Method for treating autism spectrum disorder using ergothioneine or selenoneine

Abstract

To provide a pharmaceutical composition for use in treating autism spectrum disorders with ergothioneine and / or its analogue, selenoneine.SOLUTION: Provided is a pharmaceutical composition comprising ergothioneine (ET), selenoneine (SeET) or a combination thereof for use in treating autism spectrum disorder (ASD), the pharmaceutical composition being administered to a human subject in a therapeutically effective amount. Preferably, the ergothioneine, selenoneine, or combination thereof is administered in a powder, tablet, capsule, beverage or other edible form.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This patent relates to the treatment of autism spectrum disorders with ergothioneine and / or its analog selenoneine. [Background technology]

[0002] Autism, or autism spectrum disorder (ASD), refers to a group of neurodevelopmental disorders that generally emerge early in development. Individuals with ASD have a wide range of clinical manifestations, primarily manifested in social interactions with others, and in restricted behaviors and repetitive interests. Affected individuals also have other behavioral deficits in speech, learning, and motor skills.

[0003] The diagnosis of ASD is often behavior-based. Because there is no universal method for diagnosing ASD, several diagnostic methods are currently employed in clinical practice. The only clinically recognized method for treating ASD core behaviors is behavior analysis (BA). To date, the U.S. Food and Drug Administration has not approved any medications for ASD core behaviors. Therefore, it is desirable to develop effective and safe treatments for ASD core behaviors.

[0004] The prevalence of ASD creates a significant treatment demand. Many treatments are being explored in depth. There are over 800 clinical studies completed or ongoing in the United States to mitigate ASD and related disorders. There is a clear lack of effective treatments, as no medications are available to treat or alleviate the ASD core phenotype.

[0005] International Patent Publication No. WO 2014 / 005132 described ergothioneine as an ASD-associated metabolite and proposed treatments that modulate the gut microbiome to alter the levels of various ASD-associated metabolites.

[0006] International Patent Publication No. WO2021 / 158601 discloses the use of ergothioneine to treat various health conditions by altering telomere length, but does not address the dosage and nature of treatment for ASD.

[0007] International Patent Publication No. WO2017 / 181158 describes the improvement of at least one symptom of social behavioral deficits using probiotic therapy for developmental disorders and other neurological disorders.

[0008] International Patent Publication No. WO 2020 / 231906 describes ergothioneine as one of over 1,000 different compositions for treating over 90 different disease states. No direction exists suggesting the use of ergothioneine or selenoneine, alone or in combination, for the treatment of ASD.

[0009] This application describes methods for treating ASD and reducing ASD-related behavioral disorders using ergothioneine or selenoneine present in food. Summary of the Invention

[0010] This application relates to a method for treating autism spectrum disorder, comprising administering to a human subject a therapeutically effective amount of ergothioneine (ET), selenoneine (SeET), or a combination thereof. The ergothioneine (ET), selenoneine (SeET), or a combination thereof may be administered in the form of a powder, tablet, capsule, drink, or other edible form.

[0011] The dosage of ergothioneine (ET), selenoneine (SeET), or a combination thereof ranges from about 0.45 μg to about 800 mg / kg body weight per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 0.01 to about 17,600 mg per day. The dosage of ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 1 μg to about 300 mg / kg body weight per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 0.07 to about 12,000 mg per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 0.1 to about 75 mg / kg body weight per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 1 to about 1000 mg per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dose range of about 0.5 to about 20 mg / kg body weight per day.

[0012] The once-daily regimen can be administered daily for 3 months, 6 months, 1 year, 5 years, and 70 years, and these five regimens are patient-selectable.

[0013] The method of administration can include administering ergothioneine (ET) in a dose range of about 0.2 to about 20 mg / kg of body weight per day. The method can include administering ergothioneine (ET) in a dose range of about 1 to about 5 mg / kg of body weight per day. The method can include administering ergothioneine (ET) in a dose range of about 10 to about 1000 mg per day. The method can include administering ergothioneine (ET) in a dose range of about 20 to about 500 mg per day. The method can include administering ergothioneine (ET) in a dose range of 20 mg or more per day. The method can include administering ergothioneine (ET) in a dose range of 35 mg or more per day. The method can include administering ergothioneine (ET) in a dose range of 40 mg or more per day. The method can include administering ergothioneine (ET) in a dose range of 50 mg or more per day.

[0014] The CARS-2 score of the human subject can be reduced by at least 2 points. The CARS-2 score of the human subject can be reduced by at least 5 points.

[0015] The present application further relates to a method for treating autism spectrum disorder, comprising administering a therapeutically effective amount of ergothioneine (ET), selenoneine (SeET), or a combination thereof to a human subject, wherein the therapeutically effective amount of ergothioneine (ET), selenoneine (SeET), or a combination thereof is administered in a dose range of about 0.45 μg to about 800 mg / kg body weight per day, and the CARS-2 score of the human subject is reduced by at least 5 points.

[0016] The application also relates to a method of treating autism-related disorders (ASD) comprising administering to a human subject a therapeutically effective amount of a composition consisting essentially of ergothioneine (ET).

[0017] Additionally, the present application relates to a method for treating autism-related disorders (ASD) comprising administering to a human subject a therapeutically effective amount of a composition consisting essentially of selenoneine (SeET).

[0018] The present application further relates to a method of treating autism-related disorders (ASD) comprising administering to a human subject a therapeutically effective amount of a composition consisting essentially of ergothioneine (ET) and lenoneine (SeET).

[0019] The methods described herein may not require the administration of N-acetylcysteine ​​amide (NAC amide or NACA), anthocyanin or anthocyanins, astaxanthin, catechin or epigallocatechin, choline, l-citrulline, curcumin or curcumin, glutathione, phosphatidylserine, sasanin, or any combination thereof.

[0020] The method can exclude administering croton extract, chlorogenic acid, citrine choline, l-citrulline, non-cithin, sequoia base A, phosphatidylserine, Rhododendron bark extract, green tea extract, anthocyanin-3-glucoside (Cy-g), cyanin-3,5-diglucoside (Cy-dg), citrine base (also called CDP choline or renidin S′-diphosphorylcholine), citrulline, or combinations thereof.

[0021] The teachings herein further relate to compositions for treating autism-related disorders (ASD) that consist essentially of ergothioneine (ET).

[0022] The present application also relates to a composition for treating autism-related disorders (ASD) consisting essentially of selenoneine (SeET).

[0023] The present application also relates to a composition for treating autism-related disorders (ASD) consisting essentially of ergothioneine (ET), selenoneine (SeET), or a combination thereof.

[0024] The present application further relates to the use of ergothioneine (ET), selenoneine (SeET), or a combination thereof for the treatment of autism-related disorders (ASD).

[0025] The present application also contemplates a method of measuring an initial CARS-2 score of a human subject, administering to the human subject a therapeutically effective amount of a composition consisting essentially of ergothioneine (ET), selenoneine (SeET), or a combination thereof, and measuring the resulting CARS-2 score of the human subject.

[0026] The resulting CARS-2 score may be at least 2 points, or at least 5 points, lower than the initial CARS-2 score. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a graph showing changes in CARS-2 values ​​after treatment in Example 1.

[0028] [Figure 2] FIG. 2 is a graph showing changes in CARS-2 values ​​after treatment in Example 2.

[0029] [Figure 3] FIG. 3 is a graph showing changes in CARS-2 levels after treatment in Example 3.

[0030] [Figure 4] FIG. 4 is a graph showing changes in CARS-2 levels after treatment in Example 4.

[0031] [Figure 5] FIG. 5 is a graph showing the change in CARS-2 levels after the treatment in Example 5.

[0032] [Figure 6] FIG. 6 is a graph showing the change in CARS-2 levels after the treatment in Example 6.

[0033] [Figure 7] FIG. 7 is a graph showing changes in CARS-2 levels after treatment in Example 7.

[0034] [Figure 8] FIG. 8 is a graph showing changes in CARS-2 levels after treatment in Example 8.

[0035] [Figure 9] FIG. 9 is a graph showing changes in CARS-2 levels after treatment in Example 9.

[0036] [Figure 10] FIG. 10 is a graph showing changes in CARS-2 values ​​after treatment in Example 10.

[0037] [Figure 11] FIG. 11 is a graph showing changes in CARS-2 levels after treatment in Example 11.

[0038] [Figure 12] FIG. 12 is a graph showing changes in CARS-2 levels after treatment in Example 12. DETAILED DESCRIPTION OF THE INVENTION

[0039] The purpose of the descriptions and drawings presented in this application is to teach and familiarize others skilled in the art with its principles and practical applications. Those skilled in the art can adapt and apply the teachings in their numerous forms, as best suited to the requirements of a particular application. Accordingly, the specific embodiments of the present teachings described are not intended to be exhaustive or limiting of this application. Therefore, the scope of the teachings should be determined not with reference to the above description, but instead with reference to the claims appended hereto, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes. Other combinations are possible, as will be apparent from the following claims, which are also incorporated by reference herein.

[0040] Ergothioneine (ET) was discovered in 1909 and named after the ergot fungus (Claviceps purpurea). The chemical structure of ET was later determined and shown to be an analogue of the amino acid histidine. ET is present in various microorganisms and is particularly abundant in edible mushrooms. For example, the boletus mushroom (Boletus edulis) can contain up to 181 mg / 100 g of ET in its dry weight.

[0041] Selenoneine (SeET) is a close analogue of ET, in which sulfur is replaced by selenium (structure shown below). SeET was first discovered in tuna and is abundant in tuna muscle.

[0042] The structures of ergothioneine (ET), selenoneine (SeET), and histidine are shown below. ET (molecular weight 229.3 daltons) and SeET (molecular weight 275.2 daltons) are both positively charged trimethylbetaine derivatives of histidine. ET is a metabolic product synthesized in microorganisms from histidine precursors. [ka]

[0043] In general, ET is a strong antioxidant and anti-inflammatory agent. It has also been found to promote neurogenesis. Like ET, SeET has also been found to have antioxidant activity. SeET has also been found to be able to detoxify mercury in marine animals and fish species. Human studies have revealed that ET has anti-aging functions. Clinical metabolic studies have also found an inverse correlation between ET and cognitive decline. As a result, ET has been found to be significantly reduced in various cognitive-related disorders, such as mild cognitive impairment and frailty. Clinically, supplemental ET has improved stress-induced sleep disorders.

[0044] The prevalence of ASD has increased dramatically in recent decades. Currently, the prevalence of ASD among children in the United States is approximately 2.27% (1 in 44 children), and it is becoming a common condition worldwide. ASD encompasses a wide range of behavioral manifestations and is typically diagnosed early in development. ASD behaviors relate to social skills and communication, repetitive behaviors, and language skills. These disorders can be mild, moderate, or severe, with different signs and symptoms.

[0045] Four diagnostic systems based on behavioral descriptions are: 1) CARS-2 (Children's Autism Rating Scale, 2nd Edition), 2) DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition), 3) ABC Autism Behavior Inventory, and 4) ADOS-2 (Autism Diagnostic Observation Schedule, 2nd Edition). Each of these methods has specific applications. Here, CARS-2 has proven to have several advantages. Regarding sensitivity and specificity, the CARS-2 standard validity showed better sensitivity (sensitivity score 0.86) than DSM-IV (sensitivity score 0.71) and better specificity (specificity score 0.79) than DSM-IV (specificity score 0.75). The ABC diagnostic method lacked specificity in distinguishing ASD from other types of developmental disorders, with a relatively high false-negative rate (46%), whereas the CARS-2 had a 0% false-negative rate. A comparison of the CARS-2 and ADOS-2 showed that clinical judgments were consistent with each other, but the CARS-2 is a simpler and less expensive autism assessment tool. In general, the CARS-2 has proven to be a reliable and widely adopted method for assessing and diagnosing autism.

[0046] The specific cause of ASD is unknown. Genetic and environmental factors may contribute to the development of ASD. The most well-known genetically linked ASD is fragile X-ASD, in which a mutation occurs on the X chromosome.

[0047] Concomitant disorders are also common in patients with ASD, such as gut microbial dysbiosis (gut microecology dysbiosis) and impaired gut function, impaired detoxification of neurotoxins and heavy metals, and increased oxidative stress and inflammation. However, the relationship between these types of concomitant disorders and core behavioral disorders has not yet been well documented.

[0048] Behavioral treatment remains the primary treatment for core ASD symptoms, including communication disorders, social problems, and repetitive behaviors. Pharmacological interventions for treating core ASD behaviors are rarely used. Currently, only two medications (riperidone and aripiprazole) are approved by the U.S. Food and Drug Administration to treat ASD-related anger problems in children. Antiepileptic medications and medications used to treat common comorbid conditions of ASD are also used for these specific symptoms.

[0049] ASD is a disorder characterized by abnormal synaptic function, connectivity, and neurogenesis. Neurotrophins are important nerve growth factors that regulate neural development, including nervous system development, maintenance, and function. Therefore, their function is crucial for normal brain physiology, and altered expression is associated with complex neurological disorders, including ASD. Promoting neurogenesis is considered an effective strategy for treating several neuropsychiatric disorders.

[0050] Four structurally related mammalian neurotrophins have been identified and named NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin 3), and NT-4 / 5 (neurotrophin 4 / 5). All of these are required for neuronal differentiation, survival, and function. The neurotrophins NT-3 and NT-4 / 5 induce the differentiation of spinal cord and basal forebrain cholinergic neurons and hippocampal neurons. They also play an active role in supporting the survival of cultured fetal dopaminergic neurons. The neurotrophins NT-3 and NT-4 / 5 can also transiently support the survival of trigeminal and jugular neurons during embryonic development.

[0051] There is increasing evidence that neurotrophins play an important role in ASD. Preliminary studies have shown that NT-3 and NT-4 / 5 expression is reduced in patients with ASD compared with controls. Therefore, promoting neurotrophin expression may help maintain synaptic plasticity and alleviate ASD symptoms.

[0052] ET can penetrate the blood-brain barrier using its unique transporter system, OCTN (encoded by SLC22A4). ET has been found to significantly increase the expression of neurotrophins NT-3 and NT-4 / 5, suggesting the potential for treating neurological disorders by increasing neurotrophin levels. Animal studies have shown that oral administration of ET promotes neurogenesis in the hippocampal dentate gyrus, increases the number of neural stem cells (NSCs), and exerts antidepressant effects. Cellular and animal evidence provides a scientific rationale for the use of ET in the treatment of ASD.

[0053] The potential of ET in alleviating neurological disorders has been reported. In humans, serum ET levels have been found to be inversely correlated with several neurodegenerative conditions, including dementia and cognitive decline in Alzheimer's disease. ET has also been claimed to have protective effects against degenerative retinal damage, Parkinson's disease, and Alzheimer's disease (Identification methods for ergothioneine transporter modulators and therapeutic uses thereof, D. Grundemann and E. Schomig, U.S. Patent No. 8,492,106 B 2).

[0054] Based on the potential functions of ET, this application proposes the use of ET and SeET for the treatment of ASD. ET may promote neurogenesis by increasing the expression of neurotrophins, including BDNF. ET directly regulates the central nervous system and can protect neurons from oxidative stress and inflammation-induced neuronal damage.

[0055] The following describes an example of treating an individual with ASD using ET. Each of the four individuals in the example has ASD symptoms of varying severity. The example described in this instruction manual covers the use of ET supplements for three months. Each individual showed significant improvement in their ASD symptoms, along with a reduction in scores assessed by the CARS-2.

[0056] SeET is a structural analog of ET, in which the sulfur (S) on the imidazole ring is replaced with selenium (Se). Theoretically, SeET has a standard reduction potential of -0.49 V (E°' -0.49 V) compared to ET (-0.06 V), making it a more potent antioxidant. Previous studies have shown that SeET has potent antioxidant and anti-inflammatory properties and a detoxifying function against heavy metal toxicity in fish. The biosynthesis of SeET and its biological function are similar to those of ET. SeET can also cross the blood-brain barrier. Consequently, SeET and ET may share similar functions in the treatment of ASD and related neurological disorders.

[0057] ETs are naturally found in a variety of foods. Mushrooms are known to contain the highest concentrations of ETs. Gut microorganisms can also synthesize ETs. Animal studies have shown that stress caused by social abuse increases the growth of gut microorganisms, such as Lactobacillus reuteri, which in turn is associated with increased ET levels synthesized by Lactobacillus reuteri. To improve intestinal function, fecal transplantation of ET-producing Lactobacillus reuteri has been proposed.

[0058] In 2016, the European Food Safety Authority (EFSA) approved the use of ET as a food additive and supplement, including for pregnant women and infants. In 2017, the US Food and Drug Administration (FDA) granted ET "Generally Recognized as Safe" (GRAS) status and used it as a food additive and supplement (ERGOTHIONINE GRAS Publication #734;1-209). Therefore, ET is safe and is often used as a dietary supplement.

[0059] The European Food Safety Authority (EFSA) approved ET dosages of 2.82 mg / kg body weight per day for infants, 3.39 mg / kg body weight per day for toddlers, and 1.31 mg / kg body weight per day for adults, including pregnant and lactating women. The maximum tolerated dose of ET reached 800 mg / kg body weight per day based on the no-observed-adverse-effect level (NOAEL). The following examples use ET doses of 1 and 2 mg / kg body weight per day for 3 months to treat patients with ASD within the EFSA-approved dose range. ET was purchased from a manufacturer recognized as safe (GRAS) by the U.S. Food and Drug Administration.

[0060] SeET was discovered in tuna in Japan. SeET is the major selenium compound in fish muscle, making fish an important source of selenium for fish-eating populations. Many island nations have long recognized and utilized the health benefits of foods containing SeET. Therefore, SeET is considered safe for humans. Therefore, SeET is considered a food ingredient.

[0061] Treating ASD with supplements containing ET and SeET may offer certain benefits. These are all food-derived compounds that may have general functions of promoting neurogenesis and reducing oxidative stress and inflammation. They can also be provided as regular supplements.

[0062] A combination of compounds may not be required to achieve the improvement in CARS-2 scores described herein. For example, the treatment methods described herein may use only ergothioneine, selenoneine, or a simple combination of ergothioneine and selenoneine. As another example, the treatment methods described herein may not require the administration of N-acetylcysteamide (NACamide or NACA), anthocyanins, astaxanthin, catechins, epigallocatechins, choline, l-citrulline, curcumin, glutathione, phosphatidylserine, sasanin, or any combination thereof. The methods described herein may not require the administration of croton extract, chlorogenic acid, choline, l-citrulline, cysteine, sequoia base A, phosphatidylserine, red ginger extract, or any combination thereof. The methods described herein may not require the administration of green tea extract, stearin-3-glucoside (Cy-g), or complex proteins.

[0063] Among various useful diagnostic methods, the CARS-2 Childhood Autism Rating Scale scoring system is a sensitive and specific method that can evaluate the overall psychological and behavioral status. Therefore, in the following example, the CARS-2 system was used to evaluate the ET treatment effects of 12 ASD patients.

[0064] To obtain the CARS-2 score, each patient was rated from 1 (normal) to 4 (severely abnormal) based on 15 behavioral category criteria. The 15 behavioral categories were "Relationships with Others," "Imitation," "Emotional Reactions," "Body Use," "Object Use," "Adaptation to Change," "Visual Reactions," "Listening Responses," "Taste, Smell, and Touch Responses," "Fear and Tension," "Verbal Communication," "Nonverbal Communication," "Activity Level," "Level and Certainty of Intellectual Reactions," and "General Impression." Scores for the 15 behavioral categories were added together to obtain a total score (ranging from 15 to 60). A score of 15 was considered normal, a score of 30 or less was considered very mild or non-autistic. A score of 30–36.5 was considered mild to moderate ASD, and a score greater than 36.5 was considered severe ASD. Scores were provided by primary care staff or parents. Treatment outcomes were summarized as follows: [Example]

[0065] Example 1: Treatment of an 8-year-old girl with ASD using ET

[0066] An 8-year-old girl weighing 27 kg was diagnosed with ASD at age 4.

[0067] Treatment method: ET (2 mg / kg body weight, 54 mg / day) powder was dissolved in drinking water (200 ml). The patient received ET treatment for 3 months. ET is tasteless and odorless when dissolved in water.

[0068] Results: CARS-2 scores before and after ET treatment are provided. Each category was given a score of 1 to 4, as shown in Table 1. Before treatment, this patient had high scores in "Verbal Communication" and "Level and Certainty of Intellectual Response." She achieved a total score of 33, which indicates mild ASD.

[0069] After treatment, the scores for "fear and tension," "verbal communication," "level and certainty of intellectual responses," and "general impression" improved significantly (Table 1). "Relationships with others" improved slightly. There were no significant changes in other categories. The total score decreased from 33 points (before treatment) to 28.5 points (after treatment). A visualization of the scoring results is shown in Figure 1.

[0070] [Table 1]

[0071] Example 2: Treatment of a 5-year-old girl with ASD with ET

[0072] A 5-year-old girl weighing 21 kg was diagnosed with ASD at age 4.

[0073] Treatment method: ET (2 mg / kg body weight, 42 mg / day) powder was dissolved in drinking water (200 ml). The patient received ET treatment for 3 months.

[0074] Results: CARS-2 scores before and after ET treatment are shown. Each category was assigned a score of 1 to 4, as shown in Table 2. This individual received high scores in the areas of "Relationships with Others," "Verbal Interactions," "Nonverbal Interactions," and "Activity Level." She received a score of 32, which indicates mild ASD.

[0075] After treatment, there was a significant improvement in scores for "Relationships with Others," "Verbal Communication," "Nonverbal Communication," and "Auditory Response" (Table 2, Figure 2). No significant changes were observed in other categories. The total score after treatment decreased from 32 points (before treatment) to 27.5 points. A visualization of the scoring results is shown in Figure 2.

[0076] [Table 2]

[0077] Example 3: Treating a 5-year-old boy diagnosed with ASD and Asperger's syndrome with ET

[0078] A 5-year-old boy weighing 22 kg was diagnosed with Asperger's syndrome at age 3. Currently, technically, Asperger's syndrome is not diagnosed as a separate disorder, but is part of the broader category of ASD.

[0079] Treatment method: ET (2 mg / kg body weight, 44 mg / day) powder was dissolved in drinking water (200 ml). Patients received ET treatment for 3 months.

[0080] Results: CARS-2 scores were provided before and after ET treatment. In each category, a score of 1 to 4 was assigned, as shown in Table 3. He received a score of 20.5, indicating mild ASD.

[0081] After treatment, the scores for "Relationships with Others" improved significantly (Table 3, Figure 3). "Relationships with Others," "Visual Reactions," and "Fear and Tension" returned to normal (score of 1). The total score after treatment dropped from 20.5 points (before treatment) to 19 points. A visualization of the scoring results is shown in Figure 3.

[0082] After ET treatment, the diagnosis is likely to be mild attention-deficit / hyperactivity disorder (ADHD) rather than ASD. Hyperactivity disorder is one of the most common neurodevelopmental disorders in childhood. ASD and ADHD overlap in several behavioral category criteria, including emotional reactivity, dysregulation, and hyperfocused attention. It is estimated that 30% to 80% of ASD individuals meet ADHD behavioral category criteria, and conversely, 20% to 50% of ADHD individuals also meet ASD behavioral category criteria.

[0083] [Table 3]

[0084] Example 4: Treatment of a 32-year-old male with ASD with ET

[0085] A 32-year-old man weighing 74 kg was diagnosed with ASD at age 4.

[0086] Treatment method: ET (1 mg / kg body weight, 74 mg / day) powder was dissolved in drinking water (200 ml). Patients received ET treatment for 3 months.

[0087] Results: CARS-2 scores before and after ET treatment are shown in Table 4. For each category, a score of 1 to 4 was given, as shown in Table 4. This individual obtained high scores in the following areas: "Imitation," "Use of Objects," "Listening Response," "Taste, Smell, and Touch Response," "Verbal Interaction," "Activity Level," and "Level and Certainty of Intellectual Response." In general, his score was 37.5, which indicates severe ASD.

[0088] After treatment, the scores for "auditory response," "gustatory-smell-tactile response," "fear and tension," "verbal communication," and "intellectual response level and reliability" improved significantly (Table 4, Figure 4). The total score improved from 37.5 points (severe ASD) before treatment to 31.5 points (mild ASD) after treatment. A visualization of the scoring results is shown in Figure 4.

[0089] [Table 4]

[0090] Example 5: Treatment of a 21-year-old male with ASD with ET

[0091] Treatment method: 100 mg of ET powder was dissolved in drinking water (200 mL). The patient received ET treatment for 3 months.

[0092] Results: CARS-2 scores before and after ET treatment are shown in Table 5. In each category, a score of 1 to 4 was given as shown in Table 5. This man received a score of 28, which indicates mild ASD.

[0093] After treatment, there was a significant improvement in the scores for "emotional response," "fear and tension," "activity level," and "level and certainty of intellectual response." The total score improved from 28 points before treatment to 23 points after treatment. A visualization of the scoring results is shown in Figure 5.

[0094] [Table 5]

[0095] Example 6: Treating a 17-year-old male with ASD with ET

[0096] Treatment method: 100 mg of ET powder was dissolved in drinking water (200 mL). The patient received ET treatment for 3 months.

[0097] Results: CARS-2 scores before and after ET treatment are shown in Table 6. In each category, a score of 1 to 4 was given as shown in Table 6. This man received a score of 40, which indicates severe ASD.

[0098] After treatment, improvements were seen in the level and certainty of "body use," "visual response," "verbal communication," and "intellectual response." The total score improved from 40 points (severe ASD before treatment) to 34 points (mild ASD). A visualization of the scoring results is shown in Figure 6.

[0099] [Table 6]

[0100] Example 7: Treating a 9-year-old boy with ASD with ET

[0101] Treatment method: 50 mg of ET powder was dissolved in drinking water (200 mL). Patients received ET treatment for 3 months.

[0102] Results: CARS-2 scores before and after ET treatment are shown in Table 7. For each category, a score of 1 to 4 was assigned, as shown in Table 7. The boy achieved the maximum score of 4 in each of the following categories: "Relationships with Others," "Imitation," "Body Use," "Use of Objects," "Adaptation to Change," "Verbal Communication," "Nonverbal Communication," "Activity Level," "Level and Certainty of Intellectual Response," and "General Impression." The boy achieved a score of 55, indicating severe ASD.

[0103] After treatment, the "activity level" and "general impression" scores improved. The total score improved from 55 points before treatment to 53 points. The visualization of the score results is shown in Figure 7.

[0104] [Table 7]

[0105] Example 8: Treating an 11-year-old boy with ASD with ET

[0106] Treatment method: 50 mg of ET powder was dissolved in drinking water (200 mL). Patients received ET treatment for 3 months.

[0107] Results: CARS-2 scores before and after ET treatment are shown in Table 8. In each category, a score of 1 to 4 was given as shown in Table 8. The boy received a score of 48 before treatment, which indicates severe ASD.

[0108] After treatment, the "visual response" and "level and certainty of intellectual response" improved. The total score improved from 48 points before treatment to 45 points. The visualization of the scoring results is shown in Figure 8.

[0109] [Table 8]

[0110] Example 9: Treating an 11-year-old boy with ASD with ET

[0111] Treatment method: 50 mg of ET powder was dissolved in drinking water (200 mL). Patients received ET treatment for 3 months.

[0112] Results: CARS-2 scores before and after ET treatment are shown in Table 9. In each category, a score of 1 to 4 was given as shown in Table 9. The boy received a score of 48 before treatment, indicating severe ASD.

[0113] After the treatment, "adaptation to change," "verbal communication," "level and certainty of intellectual response," and "general impression" improved. The total score improved from 48 points before treatment to 44 points. The visualization of the scoring results is shown in Figure 9.

[0114] [Table 9]

[0115] Example 10: Treating a 15-year-old boy with ASD with ET

[0116] Treatment method: 50 mg of ET powder was dissolved in drinking water (200 mL). Patients received ET treatment for 3 months.

[0117] Results: CARS-2 scores before and after ET treatment are shown in Table 10. In each category, a score of 1 to 4 was given as shown in Table 10. The boy received a score of 55 before treatment, which indicates severe ASD.

[0118] After the treatment, "visual response," "verbal communication," and "general impression" improved. The total score improved from 55 points before treatment to 53 points. The visualization of the scoring results is shown in Figure 10.

[0119] [Table 10]

[0120] Example 11: Treating an 18-year-old male with ASD with ET

[0121] Treatment method: 100 mg of ET powder was dissolved in drinking water (200 mL). The patient received ET treatment for 3 months.

[0122] Results: CARS-2 scores before and after ET treatment are shown in Table 11. In each category, a score of 1 to 4 was given as shown in Table 11. This man scored 47 before treatment, indicating severe ASD.

[0123] After treatment, there was a significant improvement in "body use," "visual response," "fear and tension," "verbal communication," "level and certainty of intellectual response," and "general impression." The total score improved from 47 points before treatment to 41 points. The visualization of the scoring results is shown in Figure 11.

[0124] [Table 11]

[0125] Example 12: Treatment of a 19-year-old male with ASD with ET

[0126] Treatment method: 100 mg of ET powder was dissolved in drinking water (200 mL). The patient received ET treatment for 3 months.

[0127] Results: CARS-2 scores before and after ET treatment are shown in Table 12. In each category, a score of 1 to 4 was given as shown in Table 12. This man scored 49 before treatment, indicating severe ASD.

[0128] After treatment, "visual response," "verbal communication," "level and certainty of intellectual response," and "general impression" improved significantly. The total score improved from 49 points before treatment to 45 points. The visualization of the scoring results is shown in Figure 12.

[0129] [Table 12]

[0130] In Examples 1 to 12, the mean CARS-2 score decreased from 41.08 to 37.04, which was statistically significant (paired-samples t-test, T = 8.66, P = 0.00003). The salient categories were "visual response" (T = 3.18, P = 0.0086), "fear and tension" (T = 2.69, P = 0.0209), "verbal communication" (T = 4.69, P = 0.0006), "level and certainty of intellectual response" (T = 4.69, P = 0.006), and "general impression" (T = 6.51, P = 0.0004).

[0131] ASD core behaviors are classified into three categories: "social communication," "emotional reactivity," and "stereotypic behaviors and sensory sensitivity." Statistical analysis showed significant improvements in all three categories of behaviors. The treatment effects for each behavior are shown in Table 13 and were statistically significant (P<0.05).

[0132] [Table 13]

[0133] This application relates to the application of ET and SeET to treat ASD by alleviating conditions associated with ASD behaviors, such as bowel dysfunction, sleep disorders, anxiety, communication, language, and motor problems. This application also examined the role of ET in 12 patients diagnosed with ASD of varying severity. Results showed, for example, that ET supplementation at 1 and 2 mg / kg body weight daily significantly improved ASD behavior scores (CARS-2). Using the technology described in this application, ET can be used as a therapeutic agent for the management and treatment of ASD. Based on the safe dose range for ET as a dietary supplement established by the European Food Safety Authority, this range is set at 0.1 to 800 mg / kg body weight or 2 to 1760 mg / day. SeET, a close ET analog, has similar therapeutic effects and functions as a neurogenetic agent. The application of ET and SeET to the treatment of ASD may provide a novel and safe therapeutic strategy.

[0134] The methods or compositions provided herein can include purified ET or purified SeET. Purified ET or SeET can be in a purified natural form. Purified ergothioneine can have a purity of about 98% or more. ET can include L-ergothioneine.

[0135] Dosages can vary depending on whether ergothioneine (ET), selenoneine (SeET), or a combination of both is selected, and the ratio of ergothioneine (ET) to selenoneine (SeET) in the therapeutic agent can be varied. Generally, the dosage range for any supplement is about 0.45 μg to about 800 mg per kilogram of body weight per day. Ergothioneine (ET), selenoneine (SeET), or a combination thereof can be administered in a dosage range of about 0.01 to about 17,600 mg per day.

[0136] When ET is used alone, the dosage of ET may be 0.01 to about 800 mg / kilogram body weight per day. ET can be administered in an amount of 0.01 to about 0.2 mg / kilogram body weight per day. ET can be administered in an amount of 0.2 to about 2 mg / kilogram body weight per day. ET can be administered in an amount of 2 to about 50 mg / kilogram body weight per day. ET can be administered in an amount of 50 to about 800 mg / kilogram body weight per day. ET can be administered in an amount of at least 0.01 mg / kilogram body weight daily. ET can be administered in an amount of at least 0.2 mg / kilogram body weight daily. ET can be administered in an amount of at least 2 milligrams per kilogram body weight per day. ET can be administered in an amount of at least 50 milligrams per kilogram body weight per day. ET can be administered in a dosage range of 20 milligrams per day or greater. ET can be administered in a dosage range of 35 milligrams per day or greater. ET can be administered in a dosage range of 40 milligrams per day or greater. ET can be administered in a range of doses from 50 milligrams daily onwards.

[0137] When SeET is used alone, the dosage of SeET may be 1 μg to about 1 mg / kilogram body weight per day. SeET can be administered in an amount of 1 mg to about 10 mg / kilogram body weight per day. The dosage of SEET may be at least 1 microgram per kg of body weight. The dosage of SeET may be at least 1 mg / kilogram body weight per day. The dosage of SeET may be at least 10 mg / kilogram body weight per day. SeET can be administered in a dosage range of 0.01 mg or more per day. SeET can be administered in a dosage range of 0.1 mg or more per day. SeET can be administered in a dosage range of 1 mg or more per day. SeET can be administered in a dosage range of 10 mg or more per day.

[0138] The duration of treatment may vary depending on the patient's age, severity of the disease, prevalent symptoms, and other factors, and it is known that treatment durations for patients with ASD vary. The supplements are administered at least once daily for 3 months, 6 months, 1 year, 5 years, and 70 years.

[0139] When the treatments described herein are implemented, results show improvement in ASD pathology using any of the assessment methods in the measurement protocols for determining the presence of ASD. Specifically, CARS-2, DSM-IV, ABC, and ADOS-2 measurement scores are improved by the treatments described herein. More specifically, CARS-2 scores can be reduced by at least 2 points, at least 5 points, or at least 10 points.

[0140] The methods described herein may not include a fecal transplant process. The methods described herein may not include an injection process. The methods described herein do not require a process of directly contacting cells or any bodily organ with ET, SeET, or a combination thereof. The methods described herein may not include an incubation process at all. The methods described herein may not require a blood test to determine the level of ET or SeET. The methods described herein may not require the administration of additional adjuvants, excipients, or other active ingredients.

[0141] The methods described herein include administering to a human subject a therapeutically effective amount of a supplement consisting primarily of ergothioneine (ET), selenoneine (SeET), or a combination thereof. The methods described herein can include administering to a human subject a therapeutically effective amount of a supplement consisting primarily of ergothioneine (ET). The methods described herein can include administering to a human subject a therapeutically effective amount of a supplement consisting primarily of selenoneine (SeET).

[0142] As used in this application, any member of a teaching assumed group (list) can be excluded from that group unless otherwise specified, and / or any member of a Markush structure group can be excluded from the group.

[0143] Unless otherwise specified, any value set forth herein includes all values ​​from the lower value to the higher value in increments of one unit, provided that there is an interval of at least two units between any lower and any higher value. For example, values ​​of exemplified ingredient amounts, properties, or process variables (e.g., temperature, pressure, time, etc.) ranging from 1 to 90, preferably 20 to 80, and more preferably 30 to 70, and intermediate range values ​​such as 15 to 85, 22 to 68, 43 to 51, and 30 to 32 are desirably within the teachings of the present application. Similarly, individual intermediate values ​​are also within the teachings of the present application. For values ​​less than 1, the units are 0.0001, 0.001, 0.01, or 0.1, as appropriate. These are merely examples of specific intent, and all possible combinations of values ​​between the lowest and highest values ​​listed should be considered equally expressly stated in the present application. It is understood that comparative teachings of amounts expressed as weight / volume percent of two or more ingredients include the relative weight proportions of the two or more ingredients, even if not explicitly stated otherwise. For example, if a study memorizes 2% A and 5% B, the study also includes an A:B weighting ratio of 2:5. Unless otherwise stated, all ranges include all numbers between the endpoints. The use of "about" or "approximately" in connection with a range applies to both ends of the range. Thus, "about 20 to 30" is intended to encompass "about 20 to about 30," including at least the specified endpoints.

[0144] The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes.

[0145] The term "consisting essentially of" to describe a combination shall include the identified elements, components, or steps, as well as other elements, components, or steps that do not materially affect the basic and novel characteristics of the combination. "To describe a combination of elements or steps, this application also contemplates the presence or composition of any additional elements, components, or steps that do not materially affect the properties and / or benefits resulting from the teachings."

[0146] Multiple elements, components, or steps may be provided by a single integrated element, component, or step. Alternatively, a single integrated element, component, or step may be divided into multiple individual components or steps. The disclosure of "one" or "one" to describe an element, component, or step does not imply the exclusion of additional elements, components, or steps. All references in this application to elements or metals belonging to a family refer to the Periodic Table of the Elements, published by CRC Press, 1989. References to one or more families should refer to one or more families using the 1UPAC system of numbering families in this Periodic Table.

[0147] It should be understood that the above description is intended to be illustrative, not limiting. Many embodiments, excluding the examples provided, and many applications will become apparent to those skilled in the art upon reading the above description. Accordingly, the scope of the present application should be determined not with reference to the above description, but with reference to the claims herein, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes. The omission of any aspect of the subject matter disclosed in the present application in the following claims of the present application is not a disclaimer of such subject matter, but rather an indication that the inventors regard such subject matter as part of the disclosed inventive subject matter.

[0148] The descriptions and illustrations provided in this application are intended to familiarize those skilled in the art with the teachings, principles, and their practical application. Those skilled in the art may adjust and apply this application in various ways that may best suit the requirements of a particular application. Accordingly, the specific embodiments described herein are not intended to be exhaustive or limiting of this application. Therefore, the scope of this application should be determined not with reference to the above description, but with reference to the claims herein, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes. Other combinations are possible, and as follows:

Claims

1. 1. A pharmaceutical composition comprising ergothioneine (ET) and no other active ingredient for use in treating autism spectrum disorder (ASD), wherein the composition is administered to a human subject in a therapeutically effective amount, administering the therapeutically effective amount of ergothioneine in a dose range of about 0.1 to about 75 mg / kg body weight per day for at least three months; A pharmaceutical composition that reduces the CARS-2 score of said human subject by at least 1.5 points.

2. 10. The pharmaceutical composition of claim 1, wherein the ergothioneine (ET) is administered in the form of a powder, tablet, capsule, drink, or other edible form.

3. 3. The pharmaceutical composition of claim 2, wherein the ergothioneine (ET) is administered in a dosage range of about 0.01 to about 17600 mg per day.

4. 2. The pharmaceutical composition of claim 1, wherein the ergothioneine (ET) is administered in a dosage range of about 0.07 to about 12000 mg per day.

5. 3. The pharmaceutical composition of claim 2, wherein the ergothioneine (ET) is administered in a dosage range of about 1 to about 1000 mg per day.

6. 3. The pharmaceutical composition of claim 2, wherein the administration is daily for at least three months.

7. 10. The pharmaceutical composition of claim 1, wherein the administration is daily for at least six months.

8. 10. The pharmaceutical composition of claim 1, wherein the administration is daily for at least one year, and even for at least five years.

9. 10. The pharmaceutical composition of claim 1, wherein ergothioneine (ET) is administered in a dose range of about 0.2 to about 20 mg / kg body weight per day.

10. 3. The pharmaceutical composition of claim 2, wherein ergothioneine (ET) is administered in a dose range of about 1 to about 5 mg / kg body weight per day.

11. 7. The pharmaceutical composition of claim 6, wherein ergothioneine (ET) is administered at a dose of about 10 to about 1000 mg per day.

12. 10. The pharmaceutical composition of claim 1, wherein ergothioneine (ET) is administered at a dose of about 20 to about 500 mg per day.

13. 2. The pharmaceutical composition of claim 1, wherein the CARS-2 score of the human subject is reduced by at least 2, or even at least 5.

14. 2. The pharmaceutical composition of claim 1, wherein the dosage range of ergothioneine (ET) is 20 mg or more per day, 35 mg or more per day, 40 mg or more per day, or 50 mg or more per day.

15. 1. A pharmaceutical composition comprising ergothioneine (ET) and optionally selenoneine (SeET) for use in the treatment of autism spectrum disorder (ASD), wherein the composition is administered to a human subject in a therapeutically effective amount, The therapeutically effective amount of ergothioneine (ET) and optionally selenoneine (SeET) is administered in a dose range of about 0.45 μg to about 800 mg / kg body weight per day, A pharmaceutical composition that reduces the CARS-2 score of said human subject by at least 1.

5.

16. The pharmaceutical composition of claim 15, wherein the administration is performed daily for at least three months.

17. The pharmaceutical composition of claim 15, wherein the administration is performed daily for at least 6 months.

18. The pharmaceutical composition of claim 15, wherein the administration is daily for at least one year, and even for at least five years.

19. The pharmaceutical composition described in claim 15, wherein the CARS-2 score of the human subject is reduced by at least 2.

20. The pharmaceutical composition described in claim 15, wherein the CARS-2 score of the human subject is reduced by at least 5.

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