DeCure for Autism spectrum disorder due to AUTS2 deficiency
DeCure's autonomous Psychiatry AI scientist is researching a drug-repurposing hypothesis for autism spectrum disorder due to AUTS2 deficiency — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutism spectrum disorder due to AUTS2 deficiency maps to a 4-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedMelatoninMelatonin receptor agonist
Structures already discussed alongside autism spectrum disorder due to auts2 deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of fad quinone reductase 2 — Melatonin has a real, experimentally solved structure in complex with this target (PDB 4QOG, 1.4 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet ml1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4QOG · 1.4 Å · ligand Melatonin (ML1). Experimental structure, not a prediction.
What the evidence adds up to
AUTS2 deficiency is a genetic cause of autism spectrum disorder and intellectual disability, but no drug has been tested in any clinical trial for this specific population. The available literature consists entirely of basic science and reviews. AUTS2 protein regulates transcription, actin dynamics during neuronal migration, and excitatory synapse number. In Auts2 mutant mice, excitatory synapses were specifically increased in cultured neurons and in forebrains, and electrophysiological recordings showed increased excitatory synaptic inputs and c-fos expression, suggesting an altered excitation-inhibition balance that enhances brain excitability. Those mutant mice exhibited autistic-like behaviours including impaired social interaction and altered vocal communication. The same reviews note that AUTS2 is expressed in developing mouse and human frontal cortex, dorsal thalamus, and hippocampus, regions implicated in impaired cognition and social function.
In humans, AUTS2 syndrome is defined by haploinsufficiency of the gene. A 2023 case series of three patients used the AUTS2 Syndrome Severity Scoring System, which scores 32 characteristics including growth, feeding, neurodevelopment and congenital anomalies. The three patients scored 12, 13 and 13 respectively. One had an interstitial duplication of chromosome 7; the other two had pathogenic variants in exon 9 and exon 16. All three had auditory hypersensitivity, ADHD features, and autistic features. Two had feeding problems, two had hypotonia, and one had microcephaly. The authors note that 65 patients with pathogenic AUTS2 variants are described in the literature, and that significantly higher severity scores are found in patients with variants affecting the 3' end of the gene.
For autism spectrum disorder more broadly, a 2010 review states that pharmacologic agents can reduce interfering symptoms but that a great deal of work remains, and that large-scale investigation of commonly used agents is needed. A 2018 review on sleep disturbances in ASD with psychiatric comorbidities states that behavioural interventions are the primary modality, that evidence for psychopharmacological treatments is limited, and that melatonin has a relatively large body of evidence compared to antipsychotics, antidepressants and alpha agonists. Neither review mentions AUTS2.
What is missing: no drug has been tested in AUTS2-deficient humans or animal models with the aim of reversing the molecular or behavioural phenotype. There is no clinical trial, no repurposing screen, and no published attempt to identify a compound that normalises AUTS2-related synaptic or transcriptional changes. The field lacks a patient-derived cell or animal model drug screen, any funding for such a screen, and any trial design that stratifies by AUTS2 genotype. Without these, no drug can be recommended for AUTS2 deficiency.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cells · 2021 · 79 citations · open access
AUTS2 Gene: Keys to Understanding the Pathogenesis of Neurodevelopmental Disorders
AbstractNeurodevelopmental disorders (NDDs), including autism spectrum disorders (ASD) and intellectual disability (ID), are a large group of neuropsychiatric illnesses that occur during early brain development, resulting in a broad spectrum of syndromes affecting cognition, sociability, and sensory and motor functions. Despite progress in the discovery of various genetic risk factors thanks to the development of novel genomics technologies, the precise pathological mechanisms underlying the onset of NDDs remain elusive owing to the profound genetic and phenotypic heterogeneity of these conditions. Autism susceptibility candidate 2 (AUTS2) has emerged as a crucial gene associated with a wide range of neuropsychological disorders, such as ASD, ID, schizophrenia, and epilepsy. AUTS2 has been shown to be involved in multiple neurodevelopmental processes; in cell nuclei, it acts as a key transcriptional regulator in neurodevelopment, whereas in the cytoplasm, it participates in cerebral corticogenesis, including neuronal migration and neuritogenesis, through the control of cytoskeletal rearrangements. Postnatally, AUTS2 regulates the number of excitatory synapses to maintain the balance between excitation and inhibition in neural circuits. In this review, we summarize the knowledge regarding AUTS2, including its molecular and cellular functions in neurodevelopment, its genetics, and its role in behaviors.
Expert Opinion on Emerging Drugs · 2010 · 35 citations
Emerging drugs for the treatment of symptoms associated with autism spectrum disorders
AbstractIMPORTANCE OF THE FIELD: Autism spectrum disorders, or pervasive developmental disorders (PDDs), are neurodevelopmental disorders defined by qualitative impairment in social interaction, impaired communication and stereotyped patterns of behavior. The most common forms of PDD are autistic disorder (autism), Asperger's disorder and PDD not otherwise specified. Recent surveillance studies reveal an increase in the prevalence of autism and related PDDs. The use of pharmacologic agents in the treatment of these disorders can reduce the impact of interfering symptoms, providing relief for affected individuals and their families. AREAS COVERED IN THIS REVIEW: This review examines results from neurobiologic research in an attempt to both elucidate the pathophysiology of autism and guide the development of pharmacologic agents for the treatment of associated symptoms. The safety and efficacy data of drugs currently in clinical use for the treatment of these symptoms, as well as pharmaceuticals currently under development, are discussed. WHAT THE READER WILL GAIN: This comprehensive review will deepen the reader's current understanding of the research guiding the pharmacologic treatment of symptoms associated with autism and related PDDs. Areas of focus for future research are also discussed. The need for large-scale investigation of some commonly used pharmacologic agents, in addition to the development of drugs with improved efficacy and safety profiles, is made evident. TAKE HOME MESSAGE: Despite progress in the development of pharmacologic treatments for a number of interfering symptom domains associated with autism and other PDDs, a great deal of work remains.
Medical Sciences · 2018 · 33 citations · open access
Pharmacological Approach to Sleep Disturbances in Autism Spectrum Disorders with Psychiatric Comorbidities: A Literature Review
AbstractAutism is a developmental disability that can cause significant emotional, social and behavioral dysfunction. Sleep disorders co-occur in approximately half of the patients with autism spectrum disorder (ASD). Sleep problems in individuals with ASD have also been associated with poor social interaction, increased stereotypy, problems in communication, and overall autistic behavior. Behavioral interventions are considered a primary modality of treatment. There is limited evidence for psychopharmacological treatments in autism; however, these are frequently prescribed. Melatonin, antipsychotics, antidepressants, and α agonists have generally been used with melatonin, having a relatively large body of evidence. Further research and information are needed to guide and individualize treatment for this population group.
Frontiers in Psychiatry · 2021 · 25 citations · open access
Untangle the Multi-Facet Functions of Auts2 as an Entry Point to Understand Neurodevelopmental Disorders
AbstractNeurodevelopmental disorders are psychiatric diseases that are usually first diagnosed in infancy, childhood and adolescence. Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by core symptoms including impaired social communication, cognitive rigidity and repetitive behavior, accompanied by a wide range of comorbidities such as intellectual disability (ID) and dysmorphisms. While the cause remains largely unknown, genetic, epigenetic, and environmental factors are believed to contribute toward the onset of the disease. Autism Susceptibility Candidate 2 (Auts2) is a gene highly associated with ID and ASD. Therefore, understanding the function of Auts2 gene can provide a unique entry point to untangle the complex neuronal phenotypes of neurodevelpmental disorders. In this review, we discuss the recent discoveries regarding the molecular and cellular functions of Auts2. Auts2 was shown to be a key-regulator of transcriptional network and a mediator of epigenetic regulation in neurodevelopment, the latter potentially providing a link for the neuronal changes of ASD upon environmental risk-factor exposure. In addition, Auts2 could synchronize the balance between excitation and inhibition through regulating the number of excitatory synapses. Cytoplasmic Auts2 could join the fine-tuning of actin dynamics during neuronal migration and neuritogenesis. Furthermore, Auts2 was expressed in developing mouse and human brain regions such as the frontal cortex, dorsal thalamus, and hippocampus, which have been implicated in the impaired cognitive and social function of ASD. Taken together, a comprehensive understanding of Auts2 functions can give deep insights into the cause of the heterogenous manifestation of neurodevelopmental disorders such as ASD.
bioRxiv (Cold Spring Harbor Laboratory) · 2019 · 7 citations · open access
AUTS2 regulation of synapses for proper synaptic inputs and social communication
AbstractAbstract Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 ( AUTS2 ) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2 -deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.
AUTS-2 Syndrome. Gravity comparison of three cases: a case series and review of the literature
AbstractINTRODUCTION: Haploinssufficiency of AUTS2 gene has been associated with a syndromic form of neurodevelopmental delay called AUTS2 Syndrome (AUTS2S). It is characterized for having attention/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mild global development delay (GDD) and intellectual disability (ID). Clinicians also reported microcephaly, feeding difficulties, generalized hypotonia and ptosis.Due to its great variability, the AUTS2 Syndrome Severity Scoring System (ASSS) was established to assess the severity of the syndrome presentation. It is based on 32 characteristics including items of growth, feeding, neurodevelopment and congenital anomalies. At the molecular level, the AUTS2 gene consists of 19 exons that are divided into a non-conserved N-terminal region and a conserved 3’ terminal end. There is a short isoform expressed primarily in the brain that initiates at an alternative transcription site and includes the last 11 exons. Variants that disrupt this final part of the gene have been associated with a severe phenotype. OBJECTIVES: To describe and compare 3 patients affected with AUTS2 syndrome using the ASSS. METHODS: (1) Case series: Comparison of the patients diagnosed with AUTS2 Syndrome using the AUTS2 Syndrome Severity Score. (2) Narrative review of the AUTS2 syndrome and the genotype-phenotype correlation through PubMed database (1990-2020). Key terms: “AUTS2”, “AUTS2 syndrome”, “ADHD”, “neurodevelopmental disorder”, “autism”. RESULTS: 1 (ASSS score: 12). Interstitial duplication long arm of chromosome 7. Characteristics: microcephaly, GDD, ASD features, ADHD, auditory hypersensitivity. Finger flexion and syndactylia, arched eyebrows, palpebral fissures, epicanthus, nares, micrognathia, narrow mouth. 2 (ASSS score: 13). Pathogenic variant exon 9. Characteristics: GDD, feeding problems, ID, ASD features, auditory hypersensitivity, ADHD, hypotonia, cerebral anomalies, hypertelorism, anteverted nostrils, broad nasal bridge, micrognathia, low-set ears, narrow mouth. 3 (ASSS score: 13). Pathogenic variant exon 16. Characteristics: ID, short stature, feeding problems, auditory hypersensitivity, ADHD, hypotonia, umbilical hernia, hypertelorism, proptosis, short palpebral fissures, epicanthus, prominent nasal tip, anteverted nares, low-set ears. CONCLUSIONS: Currently, 65 patients with pathogenic variants in AUTS2 are described in the literature. Significantly higher ASSS values have been found in patients with pathogenic variants affecting the 3’ end of the gene. Further research is needed, since genetic diagnosis of affected patients contributes to improved clinical protocols and personalized treatment. DISCLOSURE OF INTEREST: None Declared
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
