Compositions comprising a nnrti and uses thereof for treating TCF4 mediated autism or pitt-hopkins syndrome

Abstract

The present invention relates to compositions for use in the treatment, management or amelioration of TCF4 mediated autism and Pitt Hopkins Syndrome (PTHS), wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors or derivatives thereof. The invention also relates to one or more non- nucleoside reverse transcriptase inhibitors or derivatives thereof for use as medicaments for treating a range of autistic diseases and diseases having an autistic component.

Description

COMPOSITIONS COMPRISING A NNRTI AND USES THEREOF FOR TREATING TCF4 MEDIATED AUTISM OR PITT-HOPKINS SYNDROMECross-Reference to Related Applications

[0001] The present application claims priority from U.S. Provisional Application No. 63 / 596,571 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 Pitt Hopkins Syndrome (PTHS).Background to the Invention

[0003] Pitt Hopkins Syndrome (PTHS, MIM# 610954) is a rare neurodevelopmental disorder caused by genetic changes in the transcription factor 4 (TCF4) gene or the 18q21 .2 chromosome region in which it is located (Amiel et al., 2007; Brockschmidt et al., 2007; Zweier et al., 2007). It was first identified as a separate syndrome by Pitt and Hopkins in 1978, who presented the case studies of two children with intellectual disability and similar facial characteristics (i.e. unusually wide mouth and palate, thick lips, beaked nose with a broad bridge and flared nostrils). Other clinical features included cluster breathing (episodes of hyperventilation followed by apnoea), clubbed fingers / toes, and abnormal electroencephalograms (EEG) (Pitt & Hopkins, 1978).

[0004] TCF4 encodes a basic helix-loop-helix (bHLH) E-protein, which is involved in early brain and neuronal developmental processes (De Pontual et al., 2009; Forrest et al., 2014; Li et al., 2019; Mesman et al., 2020; Wang et al., 2020), while it may be also involved in mature neuron synaptic plasticity (Crux et al., 2018). Multiple TCF4 isoforms have been reported, resulting from the combination of different 5’ exons with alternative splicing products (Sepp et al., 2011 ). Various types of mutations affecting TCF4 (missense, nonsense, frame-shifting, splice mutations) or the 18q21 locus (deletions and translocations) have been described in the literature, with a hot spot identified within the basic portion of the bHLH domain (De Pontual et al., 2009; Whalenet al., 2012). Point mutations in TCF4 have been found in 40% of the patients, small deletions or insertions were scored in 30% and the remaining 30% was characterised by larger chromosomal abnormalities (Whalen et al., 2012). The vast majority of PTHS cases appear as sporadic autosomal dominant conditions, arising from de novo mutations, although some exceptions of familial heredity have been reported (De Pontual et al., 2009; Kousoulidou et al., 2013; Steinbusch et al., 2013).

[0005] The prevalence of the syndrome varies as it is estimated according to Orphanet in 1-9 / 1 ,000,000, based on the number of known affected individuals in the United Kingdom and the Netherlands, and between 1 :34,000 and 1 :41 ,000, based on 18q21 deletions identified in an array-comparative genomic hybridization (aCGH) screening of 13,186 intellectually disabled individuals (Rosenfeld et al., 2009). However, no reliable prevalence numbers have been made available so far (De Winter et al., 2016). Despite this, there are believed to be only or less than 500 confirmed cases worldwide and according to the HGMD database, currently, only 123 variants are known to be associated with PTHS (Sparber et al., 2020).

[0006] Individuals with PTHS are characterised by distinctive facial features including deep-set eyes, wide mouth with widely spaced teeth and a high nasal root with wide prominent nasal bridge, wide nostrils and down-turned nasal tip. Other associated symptoms include severe intellectual disability, developmental delay, recurrent seizures, constipation [potential role of TCF4 in the development of the enteric nervous system (De Pontual et al., 2009)], balance problems (ataxia) and sleep disturbances (less common). Psychomotor delay and breathing pattern abnormalities are common criteria for PTHS diagnosis as they have been reported in many cases. EEG abnormalities, magnetic resonance imaging (MRI) findings, such as hypoplasia of the corpus callosum (Brockschmidt et al., 2011 ; Edwards et al., 2014; Hasi et al., 2011), and immunological testing provide additional evidence to sustain the diagnosis (De Pontual et al., 2009). Although episodes of hyperventilation are a daily symptom, hypoxia can be severe and frequent enough to generate clubbing of fingers. Due to delay of mental and motor developmental skills, affected individuals have difficulty in learning to walk and speak and can only learn to say a few words. Severe nearsightedness (myopia) and behavioural abnormalities are some other commonfeatures, although children often display happy disposition (Amiel et al., 2007; Dean, 2012).

[0007] Onset of symptoms occurs at neonatal age. Specifically, the distinctive facial gestalt and the abnormal psychomotor development have been reported to a majority of PTHS patients from the neonatal period (Amiel et al., 2007). It has been also found that seizures and hyperventilation episodes occur only in the first decade. Seizures are more likely to be detected in patients with missense TCF4 mutations (Rosenfeld et al., 2009). Clinical diagnosis can be asserted based on a combination of common PTHS signs and symptoms. According to the first international consensus statement for PTHS, facial gestalt, severe intellectual disability with absent or limited speech and breathing anomalies are recommended as cardinal diagnostic criteria, while myopia, constipation, slender fingers or abnormal hand creases and unstable gait have been proposed as supportive criteria (Zollino et al., 2019).

[0008] Some patients meet autism spectrum disorder features as well, while TCF4 mutations have been independently associated with ASD, schizophrenia and moderate to severe non-syndromic intellectual disability (Blake et al., 2010; Hasi et al., 2011 ; Mary et al., 2018; Navarrete et al., 2013; Popp et al., 2022; Quednow et al., 2014; Sirp et al., 2021 ; Stefansson et al., 2009; Stessman et al., 2017). An exploratory investigation assessing the social, communication and behavioural deficits of a small cohort of patients carrying TCF4 mutations concluded that the PTHS phenotype may formally include ASD with varying degrees of severity (Van Balkom et al., 2012).

[0009] PTHS is thought to be underdiagnosed and, since the identification of TCF4 mutations, there has been substantial effort to molecularly map individuals with PTHS clinical features. Given that PTHS presents overlapping symptoms with Rett, Angelman and Mowat-Wilson syndromes (Marangi & Zollino, 2015), genetic testing has revealed multiple cases of PTHS misdiagnosis (Takano et al., 2010). On the other hand, only -12% of patients referred as suspected PTHS cases have been confirmed for carrying TCF4 mutations, which led to the identification of key downstream targets that may be implicated in the development of the core symptoms (i.e. mental retardation, breathing anomalies, epileptic seizures, autistic behaviour).

[0010] Recessive point mutations and copy-number variations (CNVs) affecting CNTNAP2 and NRXN1 have been reported in patients with PTHS-like clinical presentation hinting to a hypothesis of common molecular pathogenesis (Zweieret al., 2009), which has been further supported by in vitro luciferase reporter assays demonstrating NRXNi p and CNTNAP2 promoter transactivation by TCF4 (Forrest et al., 2012). In contrast to patients carrying TCF4 mutations, individuals with CNTNAP2 and NRXN1 defects presented normal or moderately impaired motor skills. Heterozygous SNPs or CNVs in both CNTNAP2 and NRXN1 had been previously associated with autism spectrum disorder (ASD), epilepsy and schizophrenia, while CNTNAP2 mutations were reported in cases of Gilles de la Tourette syndrome, obsessive-compulsive disorder (OCD) and a series of patients with cortical dysplasia focal-epilepsy syndrome with early onset within the Amish population (Zweier et al., 2009).

[0011] Although many cases are attributed directly to TCF4 haploinsufficiency, dominant negative effects may also contribute to the phenotype by altering its subnuclear localization and its association with its partners (Amiel et al., 2007; De Pontual et al., 2009; Forrest et al., 2012; Giurgea et al., 2008; Sepp et al., 2012). Mutations in the TCF4 bHLH domain have been shown to affect the interactions with other members of the E-protein family. Heterodimerization of TCF4 with ASCL1 , an HLH protein belonging to the PHOX-RET pathway, is thought to be of particular importance and its disruption might be implicated in the appearance of Hirschsprung disease, severe constipation and breathing abnormalities in PTHS patients (Amiel et al., 2007; de Pontual, 2003; De Pontual et al., 2009).

[0012] 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 (Gilbert & Man, 2017; Pinto et al., 2010). These ASD genes include FMR1 , LIS1 , MECP2, PTEN, SHANK1 / 2 / 3, TAOK2, TSC1 / 2, Neuroligins, Neurexins, KIAA2022 / KIDLIA (Gilbert & Man, 2016) and UBE3A / E6- associated protein (E6AP).

[0013] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0014] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0015] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping andflapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0016] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0017] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and#164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Curro et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0018] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Curro et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0019] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443),or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ;Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0020] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0021] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0022] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0023] PTHS patients display a variety of overlapping clinical features with other ASDs ranging from severe cognitive disabilities, echolalia, autistic behaviours such as anxiety, agitation, aggression, deficits in social interaction skills, self-absorption, particular interests, repetitive behaviours rituals and stereotypies (hand clapping and flapping, head banging, body rocking or finger mannerisms), self-injurious actions, epilepsy and abnormal physical characteristics (Sweetser et al., 2012; Zollino et al., 2019). Similar phenotypes occur (but not limited to) in similar encephalopathies and ASDs: Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004) (Currb et al., 2021 ; Sweetser et al., 2012; Watkins et al., 2019; Zollino et al., 2019).

[0024] TCF4, CNTNAP2 and NRXN1 are well conserved and their orthologs (daughterless, Nrx-IV and Nrx-I respectively) are present in Drosophila. Both Nrx-IV and Nrx-I are recognized as synaptic proteins in Drosophila that regulate the levels of bruchpilot protein, indicating a common underlying synaptic pathogenetic mechanismleading to similar phenotypic traits in individuals with CNTNAP2 and NRXN1 defects (Zweier et al., 2009). A TCF4 ortholog has been also identified in zebrafish (Danio rerio). The zebrafish tcf4 expression pattern is well conserved in the brain of developing embryos (Brockschmidt et al., 2007), while knockdown morphants exhibited differentiation delays during later stages of neural development (Brockschmidt et al., 2011 ).

[0025] Mice carrying homozygous mutations of Tcf4 result in embryonic to postnatal day 1 (P1 ) lethality. T cf4(+ / ) mouse has a deletion of the exons that code for the bHLH domain (Grubisic et al., 2015; Zhuang et al., 1996). Approximately seven out of ten PTHS cases are caused by SNPs that generate a premature stop codon or a point mutation in the bHLH domain of Tcf4 protein (Sepp et al., 2012), disrupting either transcription factor dimerization or mutating one of the basic residues required for DNA backbone engagement. Loss of function mutations within the exons 1 -4 or 4- 6 of TCF4 have been associated with a recurrent form of mild intellectual disability, without the typical presentation of PTHS clinical features (Bedeschi et al., 2017). The concentration of PTHS SNPs in the bHLH motif highlights a more specific molecular feature of PTHS, namely, the loss of Tcf4 protein and DNA association, and further distinguishes them from other SNPs elsewhere in the Tcf4 locus that are strongly associated with schizophrenia. The Tcf4(+ / -) mouse should therefore be considered a functional model of PTHS rather than schizophrenia per se, because the coding region for the bHLH domain has been deleted.

[0026] In vitro TCF4 knockdown in neuroblastoma cell lines revealed a large set of putative TCF4 transcriptional targets, including several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C, suggesting that these genes might be linked through convergent signalling pathways (M. P. Forrest et al., 2013).

[0027] There is no standardised treatment available. Caregivers are advised to seek occupational, physical and speech therapy interventions early after diagnosis, while patients may be offered treatments for the alleviation of specific symptoms. Low doses of aripiprazole and risperidone have been tested for the treatment of behavioural problems (Lambrechts et al., 2018). Valproate acid and acetazolamidehave been tested for the treatment of apneic episodes (Gaffney & McNally, 2015; Maini et al., 2012; Verhulst et al., 2012). Seizures can be successfully controlled in most patients with anti-epileptic drugs, mainly valproate, levetiracetam and lamotrigine, alone or in combinations (De Winter et al., 2016). Gastroesophageal reflux and constipation are treated as in the general population (Zollino et al., 2019).

[0028] Although TCF4 expression is critical during early brain development, loss of TCF4 function may also have a continued impact on the neuronal function and hippocampal neurogenesis of PTHS patients (Braun et al., 2020; Crux et al., 2018), suggesting they might benefit from pharmacological restoration of TCF4 levels. Indeed, postnatal genetic restoration of TCF4 levels, mediated by viral gene therapy approaches, partially corrected EEG abnormalities and resulted in behavioural and cognitive improvements in a conditional Tcf4 mouse model of PTHS (Kim et al., 2022).

[0029] 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 PTHS. A further object of the present invention is to provide treatments for autism mediated by a TCF4 gene mutation. A preferred object of the present invention is to provide treatments for PTHS. It would be beneficial if treatments are based on preexisting pharmaceutically active ingredients.Summary of Invention

[0030] In accordance with the present invention, there is provided a composition for use in the treatment, management or amelioration of TCF4 mediated autism, wherein the composition comprises one or more non-nucleoside reverse transcriptase inhibitors (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 TCF4 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.

[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 TCF4 mediated autism in an individual.

[0033] The TCF4 mediated autism may be due to the TCF4 gene sequence comprising missense, truncating, point mutations affecting splice sites, small frameshifting insertions or deletions, as well as large deletions involving all or part of the gene. Alternatively, the autism may be due to homozygous or compound heterozygous loss-of-function mutations in the CNTNAP2 (Pitt-Hopkins-Like Syndrome 1 , M IM #610042) or NRXNI (Pitt-Hopkins-Like Syndrome 2, MIM #614325) gene sequence.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] The TCF4 mediated autism may be related to Pitt Hopkins Syndrome (PTHS).

[0038] In accordance with a second aspect of the present invention, there is provided a composition for use in the treatment, management or amelioration of PittHopkins Syndrome (PTHS), wherein the composition comprises one or more NNRTIs or derivatives thereof.

[0039] In accordance with a related aspect of the present invention, there is provided a method of treatment, management or amelioration of Pitt Hopkins Syndrome (PTHS) 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.

[0040] 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 Pitt Hopkins Syndrome (PTHS) in an individual.

[0041] 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.

[0042] 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 800 mg.

[0043] 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.

[0044] Suitably these daily doses are of the NNRTIs in the composition. Suitably these daily doses are of Etravirine.

[0045] The NNRTI may comprise Etravirine. The composition comprising one or more NNRTIs may consist essentially or consist of Etravirine. The present inventionmay therefore provide Etravirine for use in the treatment, management or amelioration of TCF4 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).

[0046] 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.

[0047] 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 GSK3A, GSK3B, LIMK1 , CDK5, TAAR1 , FYN, NTRK3, DYRK1A, CAMK2G, CAMKK2. Etravirine has a terminal elimination half-life of 41 hours (Havens et al., 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 (Janssen Pharmaceutical Companies, 2018).

[0048] 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.

[0049] 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.

[0050] Details of the non-nucleoside reverse transcriptase inhibitors derivatives and mimetics are as follows:

[0051] Rilpivirine (CAS ID 700361-47-3, DrugBank DB08864): Rilpivirine is a non- nucleoside reverse transcriptase inhibitor used in combination with other antiretroviral drugs in the treatment of HIV-1 infection in treatment-naive patients. It is a diarylpyrimidine derivative with high internal conformational flexibility and tolerance to resistance mutations.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] The composition may be for use in the treatment, management or amelioration of a behavioural or cognitive disorder.

[0057] The behavioural disorder may be one of the following: hyperactivity, social anxiety, memory loss and / or disruptive behaviour.

[0058] 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.

[0059] 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.

[0060] 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;

[0061] 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 disorder features, and minor dysmorphic facial features such as long ears, deep set eyes, abroad 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.

[0062] 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.

[0063] 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.

[0064] Autism spectrum disorder due to AUTS2 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.

[0065] 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 ).

[0066] 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.

[0067] 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 affected individuals, with onset typically between 6 months and 9 years, and may includeinfantile 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

[0068] 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.

[0069] 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.

[0070] 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 deepvoice, 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.

[0071] 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 / hy peracti vity 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 and early childhood. Additional features include dental enamel pitting, intraoral fibromas and skeletal dysplasias.

[0072] 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 comers of the mouth). Seizures have also been reported in some patients.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] The autism spectrum disorder may have overlapping phenotypes, such as Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat- Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004).

[0078] 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.

[0079] 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.

[0080] 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.

[0081] Conduct disorder is a specific developmental disorder marked by a pattern of repetitive behaviour wherein the rights of others or social norms are violated.

[0082] Generalised anxiety disorder is an anxiety disorder that is characterised by long-lasting anxiety that is not focused on any one object or situation.

[0083] Neurotic disorder is an anxiety disorder that involves distress but neither delusions nor hallucinations.

[0084] 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).

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] In some embodiments, the composition for use in the treatment, management or amelioration of TCF4 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 TCF4 mediated autism.

[0090] Therefore the present invention may provide a combination of an SSRI and a composition comprising one or more NNRTIs, derivatives or mimetics thereof for use in the treatment, management or amelioration of TCF4 mediated autism. In such embodiments, the SSRI may be administered in the typical daily dose for that SSRI and the composition comprising one or more NNRTIs may be administered in the daily doses discussed above. Suitably in such embodiments the composition comprising one or more NNRTIs is Etravirine.

[0091] 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 thefeatures 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

[0092] Embodiments of the invention are described below, by way of example only with reference to and as illustrated in the following figures:

[0093] Figure 1 is a bar graph showing the distance travelled in the open field for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (50 mg / kg);

[0094] Figure 2 is a bar graph showing the distance travelled in the open field for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (80 mg / kg), Etravirine (50 mg / kg) / Clorazepic Acid (30 mg / kg) combination and Clorazepic Acid (50 mg / kg);

[0095] Figure 3 is a bar graph showing tests of daily living for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (50 mg / kg);

[0096] Figure 4 is a bar graph showing tests of daily living for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (80 mg / kg), Etravirine (50 mg / kg) / Clorazepic Acid (30 mg / kg) combination and Clorazepic Acid (50 mg / kg);

[0097] Figure 5 is a bar graph showing novel object recognition (NOR) for vehicle- treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (50 mg / kg);

[0098] Figure 6 is a bar graph showing novel object recognition (NOR) for vehicle- treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (80 mg / kg),Etravirine (50 mg / kg) / Clorazepic Acid (30 mg / kg) combination and Clorazepic Acid (50 mg / kg);

[0099] Figure 7 is a bar graph showing sociability tests for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (50 mg / kg);

[0100] Figure 8 is a bar graph showing sociability tests for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (80 mg / kg), Etravirine (50 mg / kg) / Clorazepic Acid (30 mg / kg) combination and Clorazepic Acid (50 mg / kg);

[0101] Figure 9 is a bar graph showing the stereotypy for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (50 mg / kg);

[0102] Figure 10 is a bar graph showing the stereotypy for vehicle-treated WT and Tcf4(+ / ) mice and Tcf4(+ / ) treated with Etravirine (80 mg / kg), Etravirine (50 mg / kg) / Clorazepic Acid (30 mg / kg) combination and Clorazepic Acid (50 mg / kg).

[0103] The Kruskal- Wallis ranks test was applied, for testing the null hypothesis that samples originate from the same distribution. Pairwise comparisons (control vs drug or combination of drugs) were conducted and statistically significant results were reported by Benjamini-Hochberg adjusted p-values at a 0.05 level of significance. The figures shown are presenting the ranks of the data placed in ascending order across samples.

[0104] 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 (Janssen Pharmaceutical Companies, 2018). Its safety and efficacy were primarily established in two large Phase 3 randomised, double-blind, placebo-controlled trials (Girard et al., 2012; Katlama et al., 2010; Lazzarin et al., 2007; Madruga et al., 2007). 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 et al., 2012; Kakuda et al., 2016). Stevens-Johnson syndrome and other severe life-threatening reactions occurred in <0.1 % of all ETR recipients (Janssen Pharmaceutical Companies, 2018).

[0105] Etravirine is considered safe and well tolerated for lifelong administration (Allavena et al. , 2016). Studies on healthy subjects showed no serious adverse events nor any graded laboratory toxicities (Gupta et al., 2011 ). Although there are no previous reports for use in PTHS 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 et al., 2019; Rufini et al., 2022). Etravirine is metabolised by the hepatic CYP450 isozymes, with inhibitory effects on CYP2C9 and CYP2C19 and inductive effects on CYP3A4 (Schdller-Gyure et al., 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 PTHS phenotype through GSK3 inhibition and subsequent WNT pathway activation, which may in turn lead to the transcriptional upregulation of a subset of TCF4 isoforms (Hennig et al., 2017; Papes et al., 2022).Animal testing

[0106] Heterozygous male B6;129-Tcf4tm1Zhu / J mice were acquired from The Jackson Laboratory (stock #013598) and bred with female hybrid B6129SF1 / J wild type (WT) mice (stock #101043) to produce Tcf4(+ / -) and WT littermates. TransnetYX Automated Genotyping (www.transnetyx.com / ). TRANSNETYX, INC., 8110 Cordova Rd. Suite 119, Cordova, TN 38016, USA was used for genotyping.

[0107] Mice were housed in groups of the same genotype 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. Food and water were available ad libitum. All experimental procedures were performed according to the requirements of the UK Animals(Scientific Procedures) Act, 1986. Mice were kindly provided by the Pitt Hopkins research foundation.

[0108] The animals were pretreated for 14 days. The active ingredients of Etravirine and Clorazepic Acid were in a water carrier. Ten mice per treatment group were used and testing was conducted during the light phase. 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

[0109] Behaviour testing was conducted after 2 weeks of treatment. The behavioural tests were as follows: 1. Hyperactivity, climbing, locomotion, rearing: Open field; 2. Test of daily living: nesting; 3. Cognition (Memory and Learning): Novel Object Recognition (NOR); 4. Sociability: (Three chamber) partition test; and 5. Stereotypy: Self-grooming.

[0110] For hyperactivity, climbing, locomotion and rearing 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. Tcf4(+ / -) mice show no anxiety (time in the centre) and a significant increase in activity in the OFT when compared to WT littermates. 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 et al., 2009).

[0111] For tests of daily living, nesting was assessed as nest building is an innate behaviour 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 mutationsunderlying pathological disease states (Gaskill et al., 2013). Notably, PTHS has been associated with hippocampal dysfunction, which, in turn, reportedly negatively affects nesting behaviour in rodents (Deacon, 2006).

[0112] For memory and learning (cognition), a novel object recognition (NOR) task was used to evaluate the rodents’ ability to recognize a novel object in the environment. Impaired Tcf4 function reportedly results in deficient learning and memory (Kennedy et al., 2016). 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 task procedure consists of three phases: habituation, familiarisation, and test phase (Antunes & Biala, 2012).

[0113] 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 et al., 2011 ). Typically, Tcf4(+ / -) mice cannot distinguish between the familiar and the novel mouse (Ekins et al., 2020).

[0114] 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 et al., 2016). ASD mice models generally display repetitive behaviours, including increased grooming (Crawley, 2012), and Tcf4(+ / -) mice groom themselves significantly more than WT mice.

[0115] 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:

[0116] 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)

[0117] Problems in communication and / or language: Speech delay, patient pretends to be deaf. Hearing assessment using Brainstem Evoked Response Audiometry (BERA).

[0118] Repetitive behaviour and / or apparent obsessions: stereotyped behaviour, extreme restlessness and / or hyperactivity. Connor’s scale is used to evaluate hyperactivity: >12

[0119] 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.

[0120] 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).

[0121] 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.

[0122] 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

[0123] The treatment of the mice with ETR (Etravirine) were according to the matrix shown below in Table 1 .Table 1

[0124] The behavioural experiments demonstrate that Etravirine ameliorates the PTHS phenotypes in Tcf4 (+ / -) mice and could therefore be employed as a useful and efficacious treatment for autism (including Tcf4 mediated autism), behavioural conditions and PTHS.

[0125] Conditions related to PTHS may have overlapping phenotypes, such as Pitt- Hopkins-Like Syndrome 1 (MIM #610042), Pitt-Hopkins-Like Syndrome 2 (MIM #614325), Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253), Chromosome 5q14.3 deletion syndrome (MIM #613443), or Developmental and Epileptic Encephalopathy 64 (MIM #618004). 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

[0126] 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 of TCF4 Mediated AutismFormulation 2B - Etravirine - Oral Tablet for the Treatment of Pitt HopkinsFormulation 2C - Etravirine - Oral Tablets for the Treatment of Autism Active Ingredient Form Mg Dose

[0127] 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.

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Claims

Claims1. A composition for use in the treatment, management or amelioration of TCF4 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 TCF4 mediated autism is related to Pitt Hopkins Syndrome (PTHS).

4. A composition for use in the treatment, management or amelioration of Pitt Hopkins Syndrome (PTHS), 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. The composition as claimed in any preceding claim, administered in a daily dose in the range of about 100 mg to about 800 mg.

7. 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 mg.

8. The composition as claimed in any preceding claim, wherein the one or more or non-nucleoside reverse transcriptase inhibitors derivatives thereof is selected from: Etravirine (ETR); Rilpivirine (RPV), Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV) and mixtures thereof.

9. 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.

10. A composition comprising one or more non-nucleoside reverse transcriptase inhibitors, derivatives or mimetics thereof for use in the treatment, management oramelioration of autism in an individual whose TCF4 gene sequence includes a mutation.11 . The composition for use as claimed in claim 10, wherein the mutation comprises missense, truncating, point mutations affecting splice sites, small frameshifting insertions or deletions, as well as large deletions involving all or part of the TCF4 gene.

12. The composition for use as claimed in either claim 10 or 11 , wherein the nonnucleoside reverse transcriptase inhibitor is Etravirine.

13. The composition as claimed in claims 10 to 12, wherein the TCF4 mediated autism is related to Pitt Hopkins Syndrome (PTHS).

14. The composition for use 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.

15. 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.

16. 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.

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 with Pitt-Hopkins-Like Syndrome 1 (MIM #610042), Pitt-Hopkins-Like Syndrome 2 (MIM #614325), Angelman syndrome (MIM #105830), Rett Syndrome (MIM #312750 and #164874), Mowat-Wilson Syndrome (MIM #235730), Alpha-Thalassemia / Mental Retardation Syndrome (MIM #301040), Joubert Syndrome, Cornelia de Lange Syndrome, Developmental and Epileptic Encephalopathy 2 (MIM #300672), Kleefstra Syndrome (MIM #610253),Chromosome 5q14.3 deletion syndrome (MIM #613443), and / or Developmental and Epileptic Encephalopathy 64 (MIM #618004).

18. The composition for use as claimed in claim 17, wherein the non-nucleoside reverse transcriptase inhibitor is Etravirine.

19. The composition for use as claimed in any of claims 17 or 18, administered in a daily dose in the range of about 100 mg to about 800 mg.

20. The composition for use as claimed in any of claims 17 to 19, wherein the one or more non-nucleoside reverse transcriptase inhibitors or derivatives is selected from: Etravirine (ETR); Rilpivirine (RPV), Doravirine (DOR), Delavirdine (DLV), Nevirapine (NVP), and Efavirenz (EFV) and mixtures thereof.21 . The composition for use as claimed in any one of claims 17 to 20, 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.

22. A pharmaceutical composition, comprising a composition according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier, excipient, or diluent.

23. 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 TCF4 mediated autism.

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