and to related methods of therapeutic treatment and/or prophylaxis. The present invention also relates to kits or commercial packages containing any one of the compositions of the invention as particular formulations and dosage forms.

In a first of its aspects, the present invention provides a use of at least one glucan for the preparation of a pharmaceutical composition (or a medicament) for the treatment and/or prophylaxis of food sensitivity, i.e., a condition associated with or mediated by consumption of a food allergen or a food that causes food intolerance.

The invention also provides a use of at least one glucan in a method of treatment and/or prophylaxis of food sensitivity. In another of its aspects, the invention provides a pharmaceutical composition comprising at least one glucan for the treatment and/or prophylaxis of food sensitivity.

The pharmaceutical composition comprising the at least one glucan may also be used in delaying the onset or lessening the severity of a condition associated with food sensitivity and/or in reducing a subject's sensitivity to a food allergen and/or to a food that causes food intolerance.

The term "glucan", as used herein, refers to a polysaccharide of sugar monomers linked together by glycosidic bonds. The glucan may be a- or β-glucan and may be of natural, synthetic or semi-synthetic origin. The at least one glucan may be a combination (e.g., a mixture) of two or more glucans. Within the scope of the present invention, the term does not encompass cellulose or any unoxidized form thereof (i.e., cellulose ethers, cellulose esters, etc.).

The at least one glucan may be one or more of the glucans known in the art. In some embodiments, the glucan is selected amongst polysaccharides that bind protein allergens. Non-limiting examples of the at least one glucan are oxidized cellulose, pullulan, starch, glycogen, dextran, lichenin, mannan, galactomannan, arabinoxylan, galacton and any derivative thereof. In some embodiments, the at least one glucan is oxidized cellulose.

In other embodiments, the oxidized cellulose is in the form of a salt. In further embodiments the oxidized cellulose salt is microdispersed oxidized cellulose (in short MDOC, usually prepared as a mixed calcium/sodium salt, with equal molar concentrations of calcium and sodium cations, typically in the form of a finely dispersed powder). In yet further embodiments, the at least one glucan is a derivative of oxidized cellulose.

The term "food sensitivity" refers, in general, to an undesirable response (short term or long term condition or disorder) that occurs during or after the ingestion of food or a food compound, such as an adverse reaction to food that may range from a slight rash to a severe allergic response. Food sensitivity is broadly divided into two categories: food allergy and food intolerance.

The "food allergy" is the undesirable allergic response, against the effect of which the methodologies of the invention have been formulated; it is an abnormal response of the body to a food (most often a food protein), comprising a food allergen, triggered by the body's immune system. The "food allergen" is any agent or chemical in a food product or inherently associated with the consumption thereof, which is capable of inducing, promoting, or stimulating allergy, i.e., the hypersensitive state induced by an exaggerated immune response to the food allergen, in a subject consuming the food product. The food allergen may be associated with any one food ingredient, including but not limiting to proteins, carbohydrates and fats as well as additives, artificial flavors and colors employed in the food industry. The allergen may be one which is an additive to a food product or which is derived from any one food group. Non-limiting examples of such food-groups include milk; eggs- the main allergens being the egg white proteins ovomucoid, ovalbumin, and ovotransferrin; peanuts; tree nuts, such as Brazil nuts, hazelnuts, walnut and pecan; soybeans; wheat; rye; barely; oat; fish, such as bass, flounder, cod; crustacean shellfish, such as crab, lobster, and shrimp; mustard; and vegetables such as celery.

Non-limiting examples of food allergens are ovomucoid, ovalbumin, ovotransferrin and lysozyme (egg white), Cas s 5 and 8 (chestnut), Ber e 1 and 2 (Brazil nut), Cor a 1, 2, 8, 9 and 11 (hazelnut), Jug n 1 and 2 and Jug r 1 to 4 (walnut), Ara h 1 to 8 (peanut), tropomyosin (shelfish), parvalbumins (fish), Mus xp Hevein (banana) and Pers a Hevein (avocado).

Notwithstanding, the definition provided herein, in the context of the present invention, the allergen may be any food, or ingredient thereof, which has been identified to cause an allergic reaction in sensitive individuals.

When, in the context of the present invention, food sensitivity is a food allergy the "condition mediated by or associated with food sensitivity " is typically one or more symptoms which occur after the entering of a food allergen into the gastro intestinal (GI) system or when coming in contact with any part of the GI tract. The ensued condition may be one directly induced by the food allergen or a condition which may not be directly mediated by the initial allergen exposure, but which may deteriorate due to continued exposure thereto.

Symptoms of a food allergy or of a disease or disorder associated therewith usually develop within about an hour after eating the food containing the allergen. The most common signs and symptoms of a food allergy include hives, itching, or skin rash; swelling of the lips, face, tongue and throat, or other parts of the body; wheezing, nasal congestion, or trouble breathing; abdominal pain, diarrhea, nausea, or vomiting; dizziness, lightheadedness, or fainting. In a severe allergic reaction to food (called anaphylaxis), a subject suffering from more extreme versions of the above reactions may even experience life-threatening signs and symptoms, such as swelling of the throat and air passages that makes it difficult to breathe; shock, with a severe drop in blood pressure; rapid, irregular pulse and loss of consciousness.

The symptoms may also manifest as delayed food allergy symptoms whereby the symptomatic process begins with the action of food materials in the digestive tract and continues into the blood stream and then affects the function of a target organ which receives the food. Some non-limiting examples include symptoms that are limited to the digestive tract such as tract-indigestion, abdominal pain, bloating, nausea, vomiting, and diarrhea. The symptoms may be general or systemic: fever, fatigue, sweating and chills. The lungs may be affected, such as in food-induced bronchitis and asthma. In some cases the joints are the affected target organs (such as in food allergic arthritis).

Other symptoms include pain, stiffness, and swelling of the muscles and connective tissue; weakness and reduced tolerance (which may or may not be associated with pain); itching, rashes, hives, thickening, redness, swelling, and scaling of the skin such as in eczema and psoriasis. Disorganized, disturbed thinking, feeling, remembering, and behaving may also occur in cases where the brain is the target organ.

As used herein, the term "food intolerance" refers to a negative reaction, often delayed, to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems, but it is not a true food allergy (e.g., does not require the presence of IgE antibodies against the food in contrast to food allergy). The "food that causes food intolerance" is a food or a food compound which ingestion, even at very small quantities (e.g., a few micrograms or even less) results in food intolerance or in a condition associated therewith.

In some embodiments, the food compound that causes intolerance is gluten or a gluten component. Gluten is a highly complex protein that occurs in four main grains: wheat, rye, barley and oats (Gluten is also present in all baked foods that are made from these grains, e.g. bread, pies, cake, breakfast cereals, porridge, cookies, pizza and pasta). The term 'gluten components', as mentioned herein, refers generally to gliadin (a prolamin) and glutenin (a glutelin) which are known for their role in the formation of gluten.

In some embodiments, the food that causes intolerance is gluten and the gluten intolerant people are celiacs, i.e., people having coeliac disease.

When, in the context of the present invention, food sensitivity is food intolerance the "condition mediated by or associated with food sensitivity" refers to any pharmacologic, metabolic, and gastro-intestinal responses to foods or food compounds which cause food intolerance. In some embodiments, the condition is coeliac disease.

In some embodiments, the pharmaceutical composition of the invention is formulated for mucosal application, as an oral formulation, as an intranasal administration or as a formulation suitable for inhalation.

The composition of the invention may be administered to a subject in need thereof prior to the consumption of a food product known to or suspected of containing an allergen. The composition, alternatively, is administered regularly at predetermined time periods so as to avoid or minimize any potential exposure to an allergen even where absolute avoidance of food products known to contain the allergen is practiced. Similarly, the composition of the invention may be taken after the consumption of a food. Where an allergic reaction after food consumption ensues, the composition may be taken even during that allergic episode in order to minimize or arrest further deterioration of symptoms.

The composition of the invention may comprise one or more glucans, as defined, one of which optionally being oxidized cellulose, and in addition may compirse at least one pharmaceutically active additive, such as anti-allergy agent, as known in the art.

The composition may also comprise a pharmaceutically acceptable carrier, such as a vehicle, an adjuvant, an excipient, or a diluent. Such carriers are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the glucan, e.g., oxidized cellulose or any other component of the composition and one which has no detrimental side effects or toxicity under the conditions of use. The choice of carrier will be determined in part by the particular composition, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.

In another of its aspects, the present invention provides a method for the treatment and/or prophylaxis of a condition associated with or mediated by a food allergen, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan, as defined.

The invention also provides a method for delaying the onset or lessening the severity of a condition associated with or mediated by a food allergen and/or a food that causes food intolerance, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan.

In still another of its aspects, the present invention provides a method for reducing a subject's sensitivity to a food allergen and/or a food that causes food intolerance, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan.

In some embodiments, the at least one glucan is not cellulose or any unoxidized form thereof. In other embodiments, the at least one glucan is oxidized cellulose. In some embodiments, the at least one glucan is a salt or a derivative of oxidized cellulose. In some embodiments, the at least one glucan is microdispersed oxidized cellulose. In further embodiments, said at least one glucan, e.g., oxidized cellulose, a salt or derivative thereof, is in the form of solid particulates, which may, in some embodiments be in an amorphous form.

In some embodiments, the solid particulates are microparticles or nanoparticles, e.g., having average diameter of between 0.01 and 100 microns.

In some embodiments, the food allergen, as defined herein, is associated with the consumption of milk, chicken, egg, nuts, wheat, soybeans, vegetables and legumes, fruit and melons, fish and shellfish, grains and seeds and spices.

In some embodiments, in any one method of the invention, the pharmaceutical composition of the invention is administered to the subject prior to, in conjunction with (simultaneously to) or after a meal wherein said meal comprises or is suspected to comprise a food allergen (or is known or suspected to initiate an allergic response) and/or a food that causes food intolerance.

In some embodiments, the pharmaceutical composition comprising OC is used in a method for the treatment of coeliac.

The condition associated with or mediated by food sensitivity may be one or more of those recited herein. In some embodiments, the condition may be one or more of coeliac, inflammation, allergic and non-allergic disease or disorder of the respiratory system or the skin. Some non-limiting examples of the diseases and disorders are allergic asthma, asthma, extrinsic bronchial asthma, chronic obstructive pulmonary disease, hay fever (seasonal rhinitis), allergic rhinitis, allergic conjunctivitis, hives, eczema, urticaria, angioedema, onchocercal dermatitis, atopic dermatitis, dermatitis, swelling, hypersensitivity pneumonitis and bronchopulmonary dysplasia.

The subject to be treated according to methods of the invention, for the purposes of treatment and/or prophylaxis, is a subject having predisposition (genetic or environmental) to suffer from a condition associated with or mediated by the consumption of a food allergen, a food that causes food intolerance or any disease or disorder associated therewith or a subject already suffering, at the onset of treatment, from such a condition, disease or disorder. The subject may also be one who desires to avoid a potential reaction to food allergens, independently of one's prior health and predisposition.

The term "treatment and/or prophylaxis" or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of a composition of the invention which is effective to ameliorate undesired symptoms associated with a food sensitivity or any condition, disease or disorder associated therewith, to prevent the manifestation of such symptoms before they occur, slow down the deterioration of symptoms, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the condition, disorder or disease form occurring or a combination of two or more of the above.

In another one of its aspects, the present invention provides a food additive composition comprising at least one glucan.

The present invention also provides a method of reducing the allergenicity and/or the intolerability of a food product, said method comprising adding to said food product an amount of said food additive composition.

In some embodiments, the at least one food additive composition is added to the food product during its production. In other embodiments, the food additive composition is added to the food product immediately prior to consumption by a subject, e.g., suffering or having a predisposition to suffer from food sensitivity.

Thus, the invention also provides a food product comprising a food additive composition, as defined herein.

In some embodiments said food product is selected from spreads, margarines, dressings, puddings, custards, low fat cheeses, toppings, sauces, mayonnaises, ice creams, yogurts, frozen desserts, icings, sour creams, batters, bakery creams, batter coatings, baked products, creamers, shortenings, baby foods, powdered soups, liquid soups and breadings.

Without wishing to be bound by theory, the addition of a composition of the invention, or at least one glucan, e.g., oxidized cellulose, to food comprising allergens and/or to food that causes food intolerance prevents the occurrence of food sensitivity and diseases and disorders associated therewith. As know, in the case of food allergies, in order to initiate an allergic reaction the food allergens must first pass the epithelial mucosa and reach and bind mast cell bound IgE. It is believed that, at least in some instances, the oxidized cellulose, as well as other glucans as defined herein, prevents the cross linking of IgE by allergens in two main ways: 1. due to its large size, an oxidized cellulose-allergen complex has a substantially reduced ability to penetrate the tight epithelial layer and reach mast cell bound IgE that is found beyond this layer, or

2. if an oxidized cellulose bound allergen reaches mast cell bound IgE, the oxidized cellulose would then compete with IgE on its binding to the allergenic epitopes to further diminish the potential of the allergic reaction.

The invention also provides a kit or a commercial package comprising at least one glucan and instructions of use.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Fig. 1 demonstrates the effective binding of ovalbumin (OVA) to oxidized cellulose (OC); B - bound fraction, UB - unbound fraction.

Fig. 2 shows the binding of gluten extract (gliadins) with OC microparticles; B - bound fraction, UB - unbound fraction.

DETAILED DESCRIPTION OF EMBODIMENTS

Adverse reactions to dietary proteins in food sensitivity may or may not be immune-mediated. The immune-mediated adverse reaction to food is defined as food allergy (FA) which is roughly divided into IgE-mediated or non-IgE-mediated FA (NFA), also known as delayed-type food allergy. In addition, a mixed IgE- and non- IgE-mediated FA is also possible.

As opposed to IgE-mediated FA, NFA mainly affects the GI mucosa. The gut mucosal barrier is thought to have developed to execute an enormously difficult task— the digestion and absorption of nutrients without provoking immune responses and cohabiting with commensal flora in a mutual beneficial relationship, while maintaining an immune defense against pathogenic microbes. Unlike IgE-mediated FA, NFA is rarely life-threatening. However, NFA to dietary proteins can cause significant morbidity in rapidly growing infants and young children.

As a rule, allergic symptoms in IgE-mediated FA occur within two hours of eating. Allergic symptoms in NFA do not appear for at least 2 hours, not infrequently showing up to 24 to 48 hours later (there are reports of delayed symptoms appearing 3 to 7 days after eating). Flu-like symptoms are typical manifestations of the delayed patterns of food allergy. Patients often complain of fatigue, irritability, aching and cognitive dysfunction. Delayed food allergy begins in the gastrointestinal tract mucosa and spreads inward to any body tissue if food antigens enter the circulation and interact with the circulating immune system. Incoming food antigens tend to form immune complexes, and can injure target organs by triggering inflammatory responses in a variety of ways. Consequently, the delayed (non IgE) mechanisms of food allergy tend to produce recurrent or chronic symptoms and the symptom complexes occur both generally and in target organs such as the gastrointestinal tract. These mechanisms are not demonstrable by skin tests.

The difficulty in diagnosing FA, particularly in non-IgE-mediated food allergies, lies in the identification of the allergens due to their slow, cell-mediated, non-IgE mechanism of action. This makes skin prick tests and serum measurement of food- specific IgE levels less sensitive in detecting the food allergens. Furthermore, the clinical reactivity to a food upon oral challenge may take up to a few days to develop, which adds to the difficulty in its identification. Moreover, most non-IgE-mediated allergic disorders involve more than one food allergen. Another problem with treating and diagnosing IgE-mediated FA and in particular delayed type non-IgE-mediated FA is that skin prick testing for food allergens may be unreliable and "false negatives" may occur where the reaction to food is not immediate. Thus, skin prick testing is typically restricted to IgE mediated FA.

Further, people may also still have positive skin tests to foods, even when they have grown out of the allergy and no longer have an allergic reaction on eating a problem food. Importantly, after food allergy has been diagnosed, the only treatment measure that can be offered to date is to avoid the offending food. It should be noted that food avoidance can have serious deleterious nutritional consequences when an important food group is removed from a person's diet; hence a strong need for an efficient remedy as well as prevention of food allergy exists.

Additionally, carbohydrate binding antigens are often used by pathogens to initiate the attachment and penetration to host epithelia which is covered by glycoproteins. Thus, the host immunogenic response induced by allergens that contain some sort of carbohydrate binding capacity may arise from the similarity between pathogens and allergens carbohydrates binding antigens. This further implies that CBM containing allergens may be found in many types of allergen groups including food allergens. In fact, the major latex allergen hev b 6.01 (also termed prohevein) contains a chitin binding domain from CBM family 18, termed the hevein domain. Similarly to β-expansin's CBM, the main IgE-binding epitope of hev b 6.01 is known to be the hevein domain. A group of class I chitinases food allergens from various fruits (Kiwi, Banana, avocado, chestnut and others) contain a chitin binding domain, termed the hevein-like domain that shares high sequence similarity with hevein. This similarity results in cross reactivity between latex and food allergens which is responsible for the "latex-fruit syndrome".

Example 1: Ovalbumin binding to oxidized cellulose

To study the ability of food allergens to bind oxidized cellulose (OC), the ability of OC to bind ovalbumin (OVA), a major egg allergen that is often used, due to its strong immunogenic properties to provoke different allergies, in various animal models, was examined. Purified OVA was incubated with microparticles of either oxidized cellulose or microcrystalline cellulose. Bound (B) and unbound (UB) fractions and total proteins (Total) were separated by SDS-PAGE and stained by coomassie.

As Fig. 1 shows, after incubation of OVA with OC microparticles, most of the OVA protein was found in the bound fraction (B) while only traces of the protein were found in the unbound fraction (UB). In contrast to the efficient binding of OC, the majority of OVA that was incubated with crystalline cellulose (not oxidized cellulose) was found in the UB fraction while only a minute fraction of the total protein was found in the B fraction.

To prevent food allergy, OC was added to various allergen containing food products or consumed separately as a food additive on regular bases. It is believed that the binding of OC to food allergens prevents the allergenic potential of food allergens during the production of food products that contain allergens or precursors thereof and also after the consumption of said food products.

As stated hereinabove, it is believed that in order to initiate an allergic reaction, food allergens must first pass the epithelial mucosa and reach and bind mast cell bound IgE. Additionally, the preventive binding of OC to allergen can occur in two main stages: 1. prior to consumption~OC may be added to the allergen containing foods during their production.

2. OC may be consumed separately from the allergy containing food and may encounter the allergen inside the oral cavity or digestion system.

With regards to OC consumption separately from allergy containing food, three different treatment regimens may be considered:

1. OC may be taken by allergic individuals before each meal as a preventive treatment, whether the meal is known to contain allergic food or as a precautionary measure against unknown allergic ingredients in the food;

2. If the OC treatment turns out to be efficient enough, OC may be taken in order to allow allergic patients to consume allergic food that would otherwise cause them harm; and/or

3. OC may be taken after the unintended consumption of allergenic food as an emergency procedure.

The exact location in which food allergens are absorbed is not clear, however, it is known that complete absorption takes a few hours, during which period the continuous absorption of allergens enhances the allergic reaction. Therefore, the post consumption of OC as "detoxification" treatment may prevent the continuation of allergen absorption and the enhancement of the allergic reaction.

In some embodiments, the OC is consumed orally: 1. as a pill or inside a capsule; 2. as a powder suspension in water (allowing quick delivery to the digestion system in the detoxification example, similar to the consumption of activated charcoal); or 3. as a powder inhalation. It is known that the majority of the powder in any inhalation procedure reaches the oral cavity and the digestion system. Additionally, it is known that allergens are already absorbed from the oral cavity. Thus, OC powder that is efficiently spread in the oral cavity by powder inhalation can prevent allergen absorption from this area more efficiently.

Example 2: Clearance of oxidized cellulose from the airways and intestines and its metabolism in the body.

In order to examine the clearance and metabolism of OC from the airways and digestion system, OC microparticles were fluorescently labeled with Cye5.5, intranasally administered to mouse and their clearance was followed via in vivo imaging (not shown). Intranasal administration of OC resulted in ~50%/50% distribution of OC between the airways and the digestion system. OC was detectable in the nose, tracheal area and the left lung at 40 min post-administration. OC was found in large quantities in the intestines within 4h of administration but was completely cleared from the digestion system within 24 hours. As intranasal administration of OC suspensions resulted in OC overdose in the lungs, it allowed to follow OC clearance from the lungs over time. OC was almost completely cleared from the lungs within 13 days and was completely cleared within a month, demonstrating effective clearance even at overdose OC quantities. In order to assess OC metabolism after its clearance from the respiratory and digestion system, the liver, kidney and spleen were removed from mice at different time points following intranasal OC administration for fluorescence evaluation. OC was already detected in high quantities in the liver and kidney but not in the spleen, 7 hours after its administration. OC was consistently found in the liver and kidney over the 13 days following administration and mirrored the gradual decrease in pulmonic OC levels, indicating continuous OC clearance from the lungs but no accumulation in these organs. Fluorescence levels in the liver and kidneys returned to close to basal levels by day 13.

In conclusion, OC was efficiently cleared from the airways and digestion system. A portion of OC that reached the blood circulation was metabolized by the liver and kidneys and did not accumulate in these organs. OC was further cleared from the kidneys into the urine as was evident by the detection of degradation products of fluorescent OC by FPLC in the urine of mice that received OC-Cy5.5 (data not shown).

Example 3: Gliadin binding to oxidized cellulose

As explained herein, coeliac (celiac) disease is a non allergic autoimmune disorder of the digestive system with prevalence estimates of 0.5-1% in the general population. In susceptible individuals gliadin, a gluten protein found in wheat, rye and barley, induces an inflammatory response in the small intestine which can result in diarrhea, weight loss (or stunted growth in children) and fatigue. Thus, coeliac disease is caused by a reaction to gliadin. Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small-bowel tissue, causing an inflammatory reaction. Gliadin induced inflammation leads to a truncating of the villi lining the small intestine which interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. Similarly to food allergy, the only efficient treatment for this disease is the avoidance of gluten containing foods. Gluten (or a gluten component, such as gliadin or glutenin) binding by OC can prevent the symptoms associated with coeliac disease, employing the same methodologies disclosed herein in connection with the treatment and/or prevention of food allergies.

The ability of OC to bind gliadins, extracted from gluten by deionized water, was examined. Gluten extracts were incubated with microparticles of either oxidized cellulose or crystalline cellulose. Bound (B) and unbound (UB) fractions and total proteins (Total) were separated by SDS-PAGE and stained by coomassie.

As Fig. 2 shows, after an incubation of a gluten extract with OC microparticles, most of gliadin proteins (marked by a bracket, the predominant molecular weight range of reduced α, β and γ gliadin polypeptides is 33-37 Kd in SDS PAGE) were found in the bound fraction (B) while nearly none of the protein was found in the unbound fraction (UB). In contrast to the efficient binding of OC, the majority of gliadins that were incubated with crystalline cellulose (not oxidized) were found in the unbound fraction while nearly none of the total protein was found in the bound fraction.

Claims

CLAIMS:

1. Use of at least one glucan in the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of a condition associated with or mediated by food sensitivity.

2. Use of at least one glucan in the preparation of a pharmaceutical composition for delaying the onset or lessening the severity of a condition associated with or mediated by food sensitivity.

3. Use of at least one glucan in the preparation of a pharmaceutical composition for reducing a subject's sensitivity to a food allergen and/or to a food that causes food intolerance.

4. The use according to claims 1 or 2, wherein the food sensitivity is food allergy.

5. The use according to claims 1 or 2, wherein the food sensitivity is food intolerance.

6. The use according to any one of claims 1 to 5, wherein said at least one glucan is selected from oxidized cellulose, pullulan, starch, glycogen, dextran, lichenin, mannan, galactomannan, arabinoxylan, galacton and any derivative thereof.

7. The use according to claim 6, wherein said at least one glucan is oxidized cellulose.

8. The use according to claim 7, wherein said oxidized cellulose is microdispersed oxidized cellulose.

9. The use according to claim 6, wherein said glucan is a salt or a derivative of oxidized cellulose.

10. The use according to claim 7 or 9, wherein said oxidized cellulose, a salt or a derivative thereof is in the form of solid particulates.

11. The use according to claim 10, wherein said solid particulates are in an amorphous form.

12. The use according to claim 10, wherein said solid particulates are microparticles or nanoparticles

13. The use according to claim 11, wherein said solid particulates have an average diameter of between 0.01 and 100 microns.

14. The use according to any one of claims 1 to 13, wherein said food sensitivity is associated with or mediated by a food allergen and/or a food that causes food intolerance contained in a food product selected from milk, chicken, egg, nuts, wheat, rye, barely, oat, soybeans, vegetables and legumes, fruit and melons, fish and shellfish, grains and seeds and spices.

15. The use according to claim 14, wherein the food that causes food intolerance is gluten or a gluten component.

16. The use according to any one of claims 1-2, 4 and 6 to 14, wherein said condition is selected from allergic asthma, asthma, extrinsic bronchial asthma, chronic obstructive pulmonary disease, hay fever (seasonal rhinitis), allergic rhinitis, allergic conjunctivitis, hives, urticaria, angioedema, onchocercal dermatitis, atopic dermatitis, dermatitis, swelling, hypersensitivity pneumonitis and bronchopulmonary dysphasia.

17. The use according to any one of claims 1-2 and 5 to 15, wherein said condition is coeliac.

18. The use according to any one of claim 1 to 17, wherein said composition is suitable for administration via the oral cavity, including oral administration and/or inhalation.

19. A pharmaceutical composition comprising at least one glucan for use in the treatment and/or prophylaxis of a condition associated with or mediated by food sensitivity.

20. A pharmaceutical composition comprising at least one glucan for use in delaying the onset or lessening the severity of a condition associated with or mediated by food sensitivity.

21. The composition according to claims 19 or 20, wherein the food sensitivity is food allergy.

22. The composition according to claims 19 or 20, wherein the food sensitivity is food intolerance.

23. A pharmaceutical composition comprising at least one glucan for use in reducing a subject's sensitivity to a food allergen and/or to a food that causes food intolerance.

24. The pharmaceutical composition according to any one of claims 19 to 23, wherein said at least one glucan is selected from oxidized cellulose, pullulan, starch, glycogen, dextran, lichenin, mannan, galactomannan, arabinoxylan, galacton and any derivative thereof.

25. The pharmaceutical composition according to claim 24, wherein said at least one glucan is oxidized cellulose.

26. The pharmaceutical composition according to claim 25, wherein said oxidized cellulose is microdispersed oxidized cellulose.

27. The pharmaceutical composition according to claim 24, wherein said glucan is a salt or a derivative of oxidized cellulose.

28. The pharmaceutical composition according to claim 25 or 27, wherein said oxidized cellulose, a salt or a derivative thereof is in the form of solid particulates.

29. The pharmaceutical composition according to claim 28, wherein said solid particulates are in an amorphous form.

30. The pharmaceutical composition according to claim 28, wherein said solid particulates are microparticles or nanoparticles

31. The pharmaceutical composition according to claim 29, wherein said solid particulates have average diameter of between 0.01 and 100 microns.

32. The pharmaceutical composition according to any one of claims 19 to 31, wherein said food sensitivity is associated with or mediated by a food allergen and/or a food that causes food intolerance contained in a food product selected from milk, chicken, egg, nuts, wheat, rye, barely, oat, soybeans, vegetables and legumes, fruit and melons, fish and shellfish, grains and seeds and spices.

33. The pharmaceutical composition according to claim 32, wherein the food that causes food intolerance is gluten or a gluten component.

34. The pharmaceutical composition according to any one of claims 19 to 33, wherein said composition is administered to the subject prior to, together with or after the consumption of a food product containing a food allergen and/or a food that causes food intolerance.

35. The pharmaceutical composition according to any one of claims 19 to 21 and 24 to 34, wherein said condition is selected from allergic asthma, asthma, extrinsic bronchial asthma, chronic obstructive pulmonary disease, hay fever (seasonal rhinitis), allergic rhinitis, allergic conjunctivitis, hives, urticaria, angioedema, onchocercal dermatitis, atopic dermatitis, dermatitis, swelling, hypersensitivity pneumonitis and bronchopulmonary dysphasia.

36. The pharmaceutical composition according to any one of claims 19-20, 22 and 24 to 34, wherein said condition is coeliac.

37. The pharmaceutical composition according to any one of claims 19 to 36, for administration via the oral cavity, including oral administration and/or inhalation.

38. A pharmaceutical composition for oral administration or inhalation comprising at least one glucan for the treatment or prevention of food sensitivity.

39. A pharmaceutical composition in an oral dosage form comprising at least one glucan for the treatment or prevention of food sensitivity.

40. A method for the treatment and/or prophylaxis of a condition associated with or mediated by food sensitivity, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan.

41. A method for delaying the onset or lessening the severity of a condition associated with or mediated by food sensitivity, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan.

42. A method for reducing a subject's sensitivity to a food allergen and/or to a food that causes food intolerance, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one glucan.

43. The method according to any one of claims 40 to 42, wherein said at least one glucan is selected from oxidized cellulose, pullulan, starch, glycogen, dextran, lichenin, mannan, galactomannan, arabinoxylan, galacton and any derivative thereof.

44. The method according to claim 43, wherein said at least one glucan is oxidized cellulose.

45. The method according to claim 44, wherein said oxidized cellulose is microdispersed oxidized cellulose.

46. The method according to claim 42, wherein said glucan is a salt or a derivative of oxidized cellulose.

47. The method according to claim 43 to 46, wherein said oxidized cellulose, a salt or a derivative thereof is in the form of solid particulates.

48. The method according to claim 47, wherein said solid particulates are in an amorphous form.

49. The method according to claim 47, wherein said solid particulates are microparticles or nanoparticles.

50. The method according to claim 48, wherein said solid particulates have average diameter of between 0.01 and 100 microns.

51. A food additive composition comprising at least one glucan.

52. A method of reducing allergenicity and/or the intolerability of a food product, said method comprising adding to said food product an amount of a food additive composition according to claim 51.

53. A food product comprising a food additive composition according to claim 51.