DeCure for Autosomal recessive nonsyndromic hearing loss 9
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive nonsyndromic hearing loss 9 — screening already-approved drugs against its 2-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 9 maps to a 2-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 9 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.
What the evidence adds up to
Nonsyndromic congenital hearing loss accounts for the largest proportion of paediatric sensorineural hearing loss, and comprehensive genetic testing using new sequencing technologies is changing the diagnostic work-up. One study identified a proband with postnatal deafness carrying a homozygous c.1893C>A mutation in the TECTA gene, which is located in the tectorial membrane and may cause premature termination of translation of TECTA protein. Two heterozygous mutations in USH2A were also found, one likely pathogenic and the other of unknown clinical significance. The authors concluded the homozygous TECTA mutation probably underlies the hearing loss, which conformed to autosomal recessive inheritance.
For DFNB9, caused by mutations in the otoferlin gene (OTOF), the sensory hair cells can detect sound but cannot release neurotransmitters into the synapse. Hearing aids are not effective. In zebrafish lacking functional otoferlin, hearing was restored by injecting a functional foreign otoferlin nucleotide sequence. Studies with otoferlin mutant mice concluded that a foreign copy of otoferlin could restore neurotransmitter release at the hair cell synapse of deaf mice, and viral gene therapy techniques were used to introduce the functional copy. However, the authors note that the efficiency of viral gene delivery has limited the scope of previous studies, and overcoming this challenge is key for establishing a better understanding of any role this gene has in hair cell development. The presence or absence of otoferlin protein may directly influence the maturation of the hair cell synapse.
For DFNB7/11, caused by pathogenic variants in TMC1, a retrospective analysis of three patients from two non-consanguineous Italian families found a novel disease-causing variant c.962G>A p.(Trp321*). All affected children showed prelingual, severe-to-profound hearing loss. After cochlear implantation, the patients showed an excellent functional outcome, with speech perception, nonverbal cognition, and speech performance comparable to patients with DFNB1 deafness. The authors state their results do not support the variable auditory outcome reported in the literature, which they suggest may be affected by social, environmental, and genetic factors.
What is still missing for these autosomal recessive nonsyndromic hearing loss forms are larger patient cohorts to confirm outcomes, more efficient viral delivery systems for gene therapy, and better understanding of how specific mutations affect protein function and synapse maturation. No clinical trials have yet demonstrated safe and effective gene therapy in human patients.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
Journal of the American Academy of Audiology · 2021 · 4 citations
Genetic Medicine for Hearing Loss: <i>OTOF</i> as Exemplar
AbstractAbstract Millions of people worldwide have disabling hearing loss because one of their genes generates an incorrect version of some specific protein the ear requires for hearing. In many of these cases, delivering the correct version of the gene to a specific target cell within the inner ear has the potential to restore cochlear function to enable high-acuity physiologic hearing. Purpose: In this review, we outline our strategy for the development of genetic medicines with the potential to treat hearing loss. We will use the example of otoferlin gene ( OTOF )-mediated hearing loss, a sensorineural hearing loss due to autosomal recessive mutations of the OTOF gene.
[Diagnosis and reproductive guidance for a couple carrying a novel c.1893C>T mutation of the TECTA gene].
AbstractOBJECTIVE: To explore the molecular basis for an individual with postnatal deafness and provide genetic counseling for her family. METHODS: Following extraction of genomic DNA from peripheral blood samples, 127 genes associated with deafness were subjected to targeted capturing and next generation sequencing. Suspected mutation was verified by Sanger sequencing. RESULTS: The proband was found to carry a homozygous c.1893C>A mutation in the TECTA gene, which is located in the tectorial membrane of inner ear and may cause premature termination of translation of TECTA protein. In addition, two heterozygous mutations, c.13010C>T and c.12790G>A, were found in the USH2A gene. Whilst the former is likely to be pathogenic, the latter has unknown clinical significance. Further analysis suggested that all three mutations have derived from the parents of the proband. CONCLUSION: The homozygous c.1893C>A mutation of the TECTA gene probably underlies the proband's hearing loss which conformed to an autosomal recessive inheritance.
New Otoferlin Studies Advances Gene Therapy for Congenital Hearing Loss
AbstractPrelingual hearing loss occurs in approximately one out of every 600 children.1 Among cases with a genetic basis, a nonsyndromic form known as deafness, neurosensory, autosomal recessive (DFNB) represents about 75% of autosomal recessive cases. The gene otoferlin has been identified as responsible for DFNB9, a type of auditory neuropathy in which the sensory hair cells in your inner ear can detect sound but cannot release neurotransmitters into the synapse between the hair cell and afferent fibers of the spiral ganglion. Available treatments for otoferlin-associated hearing loss are limited, and hearing aids are not effective. Recently, several studies have raised the possibility that the DFNB9 phenotype could be restored using gene therapy techniques. This research has also provided interesting information that has challenged our existing ideas about the role of this protein.Shutterstock/Marko Aliaksandr, hearing loss, genetics, gene therapyUnlike most genes, otoferlin appears to operate exclusively in sensory hair cells and plays an essential but poorly understood role in controlling neurotransmitter release from the hair cell. Hearing loss-related mutations in otoferlin typically result in a silent hair cell synapse. The rest of the peripheral auditory system seems otherwise unaltered and human patients do not exhibit any balance problems. The specific role of otoferlin in these cells has raised questions regarding if hearing could be restored by placing a functional foreign copy of otoferlin into the sensory hair cells without a functional endogenous copy. Could this restore neurotransmitter release and the encoding of sound? Recently, we and others have put this question to the test. Using zebrafish that lack a functional otoferlin gene, we found that hearing could be restored by injecting a functional copy of a foreign otoferlin nucleotide sequence.2 Similarly, studies with otoferlin mutant mice concluded that a foreign copy of otoferlin could restore neurotransmitter release at the hair cell synapse of deaf mice.2-4 Furthermore, these mouse-based studies demonstrated viral gene therapy techniques to introduce the functional copy of otoferlin, which provides a president for the further development of genetic treatment options for DFNB9.5 What exactly does otoferlin do in the hair cell? Although a definitive answer is still lacking, researchers have applied the gene transfer methods described above to test various otoferlin mutations and truncations to learn more about the gene. These studies suggest that the gene may encode for a protein that contributes to multiple steps in both neurotransmitter secretion from the hair cell and in resetting the system for another round of signaling. Specifically, otoferlin appears to operate as a kind of master organizer, linking various molecules together for fast and efficient neurotransmitter release. Most recently with support from the National Institute on Deafness and Other Communication Disorders, we have found a possible new role for otoferlin: The presence or absence of otoferlin protein directly influences the maturation of the hair cell synapse.6 In the absence of otoferlin, the hair cell synapses appear immature compared to normal hair cells. If otoferlin does indeed inhibit hair cell maturation, this may represent an entirely new and previously unreported ability of this gene. Moving forward, work to increase the efficiency of viral gene delivery would benefit the field, as this factor has limited the scope or previous studies. Overcoming this challenge will also be key for establishing a better understanding of any role this gene has in hair cell development.
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.
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.
