Composition and its use

Abstract

The present invention relates to compositions for use in the treatment, management, or amelioration of FMR1-mediated autism and Fragile X Syndrome (FXS), comprising one or more tryptophans or derivatives thereof. The present invention also relates to one or more tryptophans or derivatives thereof and one or more ergot alkaloids, derivatives, or mimetics thereof for use as pharmaceuticals to treat various autistic disorders and disorders with an autistic component.

Description

Technical Field

[0001] The present invention relates to compositions for use in the treatment, management or amelioration of neurological and developmental disorders, and in particular to compositions for the treatment of various autistic disorders, or disorders in which autism is a known component, and also for the treatment of Fragile X syndrome (FXS).

Background Art

[0002] Inactivation caused by mutation of the gene encoding Fragile X mental retardation protein (FMRP) causes a variety of symptoms including seizures, sleep disorders, anxiety, irritability, autism, mild to severe cognitive impairment, and intellectual disability. This set of symptoms is known as Fragile X syndrome (FXS).

[0003] FXS is caused by transcriptional silencing of the FMR1 gene via progressive expansion of (CGG)n trinucleotide repeats in the 5'-untranslated region of the FMR1 gene (Xq27.3) and subsequent methylation. These full mutations arise from an unstable allele called a premutation (55~200 CGG repeats). Rarely, FXS has been shown to result from intragenic FMR1 point mutations or deletions. FMR1 encodes FMRP, an RNA-binding protein that controls protein synthesis and other signaling pathways in neuronal dendrites. Silencing of FMR1 is thought to reduce synaptic plasticity and modulation throughout the brain, including the hippocampus.

[0004] In humans, this syndrome is caused by an unstable CGG triplet elongation (more than 200 repeats) in the 5' untranslated region of the Fmr1 gene located on the X chromosome, resulting in gene methylation, inactivation, and a resulting loss of fragile X intellectual disability protein (FMRP) expression. FMRP functions as a translation regulator and affects the synthesis of many proteins, including those involved in synaptic pruning during development (Razak, 2020). Meta-analyses estimate the frequency of individuals with the complete mutant FXS allele to be approximately 1 in 7,000 males and 1 in 11,000 females (Hunter, 2014). FXS results in severe debilitation in males. Generally, females are less affected than males due to mosaicism resulting from randomly occurring X chromosome inactivation early in lung development (ME Gurney, 2017).

[0005] Fragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disorder manifests in childhood and is characterized by delays in developmental survey items. The severity of intellectual disability varies and may include problems with work and short-term memory, executive function, language, mathematics, and visuospatial abilities. Behavioral abnormalities can range from mild (e.g., anxiety, mood swings) to severe (e.g., aggressive behavior, autism). Autism-like behaviors may include hand flailing, insufficient eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits, and tactile defensiveness. In females, intellectual and behavioral problems are usually mild, mostly consisting of shyness, social anxiety, and mild learning difficulties with a normal IQ, although 25% of girls have an IQ below 70. Attention-deficit hyperactivity disorder (ADHD) is present in over 89% of males and over 30% of females, and disinhibition of behavior is very common. Recurrent otitis (60%) and seizures (16–20%) may also be observed. FXS patients exhibit a variety of neuropsychiatric symptoms, including intellectual disability, delayed language acquisition, poor social interaction, hyperarousal, irritability, repetitive behaviors, sleep disturbances, attention deficit hyperactivity disorder (ADHD), and autism. These behavioral changes are most widely modeled in adult male Fmr1 knockout (KO) mice, which exhibit a variety of behavioral phenotypes due to deletion of the fmr1 gene. Mutant mice exhibit hyperarousal in open-field studies, impaired social interaction, less nesting when given purified cotton, and less burying of marbles in cage bedding. Because male FXS patients typically suffer from more severe symptoms than female patients due to having only one X chromosome, adult male mice were used in all studies. In both FXS patients and fmr1 KO mice, alterations have been observed in the density, size, shape, and maturity of dendritic spines, which are the principal recipients of excitatory input from other neurons (ME Gurney, 2017).

[0006] Patients with FXS most often have a combination of ADHD and hyperarousal, but similar unpredictable behaviors can also occur in other disorders such as Smith-Maginis syndrome and males with XYY chromosomes (Hagerman, 1999). Mood problems and anxiety are common in fetal alcohol syndrome (FAS), Williams syndrome (WS), FXS, Tourette syndrome, and some sex chromosome disorders, and their identification and psychopharmacological treatment can dramatically improve patient well-being and, in some cases, significantly reduce aggression or outbursts (Hagerman, 1999). Finally, marked distortions of thought within a relatively high range of psychotic idealization have been studied in several disorders, including FAS, FXS, extracardiofacial syndrome (VCFS), and Prader-Willi syndrome (PWS), because antipsychotic medications may significantly improve these distortions and overall functional levels.

[0007] Multiple studies suggest that variants within the FMR1 gene other than CGG-repeat extension mutations may cause FMRP dysfunction (Suhl, 2015). Similar to the I304N mutation, the G266E mutation is located within a conserved amino acid in the KH domain and is very likely to be the cause of intellectual and behavioral impairments in patients. The S27X mutation is very severe truncation and, given that FMRP is deficient in patient-derived cell lines, is very likely to be the root cause of patients' symptoms.

[0008] The genetic basis of autism spectrum disorder (ASD) is highly heterogeneous, with hundreds of genes involved in its cause. Interestingly, most genes exhibit expression profiles in the early stages of development, and their functionality shares strong enrichment in cell adhesion and migration, cytoskeletal regulation, synapse formation, and kinase signaling (Pinto et al., 2010; Gilbert and Man, 2017). These ASD genes include FMR1, LIS1, MECP2, PTEN, SHANK1 / 2 / 3, TAOK2, TSC1 / 2, neuroligin, neurexin, KIAA2022 / KIDLIA (Gilbert and Man, 2016), and UBE3A / E6-related protein (E6AP).

[0009] FXS patients exhibit a range of intellectual disabilities that overlap with other ASDs, including severe cognitive impairment, autistic behaviors such as aggression, social anxiety, and repetitive behaviors, attention deficit hyperactivity disorder, epilepsy, and abnormal physical features such as megatestis (Hagerman, 1997). FXS and ASD patients exhibit a range of repetitive behaviors, including stereotypic behaviors, rituals, obsessions, compulsions, and self-injury. Similar phenotypes occur in ASDs: Angelmann syndrome (AS), Rett syndrome (RS), Phelan-McDiarmid syndrome (PMS), and Pitt-Hopkins syndrome (PTHS) (but are not limited to these).

[0010] Significant efforts to treat FXS have involved numerous studies, but have not been widely successful, leading to the search for additional new therapies. Management is symptom-based and requires a multidisciplinary approach. Speech therapy, physical therapy, sensory integration therapy, and individualized educational programs and behavioral interventions may be combined with medications such as stimulants for attention deficit hyperactivity disorder, selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, and obsessive-compulsive disorder, and atypical antipsychotics for self-injurious and aggressive behaviors. Novel targeted therapies for FXS are being investigated. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] An object of the present invention is to overcome one or more of the problems with current treatments for neurological and developmental disorders such as autism and FXS. A further object of the present invention is to provide a treatment for autism mediated by FMR1 gene mutations. A preferred object of the present invention is to provide a treatment for FXS. It is beneficial if the treatment is based on existing pharmaceutically active ingredients. [Means for solving the problem]

[0012] According to the present invention, a composition is provided for use in the treatment, management, or improvement of FMR1-mediated autism, comprising one or more tryptophans or derivatives thereof.

[0013] According to a related aspect of the present invention, a method for treating, managing, or improving FMR1-mediated autism is provided, comprising administering a therapeutically effective amount of one or more tryptophans or derivatives thereof to an individual in need of such prevention, management, and / or treatment.

[0014] According to related, but further alternative, aspects of the present invention, the use of one or more tryptophans or derivatives thereof in the manufacture of a medicament for the treatment, management, or improvement of FMR1-mediated autism in an individual is provided.

[0015] FMR1-mediated autism is as follows: a. Elongation of the (CGG)n trinucleotide repeat in the 5'-untranslated region of the FMR1 gene and subsequent methylation. b. Intragenetic point mutation or deletion in FMR1, c.I304N mutation, d.G266E mutation, or e.S27X mutation This may be due to a mutation in the FMR1 gene sequence that includes one of the following.

[0016] According to related, but still alternative, embodiments of the present invention, a pharmaceutical composition is provided comprising one or more tryptophans or derivatives thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0017] As used herein, the terms “treatment,” “treating,” and “treat” refer to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in the sense of completely or partially preventing a disease or its symptoms, and / or therapeutic in the sense of partial or complete cure of the disease and / or adverse effects contributing to the disease. As used herein, “treatment” refers to any treatment of a disease in mammals, in particular humans, and includes (a) preventing the development of the disease in a subject that is susceptible to the disease but has not yet been diagnosed with it, (b) inhibiting the disease, i.e., preventing or delaying its development, and (c) alleviating the disease, i.e., causing regression of the disease.

[0018] As used herein, the terms “subject” or “individual” include any human or non-human animal. The term “non-human animal” includes all mammals, such as non-human primates, sheep, dogs, cats, cattle, and horses.

[0019] One or more tryptophans or derivatives preferably include 5-hydroxytryptophan (5-HTP) (oxytriptan). Alternatively, one or more tryptophans or derivatives may be selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and oglufanide, or mixtures thereof.

[0020] FMR1-mediated autism may be associated with fragile X syndrome (FXS). According to a second aspect of the present invention, there is provided a composition for use in the treatment, management or amelioration of fragile X syndrome (FXS), wherein the composition comprises one or more tryptophan or derivatives thereof.

[0021] According to a related aspect of the present invention, there is provided a method for treating, managing or ameliorating fragile X syndrome (FXS), comprising administering a therapeutically effective amount of one or more tryptophan or a derivative thereof to an individual in need of such prevention, management and / or treatment.

[0022] According to a related but further alternative aspect of the present invention, there is provided use of one or more tryptophan or a derivative thereof in the manufacture of a medicament for treating, managing or ameliorating fragile X syndrome (FXS) in an individual.

[0023] According to a related but still alternative aspect of the present invention, there is provided a pharmaceutical composition comprising one or more tryptophan or a derivative thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0024] The one or more tryptophan or derivative thereof will preferably comprise 5-hydroxytryptophan (5-HTP) (oxitriptan). Alternatively, the one or more tryptophan or derivative thereof may be selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxy-tryptophan, imino-tryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and oglufanide, or mixtures thereof.

[0025] A skilled addressee will understand that the optimal dosage of the composition needs to be established for both the first and second aspects. However, it is preferred that the composition is administered at a daily dosage ranging from about 20 mg to about 400 mg. In some embodiments, the composition is administered at a daily dosage ranging from about 100 mg to about 800 mg, suitably at a daily dosage ranging from about 200 mg to about 400 mg, for example approximately 300 mg daily or 300 mg daily.

[0026] The daily dosage of the composition may be administered as a single daily dose. Suitably, the daily dosage is administered in 1 to 5 divided daily doses, suitably in 2 to 4 divided daily doses or 3 divided daily doses. In some embodiments, the composition comprising one or more tryptophan or derivatives thereof is administered, for example at intervals of approximately 8 hours, at a dosage of 100 mg TID (ter in die / three times a day), thus giving a total daily dosage of 300 mg per day.

[0027] The composition comprising one or more tryptophan or a derivative thereof may consist essentially of or consist of the tryptophan or derivative thereof as defined above. Suitably, the composition consists essentially of or consists of tryptophan, for example oxitriptan. The present invention can therefore provide tryptophan or a derivative thereof, for example oxitriptan, for use in the treatment, management or amelioration of FMR1-mediated autism, suitably wherein the treatment comprises administering to a patient in need thereof a daily dosage of 100 mg to about 800 mg of tryptophan or a derivative thereof, for example oxitriptan, suitably at a daily dosage ranging from about 200 mg to about 400 mg, for example approximately 300 mg daily or 300 mg daily. Preferably, at a dosage of 100 mg TID.

[0028] According to a third aspect of the present invention, there is provided a composition comprising a combination of one or more tryptophan or a derivative thereof, and one or more ergot alkaloids, derivatives or mimetics thereof.

[0029] The composition of the third embodiment is preferably intended for pharmaceutical use. Accordingly, this third aspect of the present invention can provide a combination of one or more tryptophans or derivatives thereof and one or more ergot alkaloids, derivatives thereof or mimics for pharmaceutical use. One or more tryptophans or derivatives may include 5-hydroxytryptophan (5-HTP) (oxytriptan).

[0030] Alternatively, one or more tryptophans or derivatives may be selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and ogluphanides, or mixtures thereof.

[0031] Ergot alkaloids may include ergoloid mesylates. Ergot alkaloid derivatives and mimics may be selected from one or more of the following: methycerzide, dihydroergotamine, lisuride ergotamine nicergoline, dihydroergocristine, dihydroergocornine, dihydroergocriptine, ergometrine, methylergometrine, cabergoline, pergolide, bromocriptine, lysergic acid diethylamide, tergulide, and metergoline. Preferably, ergot alkaloid derivatives and mimics include substantially equiproportional preparations of dihydroergocornine, dihydroergocristine, and dihydroergocriptine.

[0032] The composition of the third embodiment may be for use in the treatment, management, or improvement of autism disorder or a disorder in which autism is a known component. The compositions of the third embodiment may be for use in methods of treating, managing, or improving autism disorder or a disorder in which autism is a known component, comprising administering a therapeutically effective amount of the composition to an individual requiring such prevention, management, and / or treatment.

[0033] The composition of the third embodiment may be for use in the manufacture of a medicament for the treatment, management, or improvement of an individual with autism disorder or a disorder in which autism is a known component. Accordingly, this third aspect of the present invention can provide a combination of one or more tryptophans or derivatives thereof and one or more ergot alkaloids, derivatives thereof or mimics for use in the treatment, management, or improvement of autism disorder or a disorder in which autism is a known component.

[0034] In such embodiments, one or more tryptophans or their derivatives are administered appropriately in the doses described above. In such embodiments, one or more ergot alkaloids, derivatives or mimics are administered appropriately in a daily dose in the range of about 1 to 10 mg, preferably 1 to 5 mg, preferably 2 to 4 mg, for example, about 3 mg per day or 3 mg per day. In some embodiments, the composition is administered in a daily dose in the range of about 3 mg and about 5 mg.

[0035] The daily dose of one or more ergot alkaloids described above may be administered as a single daily dose. Preferably, the daily dose is administered in 1 to 5 daily doses, preferably in 2 to 4 daily doses or 3 daily doses. In some embodiments, a composition containing one or more ergot alkaloids is administered, for example, at intervals of approximately 8 hours, in doses of 1 mg TID (ter in die / 3 times a day), and therefore a total dose of 3 mg per day.

[0036] Appropriately, these daily doses are for ergoloid mesylate. One or more ergot alkaloids may contain mesylate ergoloids. One or more ergot alkaloids are essentially composed of, or may be composed of, mesylate ergoloids.

[0037] In some embodiments, one or more tryptophans or their derivatives are administered in a dose of 100 mg TID, and one or more ergot alkaloids are administered in a dose of 1 mg TID, where preferably, one or more tryptophans are oxytriptans and one or more ergot alkaloids are ergoloid mesylates.

[0038] Preferably, the composition comprises oxytriptan and ergoloid mesylate, and is administered in doses of approximately 100 mg TID of oxytriptan and approximately 1 mg TID of ergoloid mesylate.

[0039] Autism disorders or disorders in which autism is a known component include: 1p21.3 microdeletion syndrome, adenylosuccinate lyase deficiency, autism-facial port-wine stain syndrome, autism spectrum disorder due to AUTS2 deficiency, autism spectrum disorder-epilepsy-arthrogryposis syndrome, developmental delay and unsteady gait associated with autism spectrum disorder, inverted duplicated chromosome 15 syndrome, macrocephaly-intellectual disability-autism syndrome, severe neurodevelopmental disorder with feeding difficulties-restricted hand movements-bilateral cataracts, Smith-Maginis syndrome, tuberous sclerosis, and Xq12-q13.3 duplication syndrome. It could be one of the syndromes.

[0040] Alternatively, a disorder in which autism is a known component may be one of the following: Asperger's syndrome, atypical autism, and autistic disorder. Autism can be FMR1-mediated autism.

[0041] Autism may be associated with fragile X syndrome (FXS). The composition of the third embodiment may be for use in the treatment, management, or improvement of fragile X syndrome (FXS).

[0042] In related embodiments, methods are provided for treating, managing, or improving fragile X syndrome (FXS), comprising administering a therapeutically effective amount of one or more tryptophans or derivatives thereof to individuals requiring such prevention, management, and / or treatment.

[0043] According to a related, but further alternative embodiment of a third aspect of the present invention, the use of one or more tryptophans or derivatives thereof in the manufacture of a medicament for the treatment, management, or improvement of fragile X syndrome (FXS) in an individual is provided.

[0044] The composition of the third embodiment may be for use in the treatment, management, or improvement of behavioral disorders. Behavioral disorders may include one of the following: hyperactivity, social anxiety, amnesia, and / or destructive behavior.

[0045] Behavioral disorders may include one of the following: attention deficit hyperactivity disorder, stereotyped movement disorder, conduct disorder, generalized anxiety disorder, neurotic disorder, obsessive-compulsive disorder, agoraphobia, social phobia, separation anxiety disorder, and 15q11q13 subtle overlap syndromes.

[0046] In a formulation, one or more tryptophans or their derivatives, and one or more ergot alkaloids, their derivatives, or mimics may be present in a mixture. Such a mixture may be a formulation in which both components are dispersed amongst themselves, or each component may be separated in equal doses.

[0047] One or more tryptophans or their derivatives may be administered separately, together, or sequentially with one or more ergot alkaloids, their derivatives, or mimics.

[0048] The composition may contain oxytriptan and an ergoloid mixture, and the composition is administered in a daily dose ranging from about 20 mg to about 400 mg of oxytriptan and about 1 mg to about 3 mg of the ergoloid mixture.

[0049] In all embodiments, the ergot alkaloid may include mesylate ergoloid. Ergoloid mesylate [https: / / www.drugbank.ca / drugs / DB01049] is an isometric preparation of three ergotamantriones: dihydroergocornine, dihydroergocristine, and dihydroergocriptine [Thompson 1990]. All of these components are produced by the fungus Claviceps purpurea and are all derivatives of the tetracyclic compound 6-methylergonovine [Pillay 2013]. Approximately 350 derivatives of this fungus have been identified, and among these, the components of the ergoloid mesylate mixture consist of dihydrogenated ergot alkaloid derivatives [Percheson 1954]. The ergoloid mesylate mixture was first developed by Novartis and approved by the U.S. Food and Drug Administration (FDA) on November 5, 1953, although this particular formulation is now discontinued [https: / / www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=overview.process&ApplNo=009087]. Subsequently, in 1991, the ergoloid mesylate mixture was reacquired by Sun Pharmaceutical Industries and approved by the FDA [https: / / www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=overview.process&ApplNo=009087].

[0050] Ergoloid mesylate has a known mechanism of action involving dopamine, serotonin, and alpha- and beta-adrenergic receptor proteins. Its bioactivity with OPRM1 is predicted. Ergoloid mesylate has been reported to have a plasma half-life of 3.5 hours, while its terminal phase half-life is 13 hours [Seyffart 1992]. An experimental adult dose of ergoloid mesylate has been proposed at 3 × 0.5–0.6 mg every 8 hours, for a total of 1.5 (1–3) mg per day.

[0051] Preferably, the ergot alkaloid is selected from one or more components of a mesylate ergoloid mixture: epicriptine, dihydro-alpha-ergocriptine, dihydroergocornine, and dihydroergocristine. In certain embodiments, the ergot alkaloid comprises one of the components of a mesylate ergoloid mixture selected from epicriptine, dihydro-alpha-ergocriptine, dihydroergocornine, and dihydroergocristine. In other embodiments, the ergot alkaloid comprises two or more selected from epicriptine, dihydro-alpha-ergocriptine, dihydroergocornine, and dihydroergocristine. In alternative embodiments, the ergot alkaloid comprises a mixture of epicriptine, dihydro-alpha-ergocriptine, dihydroergocornine, and dihydroergocristine.

[0052] Those skilled in the art will readily understand that ergot alkaloid derivatives and mimetic compounds have similar efficacy and can be used in conjunction with the present invention. The ergot alkaloid derivatives and mimetic compounds may be selected from one or more of the following: methycerzide, dihydroergotamine, lyslidergotamine nicergoline, dihydroergocristine, dihydroergocornine, dihydroergocriptine, ergometrine, methylergometrine, cabergoline, pergolide, bromocriptine, lysergic acid diethylamide, tergulide, and metergoline. The ergot alkaloid derivatives and mimetic compounds are expected to produce phenotypic effects similar to those of the ergot alkaloids themselves.

[0053] Details of ergot alkaloid derivatives and mimics are as follows: Methyserzide (CAS ID 361-37-5, DrugBank DB00247): Methyserzide (alternative name methyserzide maleate) is an ergot-derived prescription drug used for the prevention of migraines and other vascular headaches, as well as for serotonin antagonism in carcinoid syndrome.

[0054] Dihydroergotamine (CAS ID 511-12-6, DrugBank DB00320): A 9,10-alpha-dihydro derivative of ergotamine. Used as a vasoconstrictor, particularly for the treatment of migraines. It has similar efficacy to sumatriptan. Nausea is a common side effect.

[0055] Lislide (CAS ID 18016-80-3, DrugBank DB00589): This is an ergot derivative that acts as a dopamine D2 receptor agonist (dopamine agonist). It may also act as an antagonist at dopamine D1 receptors and as an agonist (serotonin agonist) at some serotonin receptors. It is an isoergoline antiparkinsonian agent and is chemically related to dopaminergic ergoline parkinson's drugs. Lislide is described as a free base and as a hydrogen maleate.

[0056] Ergotamine (CAS ID 113-15-5, DrugBank DB00696): An alpha-1 selective adrenergic agonist commonly used to treat migraines. Ergotamine is ergopeptine, a member of the ergot family of alkaloids, and is structurally and biochemically closely related to ergoline. It has structural similarities to several neurotransmitters and possesses biological activity as a vasoconstrictor.

[0057] Nicergoline (CAS ID 27848-84-6, DrugBank DB00699): Nicergoline is an ergot derivative used to treat senile dementia. Specifically, it reduces vascular resistance, increases cerebral arterial blood flow, and improves oxygen and glucose utilization by brain cells. It is used as a cerebral vasodilator and in peripheral vascular disease. It has been suggested to improve cognitive impairment in cerebrovascular disease.

[0058] Dihydroergocristine (CAS ID 17479-19-5, DrugBank DB13345): Dihydroergocristine is an ergot alkaloid. Along with dihydroergocornine and dihydroergocriptine, it is one of the components of mesylate ergoloids. It is a semi-synthetic ergot alkaloid and is therefore characterized by a structural framework formed by the alkaloid ergoline.

[0059] Dihydroergocornine (CAS ID 25447-65-8, DrugBank DB11273): Dihydroergocornine is an ergot alkaloid. Along with dihydroergocristine and dihydroergocriptine, it is one of the three components of ergoloids. Dihydroergocornine is one of the dihydrogenated ergot compounds that exhibit a very large antihypertensive effect. It is a crude extract of ergot and a synthetic derivative of ergocornine subsequently purified.

[0060] Dihydroergocriptine (CAS ID 25447-66-9, DrugBank DB13385): Dihydroergocriptine is an ergoline chemical dopamine agonist used as an antiparkinsonian, and is particularly effective as monotherapy in the early stages of Parkinson's disease. Along with dihydroergocristine and dihydroergocornin, it is one of the three components of ergoloids.

[0061] Ergometrine (CAS ID 60-79-7, DrugBank DB01253): Also known as ergonovine, ergometrine is a drug used to induce uterine contractions to treat heavy postpartum vaginal bleeding. It works by causing the uterine muscles to contract.

[0062] Methylergometrine (CAS ID 113-42-8, DrugBank DB00353): Methylergometrine is a synthetic analog of ergometrine, a psychedelic alkaloid discovered in ergot. It is a member of the ergoline family and is chemically similar to LSD, ergin, ergometrine, and lysergic acid. Due to its labor-inducing properties, it has medical applications in obstetrics. It is a congener of ergonovine, containing one more CH2 group.

[0063] Cabergoline (CAS ID 81409-90-7, DrugBank DB00248): Cabergoline, an ergot derivative, is a potent dopamine receptor agonist for D2 receptors. It is a long-acting dopamine agonist and prolactin inhibitor. It is used to treat hyperprolactinemia and Parkinson's syndrome. Cabergoline possesses potent agonist activity against dopamine D2 receptors.

[0064] Pergolide (CAS ID 66104-22-1, DrugBank DB01186): Pergolide is an ergoline-based, long-acting dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. It is an ergot derivative that acts on dopamine D2 and D3, alpha-2- and alpha-1-adrenergic, and 5-hydroxytryptamine (5-HT) receptors. It was needed as adjunct therapy to levodopa / carbidopa in the symptomatic treatment of Parkinson's syndrome. Pergolide acts as a dopamine to increase receptor activity, but has been found to increase the risk of heart valve disease.

[0065] Bromocriptine (CAS ID 25614-03-3, DrugBank DB01200): Bromocriptine is a semi-synthetic ergot alkaloid derivative and a dopaminergic agent with potent dopaminergic activity. It is used to treat pituitary tumors, Parkinson's disease, hyperprolactinemia, malignant syndrome, and type 2 diabetes. It is required for the management of signs and symptoms of Parkinson's syndrome. Bromocriptine also inhibits prolactin secretion and may be used to treat functional impairments associated with hyperprolactinemia. In some patients with acromegaly, it also causes persistent suppression of somatotropin (growth hormone) secretion. Bromocriptine has been associated with pulmonary fibrosis.

[0066] Lysergic acid diethylamide (CAS ID 50-37-3, DrugBank DB04829): Lysergic acid diethylamide, also known colloquially as "acid," is a hallucinogen. Its effects generally include alterations in thought, emotion, and awareness of the surroundings. Dilated pupils, increased blood pressure, and elevated body temperature are typical side effects.

[0067] Terguride (CAS ID 37686-84-3, DrugBank DB13399): Also known as trans-dihydrolisuride, terguride is an ergoline family serotonin receptor antagonist and dopamine receptor agonist. It is approved and used as a prolactin inhibitor in the treatment of hyperprolactinemia.

[0068] Methergoline (CAS ID 17692-51-2, DrugBank DB13520): Methergoline is an ergot-derived psychotropic drug that acts as a ligand for various serotonin and dopamine receptors. Methergoline is an antagonist at various 5-HT receptor subtypes and an agonist at dopamine receptors at relatively low concentrations. Its use has been studied in various clinical situations, such as the treatment of seasonal affective disorder, prolactin hormone regulation through its inhibitory effect on prolactin release, premenstrual dysphoric disorder in women, and anxiolytic treatment.

[0069] Various tryptophans or their derivatives can be used in conjunction with the present invention. Tryptophan may contain 5-hydroxytryptophan (5-HTP) (oxytriptan).

[0070] 5-HTP, also known as oxytriptan (INN) [https: / / www.drugbank.ca / drugs / DB02959], is a naturally occurring amino acid and a metabolic intermediate in the synthesis of serotonin and melatonin. 5-HTP is marketed in the UK, US, and Canada as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid, and in many European countries for the treatment of major depressive disorder under brand names such as Cincofarm, Levothym, Levotonine, Oxyfan, Telesol, Tript-OH, and Triptum. While several double-blind, placebo-controlled clinical trials have demonstrated the efficacy of 5-HTP in treating depression, a lack of high-quality research has been noted. Further research is needed to determine its efficacy in treating depression.

[0071] 5-Hydroxytryptophan, appropriately its active L-isomer, or including the active L-isomer, may also be known as 5-hydroxy-L-tryptophan or 5-hydroxytryptophan L-isomer. The IUPAC name for 5-hydroxytryptophan (5-HTP) (oxytriptan) is 2-amino-3-(5-hydroxy-1H-indole-3-yl)propanoic acid.

[0072] In some embodiments, 5-hydroxytryptophan is the D-isomer and may also be known as 5-hydroxy-D-tryptophan or 5-hydroxytryptophan D-isomer. The body produces 5-hydroxytryptophan (5-HTP) from the essential amino acid L-tryptophan (LT). 5-HTP is extracted from the seeds of the African plant Griffonia simplicifolia. Typically, 5-HTP is the rate-limiting step in the conversion of LT to serotonin. Serotonin levels regulate sleep, mood, appetite, body temperature, pain, and aggressive or sexual behavior. 5-HTP is found in many commercially available combination products and is also used alone for sleep induction, depression, anxiety, and loss of appetite.

[0073] The known mechanism of action of 5-hydroxytryptophan is trpS2. This suggests biological activity against ESR1, HTR1A, GRIA1, and GRIK1. The half-life of 5-hydroxytryptophan is 2 hours (Jacobsen JPR 2016), and an experimental adult dose of 60 (20-400) mg per day, administered at 3 × 20 mg every 8 hours, has been proposed.

[0074] Those skilled in the art will readily understand that additional compounds in the classification of tryptophan are expected to produce similar phenotypic effects and may be used in conjunction with the present invention. In certain embodiments, one or more tryptophans may be selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and oglufanide. One or more tryptophans may be a single tryptophan or a mixture of two or more tryptophans.

[0075] The composition may be used for the treatment, management, or improvement of various autistic disorders, or disorders in which autism is a known component. This disorder may be one or more of the following rare disorders associated with autism: 1p21.3 microdeletion syndrome, adenylosuccinate lyase deficiency, autism-facial port-wine stain syndrome, autism spectrum disorder due to AUTS2 deficiency, autism spectrum disorder-epilepsy-articular contracture syndrome, developmental delay and unsteady gait associated with autism spectrum disorder, chromosome 15 inversion duplication syndrome, macrocephaly-intellectual disability-autism syndrome, severe neurodevelopmental disorder with feeding difficulties-patterned hand movements-bilateral cataracts, Smith-Maginis syndrome, tuberous sclerosis, and Xq12-q13.3 duplication syndrome.

[0076] 1p21.3 microdeletion syndrome (ORPHA:293948) is an extremely rare chromosomal abnormality characterized by severe speech and language delay, intellectual disability, and autism spectrum disorder. Clinical description: 1p21.3 microdeletion syndrome is characterized by severe speech and language delay, borderline to mild to mild to moderate intellectual disability, features of autism spectrum disorder, and mild dysmorphic facial features such as long ears, sunken eyes, a broad nasal tip, and a thick lower lip. Affected individuals show normal gross motor development with no major abnormalities, and they are often very shy and friendly and prone to overeating.

[0077] Adenylosuccinate lyase deficiency (ORPHA:46) is a purine metabolism disorder characterized by intellectual disability, psychomotor retardation and / or regression, seizures, and autistic features. Clinical description: ADSL covers a continuous clinical spectrum with three main forms: lethal neonatal form, severe (Type I), and mild to moderate form (Type II). Clinical variability is observed even within the same family of patients. Onset is generally between birth and early childhood. Cases have been reported ranging from lethal neonatal encephalopathy (presenting with hypomotor impairment, intractable seizures, and respiratory failure) to mild intellectual disability. Intellectual disability is seen in all patients, various types of epilepsy are seen in the majority, and autistic features are seen in about one-third (inability to make eye contact, hypersensitivity to noise and light, repetitive behaviors, agitation, tantrums, self-aggression, and self-injury). Other less common signs include psychomotor retardation, hyperactivity, speech disorders, hypotonia, muscle wasting, and spasticity. Severe cases often result in microcephaly. Prenatal signs include intrauterine growth restriction, microcephaly, decreased fetal movement, and loss of fetal heart rate variability.

[0078] Autism-Facial Port-Wine Vase Syndrome (ORPHA:137911) is characterized by autistic developmental problems, including the presence of a unilateral hemangioma on the face, delayed language development, and atypical social interaction.

[0079] Autism spectrum disorder due to AUTS2 deficiency (ORPHA:352490) is a rare genetic symptomatic intellectual disability characterized by systemic developmental delay and borderline to severe intellectual disability, obsessive-compulsive behaviors, stereotypic behaviors, hyperactivity, but often a friendly and approachable personality, feeding difficulties, short stature, hypotonia, microcephaly, characteristic dysmorphic features (big eyes, high arched eyebrows, ptosis, deep and / or broad nasal bridge, broad / protruding nasal tip, short and / or upturned philtrum, narrow mouth, and micrognathia) and skeletal abnormalities (kyphosis and / or scoliosis, joint contractures, slender build and limbs). Other clinical features may include hernias, congenital cardiac defects, undescended testes, and seizures.

[0080] Autism Spectrum Disorder-Epilepsy-Joint Contracture Syndrome (ORPHA:370943) is a form of N-linked glycosylation congenital disorder characterized by distal joint contractures (mild flexion contractures of the fingers, displacement of the distal phalanges, swan neck deformity), retromicrognathia, generalized hypotonia, psychomotor developmental delay, autism spectrum disorder (delayed speech, abnormal language use, difficulty initiating, understanding, and maintaining social interactions, limitations in nonverbal communication, and repetitive behaviors), seizures, microcephaly, and mild to moderate intellectual disability that becomes apparent with age. This disorder is caused by mutations in the gene SLC35A3(1p21).

[0081] Autism spectrum disorder and developmental delay with unsteady gait (ORPHA:329195) is a rare genetic neurological disorder characterized by hypotonia in infants, feeding difficulties, general developmental delay, mild to moderate intellectual disability, delayed independent walking, long strides with raised arms and flexed elbows, and limitations in language skills. Behavioral patterns are highly diverse, ranging from sociable and affectionate to autistic behaviors.

[0082] Chromosome 15 inversion / duplication syndrome ORPHA:3306 is a rare and complex chromosomal duplication / inversion in the region 15q11.2–q13.1, characterized by early central hypotonia, generalized developmental delay and intellectual disability, autistic behaviors, and seizures. Clinical description: Typically presents with neonatal hypotonia, feeding difficulties, and gross motor delay. Generalized developmental delay is typical in early childhood, with speech and language particularly affected. Expressive language is absent or very poor, often reliant on echolalia. Comprehension is very limited and contextual. Willingness to communicate is absent or very limited. Most children and adults have moderate to severe intellectual disability. Distinct behavioral disturbances present in children and adolescents are broadly described as autistic or autistic-like. Seizures occur in more than half of affected individuals, with onset typically between 6 months and 9 years of age, and may include infantile spasms, as well as myoclonic seizures, tonic-clonic seizures, tonic seizures, atonic seizures, loss of consciousness, and focal seizures. Various EEG (electroencephalogram) abnormalities have been explained. Hypotonia is observed in almost all individuals, usually accompanied by joint hyperextension and drooling. Facial dysmorphism is absent or slight, and major malformations are rare.

[0083] Macrocephaly-intellectual disability-autism syndrome ORPHA:210548 is a rare genetic neurological disorder characterized by macrocephaly, dysmorphic facial features, and associated psychomotor delay resulting in intellectual disability and autism spectrum disorder. Facial dysmorphism may include frontal bulge, bilateral ocular stenosis, midface hypoplasia, nasal bridge depression, short nose, and long philtrum.

[0084] ORPHA:500545, a severe neurodevelopmental disorder with feeding difficulties, repetitive hand movements, and bilateral cataracts, is a rare pervasive developmental disorder characterized by microcephaly, severe developmental delay, intellectual disability, bilateral cataracts, severe epilepsy including infantile spasms, hypotonia, irritability, feeding difficulties resulting in poor growth, and repetitive hand movements. The disorder presents in infancy. Brain imaging shows delayed myelination and cerebral atrophy.

[0085] Smith-Maginis syndrome ORPHA:819 is a complex genetic disorder characterized by various intellectual disabilities, sleep disturbances, craniofacial and skeletal abnormalities, mental disorders, and speech and motor delays. Clinical description: Patients have a recognizable clinical picture. Craniofacial features include brachycephaly, frontal bulge, binocular eccentricity, brow folds, upslanting palpebral fissure, midface hypoplasia, chin-prominent face with a sunken nasal bridge, a protruding upper lip with a "tent-shaped" appearance, and micrognathia in infancy. Dental abnormalities include tooth aplasia and taurodontism. Short stature is common in young patients, and in adulthood, height is usually within the normal range. Overweight and / or obesity are common in teenagers and adults. Other skeletal abnormalities include brachydactyly, scoliosis, fifth-digit oblique fingertip syndrome, 2 / 3 toe syndactyly, forearm and elbow limitations, vertebral abnormalities, persistent fetal finger pads, and polydactyly. Otorhinolaryngological problems such as velopharyngeal insufficiency, hoarse voice, vocal cord nodules, and polyps are also common, and hearing loss (60% of patients) can vary from mild to moderate. Ophthalmic features (over 60%) include myopia and iris abnormalities, and rarely, retinal detachment (often resulting from violent behavior). Mild to moderate intellectual disability, marked speech delay, decreased pain sensitivity, peripheral neuropathy, and characteristic sleep disturbances and maladaptive behaviors (explosive / tantrums, attention-seeking, aggression, defiance, distractibility, and self-injurious behavior) are common. Organ malformations (30-40%) include abnormalities of the heart, kidneys, urinary tract, and central nervous system (CNS).

[0086] Tuberous sclerosis (TSC), ORPHA:805, is a neurocutaneous disorder characterized by multisystem hamartomas and neuropsychiatric features. Clinical description: TSC is characterized by multisystem hamartomas most commonly found in the skin, brain, kidneys, lungs, and heart, appearing at various ages. Skin complications include hypomelanotic macules (leaf-shaped leukoplakia) appearing within the first year of life, angiofibromas, onychofibromas, scalp and lumbar (shaglin patch) fibrous sclerosis appearing as erythematous and papulodular nodular lesions at 3-4 years of age, and "confetti" skin lesions appearing from childhood to early adolescence. The brain is affected in almost all cases of TSC, with various neuropathological lesions present, including cortical / subcortical nodules, radial migration lines, subependymal nodules, and subependymal giant cell astrocytoma (SEGA). SEGA can cause hydrocephalus (with a high growth risk during the first 30 years). Early-onset epilepsy (infantile spasms and / or focal seizures) is seen in 85% of patients. Neuropsychiatric features (intellectual disability, attention deficit / hyperactivity disorder, autism spectrum disorder (ASD), self-injury, anxiety, and obsessive-compulsive tendencies) have also been reported. Renal angiomyolipoma (AML) develops in childhood and has a high risk of growing during adolescence and adulthood, presenting with pain, hematuria / retroperitoneal hemorrhage, abdominal mass, hypertension, and renal failure. Lymphangioleiomyomatosis (LAM), multiple micronodular alveolar epithelial hyperplasia (MMPH), and pulmonary cysts develop in adulthood and present with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas (CR) appear in the fetal stage and may present with symptoms during infancy and early childhood (due to outflow tract obstruction or impaired valve function). Additional features include perforation of tooth enamel, oral fibromas, and skeletal dysplasia.

[0087] Xq12-q13.3 duplication syndrome ORPHA:314389 is a rare chromosomal abnormality syndrome caused by a partial duplication of the long arm of the X chromosome, characterized by generalized developmental delay, autistic behavior, microcephaly, and facial dysmorphisms (including down-slanting palpebral fissure, sunken nasal bridge, drooping nostrils, long philtrum, and slanted corners of the mouth). Epilepsy has also been reported in some patients.

[0088] This disorder may be one or more of the following autism spectrum disorders (pervasive developmental disorders): Asperger's syndrome, atypical autism, and autism spectrum disorder. Asperger's syndrome is an autism spectrum disorder characterized by marked difficulties in social interaction, along with restrictive and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders in that language and cognitive development are relatively preserved.

[0089] Atypical autism is a type of autism spectrum disorder that presents with some autistic symptoms after the age of three, but lacks all the features necessary for a diagnosis of autism. Autism spectrum disorder is characterized by symptoms across all three symptom domains (communication, socialization, restricted repetitive interests, and behaviors), delayed language development, and symptom onset before the age of three.

[0090] Autism spectrum disorder can have overlapping phenotypes, including Angelmann syndrome (AS), Rett syndrome (RS), Phelan McDiarmid syndrome (PMS), and Pitt-Hopkins syndrome (PTHS).

[0091] This disorder may be one or more of the following behavioral disorders: attention deficit and hyperactivity disorder, stereotyped movement disorder, conduct disorder, generalized anxiety disorder, neurotic disorder, obsessive-compulsive disorder, agoraphobia, social phobia, and separation anxiety disorder, as well as 15q11q13 microduplication syndrome.

[0092] Attention-deficit and hyperactivity disorder (ADHD) is a specific developmental disorder characterized by the coexistence of attention problems and hyperactivity, with each behavior rarely occurring in isolation, and the onset of symptoms before the age of seven.

[0093] Stereotyped movement disorder is a specific developmental disorder characterized by repetitive, rhythmic, and purposeless movements or activities, such as violently banging one's head, biting one's nails, or rocking one's body. Conduct disorder is a specific developmental disorder characterized by repetitive behavioral patterns that infringe upon the rights of others or social norms.

[0094] Generalized anxiety disorder is an anxiety disorder characterized by persistent anxiety that is not focused on any single object or situation. Neurotic disorders are anxiety disorders that involve distress but do not involve delusions or hallucinations.

[0095] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurring, unwanted thoughts, feelings, ideas, or sensations (obsessions) or compulsions that compel one to perform certain actions (compulsions). Agoraphobia is a phobic disorder characterized by specific anxiety about being in a place or situation from which it may be difficult or embarrassing to escape, or from which help may not be available.

[0096] Social phobia is a phobic disorder characterized by social anxiety that occurs only in specific public or social situations, interactions with others, or when being judged or scrutinized by others. Separation anxiety disorder is an anxiety disorder characterized by an excessive and inappropriate level of anxiety about being separated from a person or place with which the individual has a strong emotional attachment.

[0097] Other behavioral disorders may include interference with social interaction (such as insufficient eye contact or a preference for solitude), communication or language problems (such as delayed speech or feigning deafness), repetitive and / or compulsive behaviors (such as stereotyped behavior or extreme agitation), signs of memory loss, and signs of disruptive behavior.

[0098] Any feature, integer, characteristic, compound, molecule, chemical site, or group described in conjunction with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless otherwise incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except for any combination in which at least part of such features and / or process is mutually exclusive. The present invention is not limited to the details of any of the aforementioned embodiments. The present invention extends to any novel one or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process disclosed herein.

[0099] In some embodiments, the compositions for use in the treatment, management, or improvement of FMR1-mediated autism according to this first embodiment, or the compositions for use in the treatment, management, or improvement of autism disorder or a disorder in which autism is a known component, according to this third embodiment, may involve administering the compositions to individuals who are already receiving treatment with other compounds and / or compositions. Appropriately, the individuals are already receiving a selective serotonin reuptake inhibitor (SSRI), such as fluvoxamine. Individuals who may benefit from treatment with the compositions of the present invention are likely to already be receiving SSRI compounds as treatment for autism or other disorders. Therefore, the compositions of the present invention may, advantageously, be co-administered with an SSRI and be effective in the presence of an SSRI in the treatment, management, or improvement of autism disorder or a disorder in which autism is a known component, such as FMR1-mediated autism.

[0100] Accordingly, the present invention can provide combinations of an SSRI and a composition comprising one or more tryptophans or their derivatives, and optionally one or more ergot alkaloids, derivatives or mimics thereof, for use in the treatment, management or improvement of autism disorder or a disorder in which autism is a known component, such as FMR1-mediated autism. In such embodiments, the SSRI may be administered at a typical daily dose of the SSRI, and the composition comprising one or more tryptophans or their derivatives, and optionally one or more ergot alkaloids, may be administered at the aforementioned daily dose. Preferably, in such embodiments, the composition comprising one or more ergot alkaloids is ergoloid mesylate.

[0101] Embodiments of the present invention are described below only as illustrative examples, with reference to the following figures. [Brief explanation of the drawing]

[0102] [Figure 1] A bar graph showing the open field for WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 2] A bar graph showing stereotypies of WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 3] A bar graph showing sociability for WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 4] A bar graph showing novel object recognition (NOR) for WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 5]A bar graph showing the suppression of novel food intake (hyponeophagia) by WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 6] A bar graph showing the daily life tests for WT-V, KO-V, sumatriptan, oxytriptan, ergoloid, and combinations (ergoloid and sumatriptan, ergoloid and oxytriptan). [Figure 7] Bar graphs showing open-field results for WT-V, KO-V, ergoloid / fluvoxamine combinations, and ergoloid / oxytriptan / fluvoxamine combinations. [Figure 8] A bar graph showing the nest-building results for WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 9] A bar graph showing the sociability results for WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 10] A bar graph showing the results of stereotypic syndromes for WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 11] A bar graph showing the results of suppressing novel food intake for WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 12] A bar graph showing the NOR results for WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 13] A bar graph showing the results of fear conditioning with WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Figure 14]A bar graph showing the results for resident intruders using WT-V, KO-V, the ergoloid / fluvoxamine combination, and the ergoloid / oxytriptan / fluvoxamine combination. [Modes for carrying out the invention]

[0103] Examples [Examples]

[0104] Studies on the phenotypic effects of ergoloid mesylate, oxytriptan, and sumatriptan in FXS and ASD Tryptophan has been shown to reduce the intensity and duration of migraines (Titus et al., 1986). However, some controversial results have been reported from a group of patients administered an amino acid beverage containing L-tryptophan (Drummond, 2006). Subsequent studies suggest that a decrease in serotonin synthesis in the brain may exacerbate photophobia and other migraine-related symptoms, and thus contribute to the pathogenesis of migraines.

[0105] Hawkins (2020) reported the case of a 15-year-old male with autism and a history of lifelong severe insomnia treated with 5-HTP since age 5. The typical dose of 5-HTP for insomnia is 50-200 mg administered in the evening. 5-HTP has been shown to stabilize the sleep schedule and increase REM sleep.

[0106] Furthermore, studies have shown that in the brains of individuals with autism, levels of tryptophan, a precursor to serotonin, are lower than normal, and that a diet lacking tryptophan can worsen autistic symptoms (Boccuto et al., 2013).

[0107] Stimulation of 5-HT7 serotonin receptors in the postsynaptic compartment reversed mGluR-LTD in hippocampal slices of FXS mouse brains, suggesting that 5-HT7 receptor agonists may be promising as novel therapeutic tools for FXS (Costa et al., 2012).

[0108] These same authors characterized two novel molecules with very high binding affinity and selectivity to the 5-HT7 receptor, as well as the ability to rescue exaggerated mGluR-LTD, which could be used as novel pharmacological tools for the therapy of FXS (Costa et al., 2015).

[0109] Increasing serotonergic signaling may potentially rescue disrupted neurobiology in FXS by increasing BDNF levels, the number of GluA1 receptors and GlutA1-LTP, increasing serotonin levels at synapses, and enhancing the dopaminergic system. These mechanisms are thought to improve synaptic plasticity and brain development. Other effects may include balancing serotonin cortical asymmetry and overall neuroprotective effects (Hanson and Hagerman, 2014).

[0110] The possibility of accelerated serotonin metabolism in autism spectrum disorder has been studied by Ritvo et al. (1971). These researchers administered L-dopa to four children with autism in an attempt to bring about clinical improvement by lowering blood levels of 5-HT. While 5-HT levels decreased significantly, no behavioral changes were observed. In conjunction with the study by Ritvo et al. (1971), the findings of this study do not encourage the idea that children with autism are likely to benefit from therapies based on the manipulation of 5-HT metabolism (Sverd et al., 1978).

[0111] Patients with autism spectrum disorder (ASD) show a greater response to sumatriptan than normal controls, independent of the placebo effect. Furthermore, in contrast to the more moderate difference in sumatriptan versus placebo GH response in normal controls, patients with autism or Asperger's disorder exhibit a significantly greater GH response to sumatriptan than to placebo. This suggests that 5-HT dysfunction in patients with autism may reflect hypersensitivity to inhibitory 5-HT1d receptors. These findings are consistent with previous findings (Novotny et al., 2000) indicating reduced 5-HT synthesis in frontal and thalamic brain regions in patients with autism or Asperger's disorder.

[0112] The results show that the severity of repetitive behaviors (measured by the YBOCS-compulsion subscale) parallels the sumatriptan-induced growth hormone response, unlike other behavioral aspects (communication and social deficits, measured by the ADI-R algorithm subscale). This suggests that a specific component of the 5HT system (5HT 1d receptor) may play a role in mediating one specific behavioral element of autism spectrum disorder (repetitive behaviors) and thus influence the heterogeneity of autism (Hollander et al., 2000).

[0113] Animal testing Fmr1 knockout mice are a valuable preclinical model for evaluating hypothetical drug therapies, as they replicate the human phenotype. The first animal model, the Fmr1 knockout (KO) mouse, was described over 20 years ago. Fmr1 KOs retain an insertion in exon 5 (Bakker et al., 1994). Fmr1 mRNA is still present, but the protein is null (Yan et al., 2004). These mice are backcrossed to C57 / Bl6 or FVB lines. Fmr1 KO2 is a null allele of Fmr1 generated by the deletion of the Fmr1 promoter and the first exon (Mientjes et al., 2006). In this case, both the protein and mRNA are null. This mutation is the same as the one resulting from Cre-mediated excision of the loxP site in Fmr1 cKO, which is described below (we have mouse models of these and other FXS).

[0114] Reduced inhibitory control of GSK3 in Fmr1 knockout mice may contribute to several socialization deficits, and lithium therapy may improve certain socialization disorders (Mines et al., 2010). Fmr1 KO mice may be useful for studying some social aspects of ASD, particularly when hyperactivity coexists (Sorensen et al., 2015).

[0115] Fragile X syndrome presents with overall symptoms very similar to autism, and the Fmr1 knockout mouse, an effective gene mouse model available for this disorder, also shows great potential as a model for autism (Bernadet and Crusio, 2006).

[0116] MeCP2 mRNA was identified as a substrate for FMRP. This X-linked MeCP2 gene is mutated in RS, another neurodevelopmental disorder with autistic features. Levels of MeCP2 protein were elevated in the brains of null-treated Fmr1 KO mice (Arsenault et al., 2016).

[0117] In Fmr1 KO mice, the synthesis of alphaCaMKII and PSD-95 proteins is impaired in the synaptoneurosomes upon mGluR5 stimulation. Furthermore, CAMKII-dependent phosphorylation of MeCP2 links these synaptic proteins to RS, another single gene disorder associated with autism, and to the transcriptional regulation of brain-derived nerve growth factor (BDNF). The results suggest that autism is a synapsopathy disease in which disruption of synapses during development produces a common clinical picture, despite heterogeneous underlying causes. The latter suggests that treatment of fragile X may also be effective in treating other causes of autism (Dolen and Bear, 2009).

[0118] Adult Fmr1 knockout mice showed reduced baseline gene expression of selected cytokines in the hippocampus compared to wild-type mice. Inflammatory cytokines IL-6 and TNF-α were significantly reduced in Fmr1 knockout mice. Inflammatory cytokines are involved in amplifying downstream CNS signaling cascades that have the ability to influence many inflammatory responses as well as cognition and behavior (Hodges et al., 2017).

[0119] The layer 4 network in Fmr1-KO mice exhibits significant changes in spike output in response to thalamocortical input and distorted sensory coding. This developmental decline in layer 4 sensory coding accuracy contributes to the subsequent developmental changes and plasticity of the layer 4-to-layer 2 / 3 connection observed in Fmr1-KO mice, as well as the underlying circuit dysfunction that underlies sensory hypersensitivity. A causal relationship exists between sensory dysfunction and social and repetitive behaviors in a mouse model of autism (Domanski et al., 2019).

[0120] Healthy hippocampal neurons (so-called place cells) exhibit place-related activity during spatial exploration, and their firing fields tend to remain stable over time. Arbab et al. found reduced stability and specificity of spatial representation in Fmr1-KO mice, which may be a potential biomarker of cognitive impairment observed in FXS and provide information about the ability to integrate sensory information into abstract representations and to successfully retain this conceptual memory. Reduced specificity and stability of CA1 place cell activity in Fmr1-KO mice were observed both within and between subsequent exploration sessions, while these mice exhibited relatively preserved field responses, with behavioral and firing rate parameters not significantly different from WT mice (Arbab et al., 2018).

[0121] Crude synaptic noidomyelia analysis of adult Fmr1 KO mice showed a significant decrease in Ube3a protein. Furthermore, blunting of Ube3a translation in response to mGluR1 / 5 stimulation was observed. The majority of AS cases result from deletions or mutations in the UBE3A gene located on chromosomes 15q11-13 (Filonova, 2014).

[0122] During the experiment, Fmr1 KO mice and wild-caught littermates backcrossed to the FVB strain were used. TransnetXY Automated Genotyping (www.transnetyx.com / ) (TRANSNETYX, INC., 8110 Cordova Rd. Suite 119, Cordova, TN 38016, USA) was used for genotyping. Animals were pre-treated for 14 days. The active ingredients of sumatriptan and ergoloid were present in a water carrier, while oxytriptan was present in a methanol carrier.

[0123] The mice were housed in plastic cages (35 × 30 × 12 cm) in groups of five. Room temperature (21 ± 2°C), relative humidity (55 ± 5%), a 12-hour light-dark cycle (lights on from 7 AM to 7 PM), and air exchange (16 times per hour) were automatically controlled. The animals had free access to commercially available food pellets and water. The experiment was conducted during the light period. Ten mice were used per treatment group in the AGS experiment. The experiment was conducted in accordance with the requirements of UK Animals (Scientific Procedures) Act, 1986.

[0124] All experiments were conducted with the experimenters blinded to genotype and drug treatment. Separate researchers prepared and coded the administration solution, assigned mice to the study treatment group, administered the drug to the animals, and collected auditory seizure data.

[0125] behavior analysis Behavioral tests were conducted in the second week. The behavioral tests included: 1. Hyperactivity: open field; 2. Stereotypic behavior: self-grooming; 3. Sociability: three-chamber partition test; 4. Memory and learning: novel object recognition; 5. Anxiety: inhibition of novel food intake; and 6. Daily living activities: marble burying.

[0126] Regarding hyperactivity, the open-field test (OFT) is a common measure of exploratory behavior and general activity in both mice and rats, and can measure both the quality and quantity of activity. Primarily, an open field (OFT) is a typical square, rectangular, or circular enclosure with walls to prevent escape. The OFT is also commonly used as a mechanism to evaluate the sedative, toxic, and irritant effects of compounds (Gould 2009).

[0127] For sociability, the three-chamber split test is used. The three-chamber paradigm test, known as Crawley's sociability and preference for social novelty protocol, has been successfully employed to study social belonging and social memory in several inbred and mutant mouse strains. The main principle of this test is that during two experimental sessions, the subject mouse is free to choose which of the three box compartments to spend time in, including indirect contact with one or two unfamiliar mice (Kaidanovich-Beilin, 2011).

[0128] For memory and learning, a novel object recognition (NOR) task was used to assess the ability of rodents to recognize novel objects in their environment. The NOR task has neither positive nor negative reinforcements, and this method assesses the natural preference rodents show for novel objects. The task procedure consists of three stages: habituation, mastery, and testing (Antunes 2012).

[0129] Regarding anxiety, a novel food intake suppression trial was conducted. Mice and rats, unable to vomit due to the rigidity of their gastric sphincter, developed a strategy of initially ingesting only very small amounts of the novel substance to overcome the potential food toxicity problem. Then, the intake was gradually increased until the animals determined whether the substance was safe and nutritious. This is similar to how rat traps in the past would first place palatable substances such as oatmeal, which could serve as a means of transporting toxins, in the areas where rats were found (Deacon 2011).

[0130] For stereotypic behaviors, self-grooming was evaluated. Self-grooming in animals is an innate behavior involved in maintaining hygiene, as well as other physiologically important processes including thermoregulation, social communication, and de-arousal. It is one of the most frequently observed behaviors in awake rodents and has a patterned, continuous structure accompanied by characteristic head-tail forward movement (Kalueff 2016).

[0131] For the daily life test, nest building was evaluated because it is an innate behavior in rodents, even when they are reared in a laboratory environment. Synthetic and / or natural materials (such as hemp twine, tissue, cotton, paper, and hay) were provided as a criterion for evaluating overall well-being and as an auxiliary assessment for predicting potential cognitive decline. Typically, changes in nest-building behavior, such as failure to build a nest, indicate changes in health or well-being. Furthermore, nest-building behavior is sensitive to many environmental and physiological challenges, as well as many gene mutations underlying pathological disease states (Gaskill 2013).

[0132] There are behavioral equivalences between humans and rodents, which allows us to use animal models to interpret how pharmaceutical active ingredients are effective in treating human conditions. Some of these equivalences are as follows:

[0133] Social interaction: Insufficient eye contact, patient prefers to be alone. Developmental Quotient (DQ) / Intelligence Quotient (IQ) / Social Quotient (SQ) using the Stanford-Binet Intelligence Scale or the Vineland Social Maturity Scale. (Borderline IQ: 71-89).

[0134] Communication and / or language problems: delayed speech, patient feigning deafness. Auditory assessment using brainstem evoked response audiometry (BERA). Repetitive behaviors and / or obvious obsessions: stereotyped behaviors, extreme agitation, and / or hyperactivity. Connor's scale is used to assess hyperactivity: >12 The term “destructive behavior” has its usual meaning in this art. It may also include repetitive behaviors, mood swings, irritability, self-injury, and aggression.

[0135] The term "memory loss" has its usual meaning in this art. It refers to the inability to retain information in the short or long term. It is also sometimes called memory impairment. It may include difficulties with cognitive abilities, executive abilities, and language abilities, executive function, and visual memory. It may also include difficulties with working memory (i.e., temporarily storing information while processing the same or other information), also known as short-term memory, and difficulties with phonological memory (or verbal working memory).

[0136] The term "social anxiety" has its usual meaning in this technical field. It is also sometimes called difficulty with social interaction or low sociability. Social anxiety may include insufficient eye contact, aversion to eye contact, a long time to initiate social interaction, social avoidance or withdrawal, and difficulty forming peer relationships.

[0137] The term "hyperactivity" has its usual meaning in the art. Hyperactivity may include having very short attention spans, hypersensitivity to visual, auditory, tactile, and olfactory stimuli, distractibility, impulsivity, restlessness, and / or excessive activity.

[0138] Treatment regime Treatment of mice with OX (oxytriptan), SU (sumatriptan), and ER (ergoloid mesylate, also referred to as ergoloid herein) followed the matrix shown in Table 1 below.

[0139] [Table 1]

[0140] result The results of the mouse behavioral tests are provided in Tables 2-12 below.

[0141] [Table 2]

[0142] [Table 3]

[0143] [Table 4]

[0144] [Table 5]

[0145] [Table 6]

[0146] [Table 7]

[0147] [Table 8]

[0148] [Table 9]

[0149] [Table 10]

[0150] [Table 11-1]

[0151] [Table 11-2]

[0152] [Table 12-1]

[0153] [Table 12-2]

[0154] Detailed results of the mouse experiments on behavior are described in Tables 13-20 below.

[0155] [Table 13]

[0156] [Table 14]

[0157] [Table 15]

[0158] [Table 16]

[0159] [Table 17]

[0160] [Table 18]

[0161] [Table 19]

[0162] [Table 20]

[0163] Behavioral experiments showed that oxytriptan improved the FXS phenotype in FMR1 mice, suggesting its potential as a useful and effective treatment for FMR1-mediated autism and FXS. Furthermore, the combination of ergoloid and oxytriptan improved all FXS phenotypes in FMR1 mice, suggesting its potential use in the treatment of autism (including FMR1-mediated autism), behavioral disorders, and FXS. [Examples]

[0164] Studies on the phenotypic effects of ergoloid mesylate, oxytriptan, and SSRIs in FXS and ASD The experimental procedure described above for Example 1 was used in the following study, with the addition of two further behavioral studies described below. SSRIs (selective serotonin reuptake inhibitors) were co-administered with ergoloid mesylate and oxytriptan to evaluate the effects of ergoloid mesylate and oxytriptan on subjects already receiving SSRI treatment.

[0165] behavior analysis In addition to the resident-intruder test and fear conditioning test, the behavioral test was conducted in the second week, as described above in Example 1.

[0166] Resident-intruder test: Aggression was assessed in cages where the animals had been accustomed for several minutes. Then, unfamiliar animals were introduced into the test cages, and the aggression latency was measured compared to baseline values ​​(WT and KO).

[0167] Fear conditioning test: After a 1-2 minute acclimatization period, the mice receive several 1-second electric shocks (0.2-0.3 mA). During the test phase, the mice are returned to the same room without shocks. The resting time is measured.

[0168] Treatment regime Three combinations of ergoloid mesylate, oxytriptan, and SSRI were compared to two combinations of ergoloid mesylate and SSRI (as well as WT and KO controls).

[0169] Treatment of mice with OX (oxytriptan), ER (ergoloid mesylate), and FL (fluvoxamine) followed the matrix shown in Table 21 below. In the three combinations, mice were administered 2 mg / kg of ergoloid mesylate, 40 mg / kg of oxytriptan, and 40 mg / kg of fluvoxamine (SSRI).

[0170] [Table 21]

[0171] result The results of the mouse behavioral tests are provided in Tables 22-30 below. Table 22 below summarizes the mitigated phenotypes achieved by different treatments.

[0172] [Table 22]

[0173] [Table 23]

[0174] [Table 24]

[0175] [Table 25]

[0176] [Table 26]

[0177] [Table 27]

[0178] [Table 28]

[0179] [Table 29]

[0180] [Table 30]

[0181] These behavioral experiments showed that tryptophans such as oxytriptan combined with ergoloid mesylate improved the FXS phenotype in FMR1 mice when administered simultaneously with the SSRI fluvoxamine. This suggests that tryptophans may be a useful and effective treatment for FXS and FMR1-mediated autism in patients already receiving SSRIs such as fluvoxamine. [Examples]

[0182] Examples of formulations and treatments Several formulation examples are provided below along with proposed dosing regimes. These are illustrative and should be understood to be optimized during further experiments, which may include clinical trials. For brevity, the formulations do not specify non-active ingredients (e.g., pharmaceutically acceptable carriers or excipients).

[0183] Formulation 3A-oxytriptan-FMR1 Oral Tablets for the Treatment of Autism

[0184] [Table 31]

[0185] Formulation 3B-oxytriptan-FMR1 Oral Tablets for the Treatment of Autism

[0186] [Table 32]

[0187] Formulation 3C-oxytriptan - Oral tablets for the treatment of Fragile X syndrome (FXS)

[0188] [Table 33]

[0189] Formulation 3D-oxytriptan + ergoloid mesylate - Oral tablets for the treatment of autism

[0190] [Table 34]

[0191] Formulation 3E-oxytriptan + ergoloid mesylate-FMR1-mediated oral tablets for the treatment of autism

[0192] [Table 35]

[0193] Formulation 3F-oxytriptan + ergoloid mesylate - Oral tablets for the treatment of Fragile X syndrome (FXS)

[0194] [Table 36]

[0195] Formulation 3G-oxytriptan + ergoloid mesylate - Oral tablets for the treatment of autism, FMR1-mediated autism, and / or fragile X syndrome (FXS)

[0196] [Table 37]

[0197] Those skilled in the art will naturally understand that the therapeutically effective dose is, of course, determined by the activity and form of the selected pharmaceutical active ingredient. The embodiments described above are not intended to limit the scope of protection granted by the claims, but rather to illustrate examples of how the present invention can be implemented.

[0198] References

[0199] [Table 38-1]

[0200] Table 38-2

[0201] Table 38-3

[0202] Table 38-4

Claims

1. A composition for use in the treatment, management, or improvement of FMR1-mediated autism, wherein the composition comprises one or more tryptophans selected from 5-hydroxytryptophan (5-HTP) (oxytriptan), tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and ogluphanide, or mixtures thereof.

2. The composition according to claim 1, wherein the composition comprises 5-hydroxytryptophan (5-HTP) (oxytriptan).

3. The composition according to claim 1, wherein the composition comprises one or more tryptophans selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and ogluphanide, or mixtures thereof.

4. The composition according to any one of claims 1 to 3, wherein the FMR1-mediated autism is related to Fragile X syndrome (FXS).

5. A composition for use in the treatment, management, or improvement of Fragile X syndrome (FXS), wherein the composition comprises one or more tryptophans selected from 5-hydroxytryptophan (5-HTP) (oxytriptan), tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and ogluphanide, or mixtures thereof.

6. The composition according to claim 5, wherein the composition comprises 5-hydroxytryptophan (5-HTP) (oxytriptan).

7. The composition according to claim 5, wherein the composition comprises one or more tryptophans selected from tryptophan (L-tryptophan), D-tryptophan, 2-hydroxytryptophan, iminotryptophan, indoximod, 1-hydroperoxy-L-tryptophan, tryptophanamide, 5-fluorotryptophan, 7-aza-L-tryptophan, and ogluphanide, or mixtures thereof.

8. The composition according to claim 2, administered in a daily dose in the range of 20 mg to 400 mg.

9. The composition according to any one of claims 1 to 8, wherein the composition is administered to a patient in need in a dose of 100 mg TID.

10. A composition according to any one of claims 1 to 9, further comprising one or more ergot alkaloids.

11. The composition according to claim 10, wherein the ergot alkaloid comprises ergoloid mesylate.

12. The composition according to claim 10, wherein the ergot alkaloid is selected from one or more of methycerzide, dihydroergotamine, lyslidergotamine nicergoline, dihydroergocristine, dihydroergocornin, dihydroergocriptine, ergometrine, methylergometrine, cabergoline, pergolide, bromocriptine, lysergic acid diethylamide, terguride, and metergoline.

13. The composition according to any one of claims 10 to 12, wherein the ergot alkaloid comprises a substantially equiproportional preparation of dihydroergocornin, dihydroergocristine, and dihydroergocriptine.

14. The composition according to any one of claims 10 to 13, wherein the mixture contains one or more tryptophans and one or more ergot alkaloids.

15. The composition according to any one of claims 10 to 13, wherein the one or more tryptophans are administered separately, together, or in succession with the one or more ergot alkaloids.

16. The composition according to any one of claims 10 to 13, wherein the composition comprises oxytriptan and an ergoloid mixture, and is administered in a daily dose of oxytriptan in the range of 20 mg to 400 mg and an ergoloid mixture in the range of 1 mg to 10 mg.

17. The composition according to any one of claims 10 to 13, comprising oxytriptan and ergoloid mesylate, administered in doses of 100 mg TID of oxytriptan and 1 mg TID of ergoloid mesylate.

18. A composition for use in the treatment, management, or improvement of FMR1-mediated autism, comprising the composition according to any one of claims 1 to 9 and an SSRI.

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