Compositions comprising a nnrti and uses thereof for treating autism, fragile x syndrome or behavioural disorders

Abstract

The present invention relates to compositions for use in the treatment, management or amelioration of FMRI mediated autism and Fragile X Syndrome (FXS), wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs). The invention also relates to one or more NNRTIs for use as medicaments for treating a range of autistic diseases, diseases having an autistic component and behavioural disorders.

Description

Compositions and Treatments for Fragile X Syndrome and Autism Spectrum DisorderCross-Reference to Related Applications

[0001] The present application claims priority from U.S. Provisional Application No. 63 / 596,579 filed November 6, 2023, the disclosures of which are incorporated herein by reference in entirety.Technical Field of the Invention

[0002] The invention relates to compositions for use in the treatment, management or amelioration of neurological and developmental disorders, and in particular for the treatment of a range of autism diseases or diseases where autism is a known component treatment of and also Fragile X Syndrome (FXS).Background to the Invention

[0003] Mutational inactivation of the gene encoding the Fragile X Mental Retardation protein (FMRP) causes a spectrum of symptoms including seizures, sleep disorders, anxiety, irritability, autism, mild to severe cognitive impairment and intellectual disability. The constellation of symptoms is known as Fragile-X syndrome (FXS).

[0004] FXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinucleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called pre-mutations (55-200 CGG repeats). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signalling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus.

[0005] The syndrome in humans is caused by expansion of an unstable, CGG triplet expansion (> 200 repeats) in the 5' untranslated region of the FMR1 gene located on the X chromosome, which leads to gene methylation, inactivation, andresultant loss of fragile X mental retardation protein expression (FMRP). FMRP functions as a translational regulator, affecting synthesis of many proteins including those involved in synaptic pruning during development (Razak, 2020). M eta-analysis estimates the frequencies of individuals with the full mutation FXS allele to be approximately 1 in 7000 males and 1 in 11 ,000 females (Hunter, 2014). FXS is severely debilitating in males. Females generally are less affected than males due to mosaicism resulting from X-chromosome inactivation which occurs randomly early in embryogenesis (Gurney, 2017).

[0006] Fragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioural anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behaviour, autism). Autistic-like behaviour can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits and tactile defensiveness. In females, intellectual and behavioural disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioural disinhibition is very common. Recurrent otitis (60%) and seizures (16 to 20%) can also be observed. FXS patients display a range of neuropsychiatric symptoms including intellectual disability, delayed language acquisition, poor social interaction, hyperarousal, hypersensitivity, repetitive behaviours, disrupted sleep, attention deficit hyperactivity disorder (ADHD) and autism. These behavioural changes are most widely modelled in adult male Fmr1 knockout (KO) mice which display a spectrum of behavioural phenotypes due to the Fmr1 gene deletion. The mutant mice show hyperarousal in the open field test, have impaired social interaction, are less likely to build nests when provided cotton batting and are less likely to bury marbles in the cage bedding. Adult male mice were used for all studies as male FXS patients typically suffer more severe symptoms than do female patients due to the single X chromosome. In both FXS patients and the Fmr1 KO mice, alterations have been found in the density, size, shape and maturity ofdendritic spines, the principal recipients of excitatory inputs from other neurons (Gurney, 2017).

[0007] Patients with FXS most frequently have a combination of ADHD and hyperarousal, but other disorders, such as Smith-Magenis syndrome and males with XYY, may have similar volatility of behaviour (Hagerman, 1999). Mood problems and anxiety are common in foetal alcohol syndrome (FAS), Williams Syndrome (WS), FXS, Tourette syndrome, and some sex chromosomal disorders, and their identification and psychopharmacological treatment may dramatically enhance the well-being of the patient, and in some cases, significantly reduce aggression or out- bursts (Hagerman, 1999). Lastly, relatively high frequency of significant distortions in thinking on the spectrum of psychotic ideation are being studied in several disorders, including FAS, FXS, velocardiofacial syndrome (VCFS), and Prader- Willi syndrome (PWS), because antipsychotic medication may significantly improve these distortions and overall functioning level.

[0008] Multiple studies suggest that variants within the FMR1 gene other than the CGG-repeat expansion mutation can cause dysfunction of FMRP (Suhl, 2015). Similar to the I304N mutation, the G266E mutation is within a conserved amino acid in a KH domain and is very likely to be responsible for the patient’s intellectual and behavioural disabilities. The S27X mutation is also very likely to be the root of the patient’s symptoms because the truncation is so severe and FMRP is absent in a cell line derived from the patient.

[0009] The genetic basis of ASDs is highly heterogeneous, as hundreds of different genes have been implicated in their cause. Interestingly, most of the genes show expression profiles at the stage of early development, and their functionalities share strong enrichment in cell adhesion and mobility, cytoskeleton regulation, synapse formation and kinase signalling (Pinto, 2010; Gilbert, 2017). These ASD genes include FMR1 , LIS1 , MECP2, PTEN, SHANK1 / 2 / 3, TAOK2, TSC1 / 2, Neuroligins, Neurexins, KIAA2022 / KIDLIA (Gilbert, 2016) and UBE3A / E6- associated protein (E6AP).

[0010] Symptoms in FXS patients include the following: intellectual impairment, such as difficulties with cognitive, executive and language performance, short-termmemory, executive function, visual memory and visual-spatial relationships; autism; social anxiety (i.e. difficulties in social interaction) such as poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships; hyperactivity and repetitive behaviour, including very short attention spans, hypersensitivity to visual, auditory, tactile, and olfactory stimuli, distractibility, impulsiveness, restlessness and over activity; disruptive behaviour, including fluctuating mood, irritability, self-injury and aggression; obsessive compulsive disorder (OCD); ophthalmologic problems, such as strabismus; seizures; difficulties with working memory, which involves the temporary storage of information while processing the same or other information; difficulties with phonological memory (or verbal working memory); and fragile X-related primary ovarian insufficiency (FXPOI).

[0011] 10] FXS patients display a variety of overlapping intellectual deficits with other ASDs ranging from severe cognitive disabilities, autistic behaviours such as aggression, social anxiety and stereotypic acting, attention-deficit hyperactivity disorder, epilepsy and abnormal physical characteristics such as macroorchidism (Hagerman, 1997). FXS and ASD patients show a range of repetitive behaviours, including stereotypies, rituals, compulsions, obsessions and self-injury. Similar phenotypes occur (but not limited to) in Autism Spectrum Disorder (ASD): Angelman Syndrome (AS), Rett Syndrome (RS), Phelan Mcdermid Syndrome (PMS), Pitt Hopkins Syndrome (PTHS).

[0012] Fmr1 knockout mice recapitulate the human phenotype and represent a valuable preclinical model for assessment of putative drug treatments. More than 20 years ago, a first animal model was described, the Fmr1 knockout (KO) mouse. The Fmr1 KO carries an insertion in exon 5 (Bakker, 1994). It is a protein null, although Fmr1 mRNA is still present (Yan, 2004). These mice have been backcrossed to the C57 / BI6 or the FVB strains. The Fmr1 KO2 is a null allele at Fmr1 generated by deletion of the promoter and first exon of Fmr1 (Mientjes et al., 2006). It is both protein and mRNA null. This mutation is the same as is produced by Ore-mediated excision of the loxP sites present in the Fmr1 cKO described below (we house these and other mice models of FXS).

[0013] The Fmr1 KO mouse might be useful to study some social aspects of ASD, particularly when hyperactivity coexists (S0rensen, 2015). Fragile X Syndrome has a symptomatology resembling autism to a very large extent and the validated genetic mouse model that is available for this disorder, the Fmr1 KO mouse, also shows much promise as a possible model for autism (Bernardet, 2006).

[0014] MeCP2 mRNA was identified as a substrate for FMRP. This X-linked MeCP2 gene is mutated in Rett syndrome, another neurodevelopmental disorder associated with autistic features. Levels of MeCP2 protein were elevated in null- treated Fmr1 KO mouse brains (Arsenault, 2016).

[0015] mGluR5 stimulated protein synthesis of alphaCaMKII and PSD-95 are impaired in synaptoneurosomes from Fmr1 KO mice. Furthermore, CAMKII dependent phosphorylation of MeCP2 links these synaptic proteins to Rett syndrome, another single gene disorder associated with autism, and transcriptional regulation of brain derived nerve growth factor (BDNF). Results suggest it may be useful to think of autism as a synaptopathy, a disease where disruption of the synapse during development produces a common clinical picture, despite a heterogeneity of interconnected causes. It also raises the interesting possibility that treatments for one cause, such as fragile X, may have efficacy in treating other causes of autism (Dblen, 2009).

[0016] Adult Fmr1 KO mice showed decreased baseline gene expression of select cytokines in the hippocampus compared with WT mice. Proinflammatory cytokines IL- 6 and TNF-a were significantly decreased in Fmr1 KO mice. Proinflammatory cytokines are involved in the amplification of many inflammatory reactions and downstream CNS signalling cascades that have the ability to affect cognition and behaviour (Hodges, 2017).

[0017] The layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer % connectivity and plasticityobserved in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity. A causal link exists between sensory dysfunction and social and repetitive behaviours in a mouse model of autism (Domanski, 2019).

[0018] Healthy hippocampal neurons (so-called place cells) exhibit place-related activity during spatial exploration, and their firing fields tend to remain stable over time. In contrast, we found impaired stability and reduced specificity of Fmr1-KO spatial representations. This is a potential biomarker for the cognitive dysfunction observed in FXS, informative on the ability to integrate sensory information into an abstract representation and successfully retain this conceptual memory. Hippocampal place cells are one of the best understood systems in the brain where we have reached an initial understanding of the relationship between neural dynamics, information encoding, and cognition. Here we have shown that they may provide a powerful tool in understanding intellectual disability and ASD in a mouse model of FXS, in which it has been surprisingly difficult to demonstrate consistent cognitive deficits despite its clear genetic aetiology. Impaired specificity and stability of CA1 place cell activity in Fmr1-KO mice was found, both within and across subsequent exploration sessions, while these mice show a relatively spared place field response and their behaviour and firing-rate parameters do not significantly differ from WT mice. Our results link impaired physiology with cognition more deeply than possible with traditional behavioural or physiological assays, and offer a potential biomarker for testing of therapeutic strategies (Arbab, 2018).

[0019] Analysis of crude synaptoneurosomes of adult Fmr1 KO mice revealed a significant reduction in Ube3a protein. Additionally, a blunted translation of Ube3a in response to mGluR1 / 5 stimulation was observed. The majority of Angelman Syndrome cases arise from deletions or mutations of the LIBE3A gene located on the chromosome 15q11-13 (Filonova, 2014).

[0020] Efforts to treat FXS have included numerous investigations have not been widely successful, which has led to the exploration for additional and new therapies. Management is symptom-based and requires a multidisciplinary approach. Speech, physical and sensory integration therapy as well as individualised educational plansand behavioural interventions may be combined with medication, such as stimulants for attention deficit-hyperactivity disorder; selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, obsessive-compulsive disorder; and atypical antipsychotic agents for self-injury and aggressive behaviours. New targeted treatments for FXS are being studied.

[0021] An object of the present invention is to overcome one or more of the issues with current treatments for neurological and developmental disorders, such as autism and FXS. A further object of the present invention is to provide treatments for autism mediated by a FMR1 gene mutation. A preferred object of the present invention is to provide treatments for FXS. It would be beneficial if treatments are based on preexisting pharmaceutically active ingredients.Summary of Invention

[0022] In accordance with the present invention, there is provided a composition for use in the treatment, management or amelioration of FMR1 mediated autism, wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs) or derivatives thereof.

[0023] In accordance with a related aspect of the present invention, there is provided a method of treatment, management or amelioration of FMR1 mediated autism comprising the administration of a therapeutically effective amount to inhibit this particular mechanism of action of one or more NNRTIs or derivatives thereof in an individual in need of such management and / or treatment.

[0024] In accordance with a related, but further, alternative aspect of the present invention According to certain embodiments, there is provided use one or more NNRTIs or derivatives thereof in the manufacture of a medicament for the treatment, management or amelioration of FMR1 mediated autism in an individual.

[0025] The FMR1 mediated autism may be due to the FMR1 gene sequence including a mutation comprising one of the following:a. expansion and subsequent methylation of (CGG)n trinucleotide repeats in the 5'-untranslated region of the FMR1 gene; b. intragenic point mutations or deletions in FMR1 ; c. a I304N mutation; d. a G266E mutation; or e. a S27X mutation.

[0026] In accordance with a related, but yet alternative, aspect of the present invention, there is provided a pharmaceutical composition, comprising one or more NNRTIs or derivatives thereof and a pharmaceutically acceptable carrier, excipient, or diluent.

[0027] As used herein, the terms "treatment", "treating", “treat” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. "Treatment" as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) inhibiting the disease, i.e., arresting or slowing its development; and (b) relieving the disease, i.e. , causing regression of the disease.

[0028] The term “subject” or “individual” used herein includes any human or nonhuman animal. The term “nonhuman animal” includes all mammals, such as nonhuman primates, sheep, dogs, cats, cows, horses.

[0029] The FMR1 mediated autism may be related to Fragile X Syndrome (FXS).

[0030] In accordance with 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 NNRTIs or derivatives thereof.

[0031] In accordance with a related aspect of the present invention, there is provided a method of treatment, management or amelioration of Fragile X Syndrome (FXS) comprising the administration of a therapeutically effective amount to inhibit this particular mechanism of action of one or more NNRTIs or derivatives thereof in an individual in need of such management and / or treatment.

[0032] According to certain embodiments, there is provided use one or more NNRTIs or derivatives thereof in the manufacture of a medicament for the treatment, management or amelioration of Fragile X Syndrome (FXS) in an individual.

[0033] According to certain embodiments, there is provided a pharmaceutical composition, comprising one or more NNRTIs or derivatives thereof and a pharmaceutically acceptable carrier, excipient, or diluent.

[0034] The skilled addressee will understand that the optimum dose of the composition will need to be established for both the first and second aspects. However, it is preferred that the composition is administered in a daily dose in the range of about 100 mg and about 8.00 mg.

[0035] The daily dose of the composition comprising one or more NNRTIs described above may be administered in a single daily dose. Suitably the daily dose is administered in one to two daily doses. In some embodiments, the composition comprising one or more NNRTIs is administered in a dose of 200 mg BID (bis in die I twice a day) and therefore a total dose of 400 mg per day, for example at approximately 12 hour intervals.

[0036] Suitably these daily doses are of the NNRTIs in the composition. Suitably these daily doses are of Etravirine.

[0037] The NNRTI may comprise Etravirine. The composition comprising one or more NNRTIs may consist essentially or consist of Etravirine. The present invention may therefore provide Etravirine for use in the treatment, management or ameliorationof FMR1 mediated autism, suitably wherein the treatment involves administering to a patient in need thereof a total daily dosage amount of the Etravirine of from 100 to 800 mg, including all ranges and subranges therebetween such as, for example, 200 to 700 mg, 300 to 600 mg and 400 to 500 mg, including all ranges and subranges therebetween such as, for example, 250 to 550 mg, 375 to 675 mg, 300 to 450 mg, etc. The total daily dosage amount can be administered in one dose or multiple doses such as twice a day (BID) or three times a day. Preferably, the total daily dosage amount is about 400 mg, preferably twice a day (e g., 200 mg BID).

[0038] The one or more NNRTIs or derivatives may be selected from: Etravirine (ETR); Rilpivirine (RPV) Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV)or mixtures thereof. The one or more NNRTIs will preferably comprise Etravirine.

[0039] Etravirine [https: / / go.drugbank.com / drugs / DB06414] is an antiretroviral agent used in the treatment of HIV-1 infection. Its mechanism of action involves direct inhibition of the HIV-1 reverse transcriptase enzyme. It has a predicted bioactivity with GSK3A, GSK3B, LIMK1 , CDK5, TAAR1 , FYN, NTRK3, DYRK1A, CAMK2G, CAMKK2. Etravirine has a terminal elimination half-life of 41 hours (Havens, 2020). Etravirine adult dosage is 400 mg (200 mg twice daily or 400 mg once daily). Etravirine is approved for antiretroviral treatment-experienced children and adolescents aged 2- 18 years old and weighing minimum 10 kg, following a weight-adjusted dosage scheme (Intelence label).

[0040] One or more NNRTIs or derivatives may be selected from: Etravirine (ETR); Rilpivirine (RPV) Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV) or mixtures thereof.

[0041] The skilled addressee will readily understand that NNRTI derivatives and mimetics would have a similar efficacy and could be employed in conjunction with the present invention. NNRTI derivatives and mimetics may be selected from one or more of the following: Etravirine (ETR); Rilpivirine (RPV) Doravirine (DOR), Delavirdine(DLV), Nevirapine (NVP), and Efavirenz (EFV). The NNRTI derivatives and mimetics would be expected to invoke similar phenotypic effects, as the NNRTIs themselves.

[0042] Details of the NNRTI derivatives and mimetics are as follows:

[0043] Rilpivirine (CAS ID 700361-47-3, DrugBank DB08864): Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used in combination with other antiretroviral drugs in the treatment of HIV-1 infection in treatment-naive patients. It is a diaryl pyrimidine derivative with high internal conformational flexibility and tolerance to resistance mutations.

[0044] Doravirine (CAS ID 1338225-97-0, DrugBank DB12301 ): Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor used in combination with other antiretroviral drugs in the treatment of HIV-1 infection. It is indicated for treatment-naive adult patients.

[0045] Delavirdine (CAS ID 136817-59-9, DrugBank DB00705): Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretroviral drugs in the treatment of HIV-1 infection. It binds directly to the HIV-1 reverse transcriptase and does not compete with template or nucleoside triphosphates.

[0046] Nevirapine (CAS ID 129618-40-2, DrugBank DB00238): Nevirapine is a non-nucleoside reverse transcriptase inhibitor used in the management of HIV-1 infection. It is usually only prescribed after evident immune system decline, commonly in combination with Retrovir or Videx. It is not recommended as monotherapy because of resistance development. Nevirapine is reportedly effective for a limited period of time.

[0047] Efavirenz (CAS ID 154598-52-4, DrugBank DB00625 ): Efavirenz is a non- nucleoside reverse transcriptase inhibitor used in the treatment and prevention of HIV- 1 infection. It is a synthetic purine derivative and its antiviral activity is dependent on the intracellular conversion to the active triphosphorylated form. Efavirenz iscommonly given in combination with other antiretroviral agents as first line treatment and as part of an expanded postexposure prophylaxis regimen.

[0048] The composition of the third aspect may be for use in the treatment, management or amelioration of a behavioural or cognitive disorder.

[0049] The behavioural disorder may be one of the following: hyperactivity, social anxiety, memory loss and / or disruptive behaviour.

[0050] The behavioural disorder may be one of the following: attention deficit and hyperactivity disorder; stereotypic movement disorder; conduct disorder; generalised anxiety disorder; neurotic disorder; obsessive-compulsive disorder; agoraphobia; social phobia; separation anxiety disorder and 15q11 q13 microduplication syndrome.

[0051] The composition may be for use in the treatment, management or amelioration of a range of autism diseases or diseases where autism is a known component.

[0052] The disease may be selected from one or more of the following rare diseases with associated autism: 1 p21 .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 with autism spectrum disorder and gait instability; inverted duplicated chromosome 15 syndrome; macrocephaly-intellectual disabilityautism syndrome; severe neurodevelopmental disorder with feeding difficulties- stereotypic hand movement-bilateral cataract; Smith-Magenis syndrome; tuberous sclerosis complex; Xq12-q13.3 duplication syndrome.

[0053] 1 p21.3 microdeletion syndrome ORPHA:293948 is an extremely rare chromosomal anomaly characterised by severe speech and language delay, intellectual deficiency, autism spectrum disorder. Clinical description: 1 p21.3 microdeletion syndrome is characterised by severe speech and language delay, a borderline-mild to mild-moderate intellectual deficiency, autism spectrum disorderfeatures, and minor dysmorphic facial features such as long ears, deep set eyes, a broad nasal tip and a thick lower lip. Affected individuals have normal gross motor development without major abnormalities, they are often very shy and friendly with a tendency to overeat.

[0054] Adenylosuccinate lyase deficiency ORPHA:46 is a disorder of purine metabolism characterised by intellectual disability, psychomotor delay and / or regression, seizures, and autistic features. Clinical description: ADSL covers a continuous clinical spectrum with three major forms: fatal neonatal, severe (type I), and mild to moderate form (type II). Clinical variability is found, even in patients from the same family. Onset is generally between birth and early childhood. Cases ranging from fatal neonatal encephalopathy (presenting with hypokinesia, intractable seizures and respiratory failure) to mild intellectual disability have been reported. Intellectual disability is found in all patients, epilepsy of various types in most, and autistic features in about one third (failure to make eye contact, hypersensitivity to noise and light, repetitive behaviour, agitation, temper tantrums, autoaggression and self-mutilation). Other less common manifestations include psychomotor delay, hyperactivity, speech impairment, muscular hypotonia, muscle wasting, and spasticity. Severely affected patients often have microcephaly. Prenatal manifestations are also reported: impaired intrauterine growth, microcephaly, foetal hypokinesia, and loss of foetal heart rate variability.

[0055] Autism-facial port-wine stain syndrome ORPHA: 137911 is characterised by the presence of a unilateral angioma on the face and autistic developmental problems characterised by language delay and atypical social interactions.

[0056] Autism spectrum disorder due to ALITS2 deficiency ORPHA:352490 is a rare genetic syndromic intellectual disability characterised by global developmental delay and borderline to severe intellectual disability, autism spectrum disorder with obsessive behaviour, stereotypies, hyperactivity but frequently friendly and affable personality, feeding difficulties, short stature, muscular hypotonia, microcephaly, characteristic dysmorphic features (hypertelorism, high arched eyebrows, ptosis, deep and / or broad nasal bridge, broad / prom inent nasal tip, short and / or upturned philtrum,narrow mouth, and micrognathia), and skeletal anomalies (kyphosis and / or scoliosis, arthrogryposis, slender habitus and extremities). Other clinical features may include hernias, congenital heart defects, cryptorchidism and seizures.

[0057] Autism spectrum disorder-epilepsy-arthrogryposis syndrome ORPHA:370943 is a form of congenital disorders of N-linked glycosylation characterised by distal arthrogryposis (mild flexion contractures of the fingers, deviation of the distal phalanges, swan-neck deformity), retromicrognathia, general muscle hypotonia, delayed psychomotor development, autism spectrum disorder (speech delay, abnormal use of speech, difficulties in initiating, understanding and maintaining social interaction, limited non-verbal communication and repetitive behaviour), seizures, microcephaly and mild to moderate intellectual disability that becomes apparent with age. The disease is caused by mutations in the gene SLC35A3 (1 p21 ).

[0058] Developmental delay with autism spectrum disorder and gait instability ORPHA:329195 is a rare, genetic, neurological disorder characterised by infant hypotonia and feeding difficulties, global development delay, mild to moderate intellectual disability, delayed independent ambulation, broad-based gait with arms upheld and flexed at the elbow with brisk walking or running, and limited language skills. Behaviour patterns are highly variable and range from sociable and affectionate to autistic behaviour.

[0059] Inverted duplicated chromosome 15 syndrome ORPHA:3306 is a rare, complex chromosomal duplication / inversion in the region 15q11.2-q13.1 characterised by early central hypotonia, global developmental delay and intellectual deficit, autistic behaviour, and seizures. Clinical description: Presentation is typically with neonatal hypotonia, feeding difficulties and gross motor delay. Global developmental delay is typical in early childhood with speech and language particularly affected. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. Most children and adults have moderate to severe intellectual disability. The distinct behavioural disorder manifesting in children and adolescents has been widely described as autistic or autistic-like. Seizures occur in over half of affectedindividuals, with onset typically between 6 months and 9 years, and may include infantile spasms and myoclonic, tonic-clonic, tonic, atonic, atypical absences, and focal seizures. Various EEG (electroencephalography) abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most cases, with joint hyperextensibility and drooling. Facial dysmorphism is absent or subtle, and major malformations are rare.

[0060] Macrocephaly-intellectual disability-autism syndrome ORPHA:210548 is a rare, genetic, neurological disease characterised by association of macrocephaly, dysmorphic facial features and psychomotor delay leading to intellectual disability and autism spectrum disorder. Facial dysmorphism may include frontal bossing, hypertelorism, midface hypoplasia, depressed nasal bridge, short nose, and long philtrum.

[0061] Severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement-bilateral cataract ORPHA:500545 is a rare pervasive developmental disorder characterised by microcephaly, profound developmental delay, intellectual disability, bilateral cataracts, severe epilepsy including infantile spasms, hypotonia, irritability, feeding difficulties leading to failure to thrive, and stereotypic hand movements. The disease manifests in infancy. Brain imaging reveals delay in myelination and cerebral atrophy.

[0062] Smith-Magenis syndrome ORPHA:819 is a complex genetic disorder characterised by variable intellectual deficit, sleep disturbance, craniofacial and skeletal anomalies, psychiatric disorders, and speech and motor delay. Clinical description: Patients have a recognizable clinical picture. Craniofacial features include brachycephaly, frontal bossing, hypertelorism, synophrys, upslanting palpebral fissures, midface hypoplasia, a broad square-shaped face with depressed nasal bridge, an everted upper lip with a "tented" appearance, and micrognathia in infancy. Dental anomalies include tooth agenesis and taurodontism. Short stature is common in young patients, with height typically in the normal range as adults. Excess weight and / or obesity in teens and adults are common. Other skeletal anomalies include brachydactyly, scoliosis, 5th-fingerclinodactyly, 2 / 3 toe syndactyly, forearm and elbow limitations, vertebral anomalies, persistent foetal finger pads, and polydactyly.Otolaryngological problems such as velopharyngeal insufficiency, a hoarse deep voice, and vocal cord nodules and polyps are also common; hearing loss (60% of patients) is variable and may be mild to moderate. Ophthalmologic features (>60%) include myopia and iris anomalies and rarely, retinal detachment (often resulting from violent behaviours). Mild to moderate intellectual deficit, significant speech delay, decreased sensitivity to pain, peripheral neuropathy, as well as characteristic sleep disturbances and maladaptive behaviours (outbursts / temper tantrums, attention seeking, aggression, disobedience, distraction, and self-injurious behaviours) are common. Organ malformations (30-40%) include cardiac, renal, urinary tract, and central nervous system (CNS) abnormalities.

[0063] Tuberous sclerosis complex (TSO) ORPHA:805 is a neurocutaneous disorder characterised by multisystem hamartomas and associated with neuropsychiatric features. Clinical description: TSC is characterised by multisystem hamartomas, most commonly skin, brain, kidney, lung and heart, appearing at different ages. Skin involvement includes: hypomelanotic macules (ash leaf) present within the first years of life; angiofibromas that appear at age 3-4 years as erythematous and papulonodular lesions; ungual fibromas; cephalic and lumbar (shagreen patch) fibrous plaques; and "confetti" skin lesions appearing in childhood to early adolescence. Brain is involved in almost all cases of TSC, with the presence of different neuropathological lesions, such as cortico / subcortical tubers, radial migration lines, subependymal nodules, SEGA. SEGA can cause hydrocephalus (growth risk higher in the first 3 decades). Early-onset epilepsy (infantile spasms and / or focal seizures) is present in 85% of patients. Neuropsychiatric features (intellectual disability, attention- deficit / hyperactivity disorder, autism spectrum disorders (ASD), self-injury, anxiety and obsessive compulsive tendencies have also been reported. Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria / retroperitoneal haemorrhage, abdominal masses, hypertension and renal failure. Lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH) and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas (CR) appear during the foetal period and may become symptomatic (outflow tract obstruction or by interfering with valvular function) during infancy andearly childhood. Additional features include dental enamel pitting, intraoral fibromas and skeletal dysplasias.

[0064] Xq12-q13.3 duplication syndrome ORPHA:314389 is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome X, characterised by global developmental delay, autistic behaviour, microcephaly and facial dysmorphism (including down-slanting palpebral fissures, depressed nasal bridge, anteverted nares, long philtrum, down-slanting corners of the mouth). Seizures have also been reported in some patients.

[0065] The disease may be selected from one or more of the following autism spectrum disorders (pervasive developmental disorders): Asperger syndrome, atypical autism and autistic disorder.

[0066] Asperger syndrome is an autism spectrum disorder that is characterised by significant difficulties in social interaction, along with restricted and repetitive patterns of behaviour and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development.

[0067] Atypical autism is an autism spectrum disorder that involves some autistic symptoms occurring after age 3 with an absence of all the traits necessary for a diagnosis of autism.

[0068] Autistic disorder is an autism spectrum disorder that is characterised by symptoms across all three symptom domains (communication, social, restricted repetitive interests and behaviours), delayed language development, and symptom onset prior to age 3 years.

[0069] The autism spectrum disorder may have overlapping phenotypes, such as Angelman Syndrome (AS), Rett Syndrome (RS), Phelan Mcdermid Syndrome (PMS), Pitt Hopkins Syndrome (PTHS).

[0070] The disease may be selected from one or more of the following behavioural disorders: attention deficit and hyperactivity disorder; stereotypic movement disorder; conduct disorder; generalised anxiety disorder; neurotic disorder; obsessive- compulsive disorder; agoraphobia; social phobia; and separation anxiety disorder and 15q11 q13 microduplication syndrome.

[0071] Attention Deficit and Hyperactivity Disorder is a specific developmental disorder that is characterised by co-existence of attentional problems and hyperactivity, with each behaviour occurring infrequently alone and symptoms starting before seven years of age.

[0072] Stereotypic movement disorder is a specific developmental disorder that is characterised by repeated, rhythmic, purposeless movements or activities such as head banging, nail biting, or body rocking.

[0073] Conduct disorder is a specific developmental disorder marked by a pattern of repetitive behaviour wherein the rights of others or social norms are violated.

[0074] Generalised anxiety disorder is an anxiety disorder that is characterised by long-lasting anxiety that is not focused on any one object or situation.

[0075] Neurotic disorder is an anxiety disorder that involves distress but neither delusions or hallucinations.

[0076] Obsessive-compulsive disorder is an anxiety disorder that involves unwanted and repeated thoughts, feelings, ideas, sensations (obsessions), or behaviours that make them feel driven to do something (compulsions).

[0077] Agoraphobia is a phobic disorder involving the specific anxiety about being in a place or situation where escape is difficult or embarrassing or where help may be unavailable.

[0078] Social phobia is a phobic disorder that involves social anxiety occurring only in specific public or social situations, interactions with others or being evaluated or scrutinised by other people.

[0079] Separation anxiety disorder is an anxiety disorder that involves the feeling of excessive and inappropriate levels of anxiety over being separated from a person to whom the individual has a strong emotional attachment or place.

[0080] Other behavioural disorders may be impeded social interaction (such as poor eye contact or solitude preference), communication or language problems (such as speech delay or pretence of deafness), repetitive and / or obsessive behaviour (such as stereotyped behaviour or extreme restlessness), signs of memory loss and signs of disruptive behaviour. In some embodiments, the composition for use in the treatment, management or amelioration of FMR1 mediated autism of this first aspect may involve administering the composition to an individual who is already receiving a treatment of other compounds and / or compositions. Suitably the individual is already receiving a selective serotonin reuptake inhibitor (SSRI), for example fluvoxamine. Individuals who may benefit from treatment with the compositions of the present invention may be likely to already be receiving an SSRI compound as a treatment for autism or other disorders. Therefore the compositions of the present invention may advantageously be co-administered with and be efficacious in the presence of an SSRI in the treatment, management or amelioration of FMR1 mediated autism.

[0081] In some embodiments, the composition for use in the treatment, management or amelioration of FMR1 mediated autism of this first aspect may involve administering the composition to an individual who is already receiving a treatment of other compounds and / or compositions. Suitably the individual is already receiving a selective serotonin reuptake inhibitor (SSRI), for example fluvoxamine. Individuals who may benefit from treatment with the compositions of the present invention may be likely to already be receiving an SSRI compound as a treatment for autism or other disorders. Therefore the compositions of the present invention may advantageously be co-administered with and be efficacious in the presence of an SSRI in the treatment, management or amelioration of FMR1 mediated autism.

[0082] Features, integers, characteristics, compounds, molecules, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and figures), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.Detailed Description of the Invention

[0083] Embodiments of the invention are described below, by way of example only with reference to and as illustrated in the following figures:

[0084] Figure 1 is a bar graph showing the open field WT-V, KO-V and KO-ETR;

[0085] Figure 2 is a bar graph showing the stereotypy WT-V, KO-V and KO-ETR;

[0086] Figure 3 is a bar graph showing sociability WT-V, KO-V and KO-ETR;Figure 4 is a bar graph showing NOR WT-V, KO-V and KO-ETR;

[0087] Figure 5 is a bar graph showing hyponeophagia WT-V, KO-V and KO-ETR; and

[0088] Figure 6 is a bar graph showing tests of daily living WT-V, KO-V and KO- ETR.Studies relating Etravirine to phenotypic effects in FXS and ASDs

[0089] Etravirine is a second generation NNRTI used in the treatment of HIV-1 infection. It is approved for treatment-experienced patients aged 2 years or older (minimum weight 10 kg). It is commonly used as a second-line treatment due to its higher genetic barrier to resistance development (Intelence label). Its safety and efficacy were primarily established in two large Phase 3 randomised, double-blind, placebo-controlled trials (Madruga, 2007; Lazzarin, 2007; Katlama, 2010; Girard, 2012). Etravirine is considered as safe and well tolerated. Common side effects include mild to moderate rash within the first 6 weeks of therapy, nausea, diarrhoea and peripheral neuropathy. Rash has been observed more frequently in female (both adult and paediatric) patients (Hodder, 2012; Kakuda, 2016). Stevens-Johnson syndrome and other severe life-threatening reactions occurred in <0.1 % of all ETR recipients (Intelence label). Etravirine is considered safe and well tolerated for lifelong administration (Allavena, 2016). Studies on healthy subjects showed no serious adverse events nor any graded laboratory toxicities (Gupta, 2011). Although there areno previous reports for use in FXS or ASD treatment, Etravirine has been recently identified as a promising candidate for the treatment of Friedreich’s Ataxia (MIM #229300) and tested in a Phase 2 clinical trial (NCT04273165) in patients aged 10 to 40 years old (Alfedi, 2019; Rufini, 2022). Etravirine is metabolised by the hepatic CYP450 isozymes, with inhibitory effects on CYP2C9 and CYP2C19 and inductive effects on CYP3A4 (Schbller-Gyure, 2009). Although unrelated to previous work associated with the compound, the inventors surprisingly believe that molecular targets include GSK3A, GSK3B, LIMK1 , CDK5, TAAR1 , FYN, NTRK3, DYRK1A, CAMK2G, and / or CAMKK2. Given this belief, the inventors expect administration of the compound should result in corrective effects in behavioural and cognitive aspects of the FXS phenotype through GSK3 inhibition and subsequent WNT pathway activation.

[0090] Dysregulation of GSK3 activity has been previously associated with ASD pathogenesis, through its effects on the Wnt / p-catenin and PI3K / Akt / mTOR pathways (Rizk, 2021). Lithium, which is considered a non-selective GSK3 inhibitor, has been considered for the management of typical ASD symptoms and a clinical trial (NCT04623398) is underway to put this hypothesis to the test. It has been shown to improve mood disorders and maladaptive behaviour in retrospective studies (Siegel at al., 2014; Mintz, 2019), while studies on preclinical ASD models have suggested that chronic lithium treatment corrects ASD-like behaviours through neurogenesis repair and balancing of excitatory / inhibitory activity at the postsynaptic membrane (Wu, 2014). Tideglusib, an allosteric non-reversible ATP competitive inhibitor, has been also tested in a Phase 2 clinical trial (NCT02586935) showing encouraging results (Anagnostou, 2018).

[0091] Evidence from preclinical studies indicates that GSK3 dysregulation is also involved specifically in the pathogenesis of FXS. For example, GSK3 activity was found upregulated in the Fmr1 KO mouse brain, while constitutive GSK3 activity was associated with impaired social preferences (Min, 2009). GSK3 activation could be responsible for increased rates of protein synthesis through mTOR activation (Sharma, 2010; Avrahami, 2020). Accordingly, treatment with lithium or other GSK3 inhibitors corrected typical behaviour phenotypes in Fmr1 KO mice, includinghyperactivity, impaired sociability and anxiety. In addition, treatment with GSK3 inhibitors resulted in improved learning and memory, normalised long term potentiation (LTP), reduced incidence of audiogenic seizures, and lower rates of protein synthesis (Min, 2009; Mines, 2010; Yuskaitis, 2010; Liu, 2011 , Liu, 2012; Guo, 2012; Chen, 2014; Franklin, 2014). Notably, selective inhibition of GSK-3o but not GSK-3P corrected FXS symptoms in Fmr1 KO mice (McCamphill, 2020). Finally, a pilot study assessing the effects of lithium treatment on FXS individuals reported a significant improvement in CGIS (clinical global improvement scale) as well as improvements in hyperactivity, learning, vocalisations, self-abuse, and anxiety (Berry-Kravis, 2008).Animal testing

[0092] Fmr1 KO mice backcrossed to the FVB strain and WT littermates were used during experiments. TransnetYX Automated Genotyping (www.transnetyx.com / ). TRANSNETYX, INC., 81 10 Cordova Rd. Suite 119, Cordova, TN 38016, USA was used for genotyping. The animals were pretreated for 14 days. The active ingredient of Etravirine was in a water carrier.

[0093] The mice were housed in plastic cages (35 x 30 x 12 cm), 5 in each. The room temperature (21 ± 2°C), relative humidity (55 ± 5%), a 12-h light-dark cycle (lights on 7 a.m.-7 p.m.) and air exchange (16 times per h) were automatically controlled. The animals had free access to commercial food pellets and water. Testing was conducted during the light phase. Ten mice per treatment group were used for the AGS experiments. Experiments were conducted in line with the requirements of the UK Animals (Scientific Procedures) Act, 1986.

[0094] All experiments were conducted with the experimenter blind to genotype and drug treatment. Separate investigators prepared and coded dosing solutions, allocated the mice to the study treatment groups, dosed the animals, and collected the data.Behavioural Analysis

[0095] Behaviour testing was conducted at 2 weeks. The behavioural tests were as follows: 1. Hyperactivity: Open field; 2. Stereotypy: Self-grooming; 3. Sociability: Three chamber partition test; 4. Memory and Learning: Novel Object Recognition; 5. Anxiety: hyponeophagia; and 6. Test of daily living: nesting.

[0096] For hyperactivity, the open field test (OFT) is a common measure of exploratory behaviour and general activity in both mice and rats, where both the quality and quantity of the activity can be measured. Principally, the open field (OF) is an enclosure, generally square, rectangular, or circular in shape with surrounding walls that prevent escape. The OFT is also commonly used as a mechanism to assess the sedative, toxic, or stimulant effects of compounds (Gould 2009).

[0097] For stereotypy, self-grooming was assessed. Self-grooming in animals is an innate behaviour that is involved in hygiene maintenance and other physiologically important processes, including thermoregulation, social communication and dearousal. It is one of the most frequently observed behaviours in awake rodents and has a patterned, sequential organisation with characteristic cephalocaudal progression (Kalueff 2016).

[0098] For sociability a three-chamber partition test was utilised. The three- chamber paradigm test known as Crawley's sociability and preference for social novelty protocol has previously been successfully employed to study social affiliation and social memory in several inbred and mutant mouse lines. The main principle of the test was based on the free choice by a subject mouse to spend time in any of three box's compartments during two experimental sessions, including indirect contact with one or two mice with which it was unfamiliar (Kaidanovich-Beilin 2011 ).

[0099] For memory and learning, a novel object recognition (NOR) task was used to evaluate the rodents’ ability to recognize a novel object in the environment. In the NOR task, there are no positive or negative reinforcers, and this methodology assesses the natural preference for novel objects displayed by rodents. The taskprocedure consists of three phases: habituation, familiarisation, and test phase (Antunes 2012).

[0100] For anxiety a hyponeophagia test was conducted. Mice and rats cannot vomit, due to the tightness of the cardiac sphincter of the stomach, so to overcome the problem of potential food toxicity they have evolved a strategy of first ingesting only very small amounts of novel substances. The amounts ingested then gradually increase until the animal has determined whether the substance is safe and nutritious. So the old rat-catchers would first put a palatable substance such as oatmeal, which was to be the vehicle for the toxin, in the infested area (Deacon 2011 ).

[0101] For tests of daily living, nesting was assessed as nest building is an innate behavior in rodents, even when raised in laboratory settings. Synthetic and / or natural materials (such as twine, tissue, cotton, paper, and hay) are provided as a gauge of their overall well-being and as an ancillary assessment to predict the possible decline in cognition. Typically, changes in nesting behaviours, such as failure to create a nest, indicate a change in health or welfare. In addition, nesting behaviour is sensitive to many environmental and physiological challenges, as well as many genetic mutations underlying pathological disease states (Gaskill 2013).

[0102] There are equivalences in human and rodent behaviour which can allow animal models to be used to translate how a pharmaceutically active ingredient would be effective in treating human conditions. Some equivalences are as follows:

[0103] Social interaction: Poor eye contact, patient prefers to be alone. Development Quotient (DQ) / Intelligence Quotient (IQ) / Social Quotient (SQ) according to the Stanford Binet Intelligence Scale or Vineland Social Maturity Scale. (IQ borderline intelligence: 71-89)

[0104] Problems in communication and / or language: Speech delay, patient pretends to be deaf. Hearing assessment using Brainstem Evoked Response Audiometry (BERA). Repetitive behaviour and / or apparent obsessions: stereotypedbehaviour, extreme restlessness and / or hyperactivity. Connor’s scale is used to evaluate hyperactivity: >12.

[0105] The term “disruptive behaviour” has its normal meaning in the art. It may also include repetitive behaviour. It may also include fluctuating mood, irritability, selfinjury and aggression.

[0106] The term “memory loss” has its normal meaning in the art. It refers to an inability to retain information either short-term or long-term. It may also be called memory impairment. It may include difficulties with cognitive, executive and language performance, executive function and visual memory. It may also include difficulties with working memory, also called short-term memory (i.e. the temporary storage of information while processing the same or other information) and difficulties with phonological memory (or verbal working memory).

[0107] The term “social anxiety” has its normal meaning in the art. It may also be termed as difficulties in social interaction or low sociability. Social anxiety may include having poor eye contact, gaze aversion, prolonged time to commence social interaction, social avoidance or withdrawal and challenges forming peer relationships.

[0108] The term “hyperactivity” has its normal meaning in the art. Hyperactivity may include having very short attention spans, hypersensitivity to visual, auditory, tactile, and olfactory stimuli, distractibility, impulsiveness, restlessness and / or over-activity.Treatment Regime

[0109] The treatment of the mice with ETR (Etravirine) was according to the matrix shown below in Table 1 .Table 1. Treatment Matrix for Etravirine in FMR1 Animal Model

[0110] The behavioural experiments demonstrated that Etravirine unexpectedly ameliorated the FXS phenotypes in FMR1 mice and, based on the interpretation of these experiments, it is believed that Etravine could therefore be employed as a useful and efficacious treatment for autism (including FMR1-mediated autism), behavioural conditions and FXS.

[0111] Similar phenotypes occur in conditions such as Autism Spectrum Disorder (ASD), Angelman Syndrome (AS), Rett Syndrome (RS), and Phelan Mcdermid Syndrome (PMS). Autism is also a known component of the following rare diseases: 1 p21 .3 microdeletion syndrome; adenylosuccinate lyase deficiency; autism-facial portwine stain syndrome; autism spectrum disorder due to AUTS2 deficiency; autism spectrum disorder-epilepsy-arthrogryposis syndrome; developmental delay with autism spectrum disorder and gait instability; inverted duplicated chromosome 15 syndrome; macrocephaly-intellectual disability-autism syndrome; severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement- bilateral cataract; Smith-Magenis syndrome; tuberous sclerosis complex; Xq12-q13.3 duplication syndrome.

[0112] The behavioural conditions associated with such conditions may be one of the following: hyperactivity; attention deficit and hyperactivity disorder; stereotypic movement disorder; conduct disorder; generalised anxiety disorder; neurotic disorder; obsessive-compulsive disorder; agoraphobia; social anxiety; social phobia; separation anxiety disorder and 15q11 q13 microduplication syndrome. Other behavioural disorders may be impeded social interaction (such as poor eye contact or solitude preference), communication or language problems (such as speech delay orpretence of deafness), repetitive and / or obsessive behaviour (such as stereotyped behaviour or extreme restlessness), signs of memory loss and signs of disruptive behaviour.

[0113] Although not wishing to be bound by any theory, inventors believe that the related conditions could be treated by agents with the same mechanism of action.Example Formulations and Treatments

[0114] A number of example formulations are provided below along with suggested dosage regimes. It will be understood that these are for illustrative purposes and these would be optimised during further experimentation, which may include clinical trials. For simplicity, the formulations do not stipulate any non-active components (such as pharmaceutically acceptable carriers or excipients etc.).Formulation 2A - Etravirine - Oral Tablet for the Treatment FMR1 Mediated AutismFormulation 2B - Etravirine - Oral Tablet for the Treatment Fragile X Syndrome (FXS)Formulation 2C - Etravirine - Oral Tablets for the Treatment of Autism

[0115] The skilled addressee will of course understand that therapeutically effective doses will of course depend on the activity and format of the chosen pharmaceutically active ingredient.

[0116] The foregoing embodiments are not intended to limit the scope of the protection afforded by the claims, but rather to describe examples of how the invention may be put into practice.ReferencesAlfedi, G., Luffarelli, R., Condo, I., Pedini, G., Mannucci, L., Massaro, D. S., Benini, M., Toschi, N., Alaimo, G., Panarello, L., Pacini, L., Fortuni, S., Serio, D., Malisan, F., Testi, R., & Rufini, A. (2019). Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich’s ataxia. Movement Disorders, 34(3), 323-334. https: / / doi.Org / 10.1002 / mds.27604Allavena, C., Katlama, C., Cotte, L., Roger, P. M., Delobel, P., Cheret, A., Duvivier, C., Poizot-Martin, I., Hoen, B., Cabie, A., Cheret, A., Lahoulou, R., Raffi, F., & Pugliese, P. (2016). Long-term efficacy and safety of etravirine-containing regimens in a real-life cohort of treatment-experienced H IV- 1 -infected patients. 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Claims

Claims1. A composition for use in the treatment, management or amelioration of FMR1 mediated autism, wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof.

2. The composition as claimed in claim 1 , wherein the one or more non- nucleoside reverse transcriptase inhibitors or derivatives thereof is Etravirine.

3. The composition as claimed in any one of claims 1 or 2, wherein the FMR1 mediated autism is related to Fragile X Syndrome (FXS).

4. A composition for use in the treatment, management or amelioration of Fragile X Syndrome (FXS), wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof.

5. The composition as claimed in claim 4, wherein the one or more non- nucleoside reverse transcriptase inhibitors or derivatives thereof is Etravirine.

6. A composition for use in the treatment, management or amelioration of an autism disease or disease where autism is a known component, wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof.

7. The composition as claimed in claim 6, wherein the autism disease or disease where autism is a known component is at least one of the following: 1 p21.3 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 with autism spectrum disorder and gait instability; inverted duplicated chromosome 15 syndrome; macrocephaly-intellectual disability-autism syndrome; severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement- bilateral cataract; Smith-Magenis syndrome; tuberous sclerosis complex; and / or Xq12-q13.3 duplication syndrome.

8. The composition as claimed in claim 6, wherein the autism disease or disease where autism is a known component is at least one of the following: Asperger syndrome, atypical autism and / or autistic disorder.

9. A composition for use in the treatment, management or amelioration of a behavioural disorder, wherein the composition comprises one or more nonnucleoside reverse transcriptase inhibitors or derivatives thereof.

10. The composition as claimed in claim 9, wherein the behavioural disorder is at least one of the following: hyperactivity, social anxiety, memory loss and / or disruptive behaviour.11 . The composition as claimed in claim 9, wherein the behavioural disorder is at least one of the following: attention deficit and hyperactivity disorder: stereotypic movement disorder; conduct disorder; generalised anxiety disorder; neurotic disorder; obsessive-compulsive disorder; agoraphobia; social phobia; separation anxiety disorder and / or 15q11 q13 microduplication syndrome.

12. The composition as claimed in any of claims 6-11 , wherein the one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof is Etravirine.

13. The composition as claimed in any preceding claim, administered in a daily dose in the range of about 100 mg to about 800 mg.

14. The composition as claimed in any preceding claim, wherein the composition comprising one or more non-nucleoside reverse transcriptase inhibitors is administered to a patient in need thereof in a dose of 100-800 mg15. The composition as claimed in any preceding claim, wherein the one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof are selected from: Etravirine (ETR); Rilpivirine (RPV) Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV) and mixtures thereof.

16. The composition as claimed in any one of claims 1 to 8, wherein the one or more non-nucleoside reverse transcriptase inhibitors, derivatives or mimetics thereof are for administration separately, together or sequentially with another pharmaceutically active ingredient.

17. A composition comprising one or more non-nucleoside reverse transcriptase inhibitors, derivatives or mimetics thereof for use in the treatment, management or amelioration of autism in an individual whose FMR1 gene sequence includes a mutation.

18. The composition for use as claimed in claim 10, wherein the mutation comprises at least one of the following: a. expansion and subsequent methylation of (CGG)n trinucleotide repeats in the 5'- untranslated region of the FMR1 gene; b. intragenic point mutations or deletions in the FMR1 ; c. a I304N mutation; d. a G266E mutation; or e. a S27X mutation.

19. The composition for use as claimed in either claim 10 or 11 , wherein the non- nucleoside reverse transcriptase inhibitor is Etravirine.

20. The composition as claimed in claims 10 to 12, wherein the FMR1 mediated autism is related to Fragile X Syndrome (FXS).21 . The composition as claimed in any of claims 10 to 13, administered in a daily dose in the range of about 100 mg to about 800 mg.

22. The composition for use as claimed in any of claims 10 to 14, wherein the one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof is selected from: Etravirine (ETR); Rilpivirine (RPV) Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV) and mixtures thereof.

23. The composition for use as claimed in any one of claims 10 to 15, wherein the one or more non-nucleoside reverse transcriptase inhibitors, derivatives or mimetics thereof are for administration separately, together or sequentially with another pharmaceutically active ingredient.

24. A pharmaceutical composition, comprising a composition according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, excipient, or diluent.

25. A combination of an SSRI and a composition comprising one or more non- nucleoside reverse transcriptase inhibitors, derivatives or mimetics thereof for use in the treatment, management or amelioration of FMR1 mediated autism.