DeCure for Autosomal recessive nonsyndromic hearing loss 18A
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive nonsyndromic hearing loss 18A — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal recessive nonsyndromic hearing loss 18A maps to a 1-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
No approved-drug candidate for autosomal recessive nonsyndromic hearing loss 18a is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
USH1 protein network component harmonin (USH1C) — USH1C is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet mltdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5XBF · 1.802 Å · ligand D-MALATE (MLT). Experimental structure, not a prediction.
What the evidence adds up to
The 2003 review notes that by that date 80 loci for nonsyndromic hearing loss had been mapped and 30 genes identified, enabling DNA diagnostic tests for some types. A 2004 clinical genetic study of 144 patients with nonsyndromic hearing loss described sex distribution, type, degree, symmetry, laterality, progression, aetiology, and inheritance pattern but gave no specific numerical outcomes. In 2014, two novel TECTA mutations were found in Korean families with autosomal dominant nonsyndromic hearing loss: c.3995G>T (p.C1332F) in the von Willebrand factor type D3-D4 interdomain of the zonadhesin domain, associated with stable high-frequency loss, and c.5618C>T (p.T1873I) in the zona pellucida domain, associated with stable mid-frequency loss. The authors noted that the cysteine-to-phenylalanine change in p.C1332F was not related to progression, arguing against a previous hypothesis, and suggested that patients with the vWFD3-D4 interdomain mutation could be candidates for middle ear implantation.
A 2018 study of a Pakistani family with profound nonsyndromic hearing impairment reported digenic inheritance of two trans heterozygous missense mutations: PCDH15 p.(Arg1034His) and USH1G p.(Asp365Asn). Both genes are known to cause autosomal recessive nonsyndromic hearing loss and Usher syndrome. The digenic mice had shown a significant decrease in hearing compared to age-matched heterozygotes, but no human examples had been reported before this family. In 2020, three children from two non-consanguineous Italian families with DFNB7/11 due to biallelic TMC1 variants, including a novel c.962G>A p.(Trp321*) mutation, all had prelingual severe-to-profound hearing loss. After cochlear implantation, they showed excellent functional outcome in speech perception, nonverbal cognition, and speech performance, comparable to patients with DFNB1 deafness. The authors stated their results do not support the variable auditory outcome reported elsewhere.
A 2025 review of gene therapy for inner ear disease notes that the recent otoferlin gene therapy trials have refocused attention on the potential to cure hearing loss. For gene replacement therapy, disorders with residual targetable cells present postnatally are needed; if hair cells degenerate during development, gene therapy cannot rescue them. The review states that genetic hearing losses occurring in the postnatal period are currently optimal targets, whereas severe-to-profound congenital losses occurring in utero will not be treatable with gene therapy for now. Gene replacement for recessive disorders is expected to precede gene editing for dominant disorders. What remains missing for autosomal recessive nonsyndromic hearing loss 18A specifically are funded clinical trials, a delivery vector that reaches the relevant hair cells at the correct developmental window, and patient stratification by residual cell count and mutation type.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Ear and Hearing · 2003 · 66 citations
Nonsyndromic Hearing Loss
AbstractIn Brief The past decade has seen extremely rapid progress in the field of hereditary hearing loss. To date, 80 loci for nonsyndromic hearing loss have been mapped to the human genome. Furthermore, 30 genes have been identified. These genes belong to a wide variety of protein classes: from myosins and other cytoskeletal proteins, over channel and gap junction components, to transcription factors, extracellular matrix proteins and genes with an unknown function. The identification of these genes has enabled geneticists to offer DNA diagnostic tests for some types of nonsyndromic hearing loss. Moreover, it holds the promise to significantly improve the molecular knowledge on the auditory and vestibular organs and on the pathological mechanisms leading to hearing loss. This opens perspectives for future therapeutic and/or preventive measures for hearing loss. This review attempts to give an overview of the current knowledge of the genes responsible for nonsyndromic hearing loss, their expression and functions in the cochlea. A broad review of genes responsible for nonsyndromic hearing loss, their expression and function in the cochlea. Also discusses the genetic tests currently offered for different types of nonsyndromic hearing loss.
BMC Medical Genetics · 2018 · 28 citations · open access
Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment
AbstractBACKGROUND: Digenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported. METHODS: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease. RESULTS: We found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p.(Arg1034His)] and another in USH1G [p.(Asp365Asn)]. Both of these genes are known to cause autosomal recessive non-syndromic hearing impairment and Usher syndrome. The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction. Epistasis between Pcdh15 and Ush1G has been previously reported in digenic heterozygous mice. The digenic mice displayed a significant decrease in hearing compared to age-matched heterozygous animals. Until now no human examples have been reported. CONCLUSIONS: The discovery of novel digenic inheritance mechanisms in hereditary hearing impairment will aid in understanding the interaction between defective proteins and further define inner ear function and its interactome.
Current Opinion in Otolaryngology & Head & Neck Surgery · 2017 · 22 citations
Evaluation and management of nonsyndromic congenital hearing loss
AbstractPURPOSE OF REVIEW: Nonsyndromic congenital hearing loss represents the largest proportion of paediatric sensorineural hearing loss. The optimal evaluation and management of affected patients remains clinically challenging. Current controversies in the diagnostic work-up of nonsyndromic congenital hearing loss are presented in this review. RECENT FINDINGS: The improved diagnostic yield of comprehensive genetic testing due to new sequencing technologies is changing the diagnostic for congenital hearing loss. Concerns for both ionizing radiation and general anaesthetic exposure are also driving shifts in imaging modality preferences for infants and toddlers. SUMMARY: A thoughtful systematic, targeted approach taking into consideration the audiologic phenotype of the patient is recommended for the work-up of nonsyndromic congenital hearing loss.
Novel <b><i>TECTA </i></b>Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications
AbstractTECTA is a causative gene of autosomal dominant (DFNA8/A12) and autosomal recessive (DFNB 21) nonsyndromic sensorineural hearing loss (NSHL). Mutations in TECTA account for 4% of all autosomal dominant NSHL cases in some populations and are thus thought to be one of the major causes of autosomal dominant NSHL. A genotype-phenotype correlation for autosomal dominant mutations in the TECTA gene has been proposed. Two families (SB146 and SB149), which segregated moderate NSHL in an autosomal dominant fashion, were included in this study. We performed targeted resequencing of 134 known deafness genes (TRS-134) and bioinformatics analyses to find causative mutations for NSHL in these 2 families. Through TRS-134, we detected 2 novel mutations, i.e. c.3995G>T (p.C1332F) and c.5618C>T (p.T1873I), in the TECTA gene. These mutations cosegregated with NSHL in the studied families and were not detected in normal controls. The mutations c.3995G>T and c.5618C>T reside in the von Willebrand factor type D3-D4 (vWFD3-D4) interdomain of the zonadhesin (ZA) domain and the zona pellucida (ZP) domain, respectively. p.C1332F is the first mutation detected in the vWFD3-D4 interdomain of the ZA domain. The mutations p.C1332F and p.T1873I were associated with stable high-frequency and mid-frequency hearing loss, respectively. Notably, the cysteine residue mutated to phenylalanine in SB146 was not related to progression of sensorineural hearing loss, which argues against the previous hypothesis. Here we confirm a known genotype-phenotype correlation for the ZP domain and propose a hypothetical genotype-phenotype correlation which relates mutations in vWFD3-D4 to stable high-frequency NSHL in Koreans. This clinical feature makes subjects with the missense mutation in the vWFD3-D4 interdomain of TECTA potentially good candidates for middle ear implantation.
American Journal of Audiology · 2004 · 1 citations
Clinical Genetic Study of 144 Patients With Nonsyndromic Hearing Loss
AbstractHearing loss constitutes an important category of congenital defects that can be isolated or part of the phenotypic spectrum of several syndromes. A clinical genetic study was performed on a sample of 144 patients with nonsyndromic hearing loss, establishing the sex distribution, type, degree, symmetry, laterality, progression, etiology, and, when possible, inheritance pattern.
Supplementary Material for: Auditory Outcome after Cochlear Implantation in Children with DFNB7/11 Caused by Pathogenic Variants in <b><i>TMC1</i></b> Gene
Abstract<b><i>Introduction:</i></b> Non-syndromic hereditary hearing loss is characterized by extreme genetic heterogeneity. So far, more than 100 pathogenic or likely pathogenic variants in <i>TMC1</i> gene have been reported in patients with autosomal recessive hearing loss (HL) DFNB7/11. The prevailing auditory phenotype of individuals with DFNB7/11 is congenital, profound, bilateral HL, but the functional outcome after cochlear implantation (CI) described in the literature is variable. The objective of this work is to evaluate the auditory outcome after CI in pediatric patients with DFNB7/11, born to non-consanguineous parents. <b><i>Methods:</i></b> A retrospective analysis of genetic and audiological data of DFNB7/11 patients followed up in a single Italian otolaryngology clinic was performed. Cases with biallelic pathogenic variants in <i>TMC1</i> were selected from the cohort of children with non-syndromic hearing loss who had undergone CI and had been molecularly characterized by multigene panel testing. All patients underwent extensive audiological assessment, and the auditory outcome after CI was evaluated. <b><i>Results:</i></b> DFNB7/11 was diagnosed in a total of 3 patients from 2 non-consanguineous families; a novel disease-causing variant in <i>TMC1</i> was detected [c.962G>A p.(Trp321*)]. All the affected children showed the typical DFNB7/11 phenotype characterized by prelingual, severe-to-profound HL. The patients showed an excellent functional outcome after CI; speech perception, nonverbal cognition, and speech performance were comparable to those of patients with DFNB1 deafness. <b><i>Discussion/Conclusion:</i></b> Our results do not support the variable auditory outcome reported in the literature, which may be affected by several social and environmental factors and by the genetic background.
Current Opinion in Otolaryngology & Head & Neck Surgery · 2025 · 0 citations
Gene therapy for inner ear disease: the next targets
AbstractPURPOSE OF REVIEW: The recent successful otoferlin gene therapy trials have refocused the fields attention on the potential of gene therapy to cure hearing loss. With over 100 known monogenetic causes of hearing loss, the key question is which will be the next set of disorders that are treatable. The current review addresses potentially targetable hearing disorders that can be addressed with current gene therapy technologies. RECENT FINDING: For gene replacement therapy, we need to consider disorders that have residual targetable cells present in postnatal to adult ages. If a target tissue (i.e. hair cells) degenerates during development, it can no longer be rescued by gene therapy. Disorders such as DFNB8 and certain mutations in DFNB1 could benefit from a gene therapy approach. Other important considerations are the size of the gene being replaced, the availability of appropriate vectors, and the overall incidence of the disease. SUMMARY: Genetic hearing losses that occur in the postnatal period are currently optimal targets and conversely hearing losses that occur in utero resulting in severe to profound congenital losses for now will not be treatable with gene therapy. Gene replacement therapy for recessive disorders will precede development of gene editing strategies for dominant disorders.
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.
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