DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for otosclerosis — screening already-approved drugs against its 29-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleOtosclerosis maps to a 29-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
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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 otosclerosis 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
creatine kinase B (CKB) — CKB 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3B6R · 2.0 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Otosclerosis is a heritable disease of the otic capsule whose genetics remain incompletely elucidated. A 1989 review discusses the hypothesis that otosclerosis may represent a heterogeneous group of diseases rather than a discrete entity, and considers whether it is an isolated manifestation of a generalised connective tissue disorder. By 2006, genetic studies had revealed evidence for defects in at least seven genes associated with six distinct chromosomal loci. High levels of osteoprotegerin expression in the normal otic capsule provide the first molecular insight into why that tissue remodels minimally; osteoprotegerin knockout mice offer the best available animal model of abnormal otic capsule remodelling that resembles otosclerosis.
Mounting evidence implicates the measles virus in pathogenesis, though the mechanisms remain unknown. In a 2004 study of 34 otosclerotic patients, 20 stapes footplate samples contained measles virus RNA; the 14 negative samples may represent genetically determined cases. A 2003 retrospective analysis of 2,362 subjects with surgically confirmed otosclerosis found only one subject with evidence of chronic otitis media, an incidence of 0.04 percent (p < 0.0001), suggesting that the genes causing otosclerosis may confer resistance to the pathogens that cause chronic otitis media. The mechanism of that resistance is unknown.
Surgical treatment is the only intervention described in these abstracts. A 2002 Canadian study of 112 primary stapedotomies and 13 revision stapedotomies reported an air-bone gap closure of 10 dB or less in 85.7 percent of primary procedures. Speech reception thresholds improved by an average of 26.7 dB after primary stapedotomy, with no significant change in speech discrimination scores. In revision stapedotomy, 38.5 percent of patients had a significant hearing gain, and the speech reception threshold improved by an average of 12.7 dB. Complications included two cases of partial hearing loss (1.6 percent), one incus fracture, one tympanic membrane perforation, and one perilymphatic fistula that was repaired. No patient experienced complete sensorineural hearing loss or facial nerve injury. A 1940 paper defends the operative treatment of otosclerosis against criticism based on a single unsuccessful case and experiments on rabbit skulls.
What is still missing is a clear molecular understanding of how the normal otic capsule's remodelling inhibition is dysregulated in otosclerosis, a definitive causal mechanism for the measles virus association, and any medical treatment that could replace or supplement surgery. No randomised trials of drug interventions are reported, and the genetic heterogeneity suggests that patient stratification will be needed before any targeted therapy can be tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Otology & Neurotology · 1989 · 71 citations
THE GENETICS OF OTOSCLEROS1S: A REVIEW
AbstractOtosclerosis is a heritable disease affecting the otic capsule. Its genetics have been studied, but remain incompletely elucidated. Presented is a detailed analysis of the literature pertaining to the mode of inheritance and epidemiology of clinical and histologic otosclerosis. Consideration is given to connective tissue abnormalities found in association with the disease. The hypothesis that otosclerosis is an isolated manifestation of a generalized connective tissue disorder is discussed. The author also suggests that otosclerosis, rather than being a discrete entity, may represent a heterogeneous group of diseases.
Current Opinion in Otolaryngology & Head & Neck Surgery · 2006 · 44 citations
Current research in otosclerosis
AbstractPURPOSE OF REVIEW: The aim of this article is to summarize and put into historical perspective current advances in research in otosclerosis, a disorder of the human temporal bone with a hereditary predisposition that is among the most common causes of acquired hearing loss. RECENT FINDINGS: Genetic studies have revealed that otosclerosis is heterogeneous, with evidence for defects in at least seven genes associated with six distinct chromosomal loci. Measurements of high levels of osteoprotegerin expression in the normal otic capsule and soft tissues of the cochlea provide the first molecular insight as to why the normal otic capsule remodels minimally, if at all. Osteoprotegerin knockout mice provide the best available animal model to date to study abnormal otic capsule remodeling that closely resembles otosclerosis. There is mounting evidence that the measles virus plays an important role in pathogenesis of otosclerosis although the mechanisms by which the virus results in otosclerosis remain unknown. Quantitative measures of angiogenesis can reliably distinguish between clinical and histological otosclerosis. Advances in the emerging field of osteoimmunology will likely impact and benefit from the research in otosclerosis. SUMMARY: Insights into molecular mechanisms that inhibit extensive remodeling in the normal otic capsule, and understanding of how these mechanisms are dysregulated in otosclerosis will allow future design of rational treatment strategies for otosclerosis.
Measles Virus Prevalence in Otosclerotic Stapes Footplate Samples
AbstractHYPOTHESIS: The cause of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. Chronic viral antigen expression on the surface of infected cells can induce a secondary autoimmune reaction against the otic capsule. BACKGROUND: In the past 15 years, some reports proposed the possible etiologic role of measles virus in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and detecting antimeasles immunoglobulin G in the perilymph samples. Many concerns were elicited by these results. METHODS: Nucleic acid was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by reverse-transcriptase polymerase chain reaction: reverse transcription and the first round polymerase chain reaction amplification was performed by heat stable recombinant Thermus thermophilus polymerase, whereas in the nested round, polymerase chain reaction Taq-polymerase was used. Measles virus nucleoprotein RNA-specific oligonucleotide primers were used in these reactions. An Edmonston-type measles virus served as a positive control and cortical bone fragments or stapes superstructures served as negative controls. RESULTS: Among 34 otosclerotic patients, 20 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients. CONCLUSION: The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 14 negative samples may be genetically determined otosclerotic cases.
Do the Genes That Cause Otosclerosis Reduce Susceptibility to Otitis Media?
AbstractHYPOTHESIS: The genetic factors that cause otosclerosis reduce susceptibility to otitis media. BACKGROUND: Susceptibility to some infectious diseases is modulated by host genetic factors. Genes that reduce the morbidity and mortality of infectious diseases may confer a selective advantage and achieve high-frequency in at-risk populations. Acute otitis media in the pre-antibiotic era frequently led to complications with high morbidity and mortality. The long-term sequela of acute otitis media is chronic otitis media. Chronic otitis media has a prevalence of 0.5 to 2 percent in the Caucasian population. Clinical otosclerosis occurs in 1 percent of Caucasians. Histologic otosclerosis occurs in 10 percent of Caucasians. MATERIALS AND METHODS: Retrospective analysis of 2,362 subjects with surgically confirmed otosclerosis. Subjects' medical records were reviewed for evidence of chronic otitis media. The incidence of chronic otitis media in the general population was compared with the subject population. RESULTS: Of the 2,362 subjects with surgically confirmed otosclerosis, one subject with evidence of chronic otitis media was identified. The incidence of chronic otitis media in the subject population is 0.04 percent (p < 0.0001). CONCLUSIONS: The incidence of chronic otitis media in subjects with a surgically confirmed diagnosis of otosclerosis is significantly lower than expected. The genes that cause otosclerosis may confer resistance to the pathogens that cause chronic otitis media and/or acute otitis media. The mechanism of resistance is unknown.
Archives of Otolaryngology - Head and Neck Surgery · 1940 · 6 citations
OPERATIVE TREATMENT OF OTOSCLEROSIS: REPLY TO A RECENT CRITICISM
AbstractFrank and open criticism of any new form of therapy is not only desirable but necessary before an evaluation of the therapy can be arrived at by members of the medical profession. For this reason physicians who treat otosclerosis surgically were particularly interested in the recent article by L. K. and P. Guggenheim<sup>1</sup>entitled "Artificial Fistula in Cases of Otosclerosis." Unfortunately, the authors' only experience with this kind of surgery was the observation of a single case in which an unsuccessful operation was performed by some one else plus some experiments on the regeneration of bone in the rabbit's skull (not on the labyrinthine capsule). As a consequence of their restricted experience, the authors were led to make certain statements which should not be allowed to go uncorrected. The authors stated: The treatment of otosclerosis by means of (1) reversal of halisteresis and (2) regeneration of the damaged neural mechanism
The Journal of Otolaryngology · 2002 · 6 citations
Small Fenestra Stapedotomy for Otosclerosis in a Canadian Teaching Centre
AbstractOBJECTIVE: This study reports the results of 112 primary stapedotomies and 13 revision stapedotomies performed by the senior author. STUDY DESIGN: Retrospective case review of all primary and revision stapedotomies performed at University Hospital between 1994 and 1999. All patients in this series had otosclerosis and underwent stapedotomy using a 0.6-mm diameter platinum wire/Teflon piston prosthesis. The air-bone gap was calculated as the difference between the preoperative boneconduction and the postoperative air-conduction thresholds. The average follow-up time post-stapedotomy to audiometric testing was approximately 2.5 months. OUTCOME MEASURES: An average air-bone gap closure at 500, 1000, and 2000 Hz to 10 dB or less was used as the criterion for success. The effects of stapedotomy on speech reception thresholds (SRTs), speech discrimination scores (SDSs), and airconduction thresholds are also reported. RESULTS: In primary stapedotomy, an air-bone gap closure of 10 dB or less was achieved in 85.7% of patients. A significant hearing gain was achieved at all frequencies (250-8000 Hz), with the greatest benefit being achieved at the lower frequencies. The SRT was significantly improved post-stapedotomy by an average of 26.7 dB, and no significant change was found in the SDS. In revision stapedotomy, 38.5% of patients had a significant hearing gain at 250 to 4000 Hz. The SRT was significantly improved postoperatively by an average of 12.7 dB, and no significant change was found in SDS. Overall complication rates were similar to other series with two cases of partial hearing loss (1.6%), one incus fracture (0.8%), one large tympanic membrane perforation (0.8%), and one perilymphatic fistula (0.8%), which was successfully repaired. No patients in this series experienced complete sensorineural hearing loss, facial nerve injury, worsened tinnitus, or reparative granuloma. CONCLUSIONS: The results of this study are comparable to other similar studies examining the use of stapedotomy in patients with otosclerosis. The high success rate and low incidence of serious complications support stapedotomy, without a laser but with resident involvement, as a highly effective treatment for otosclerosis.
Journal of Otorhinolaryngology Hearing and Balance Medicine · 2024 · 0 citations · open access
Exploring the Prevalence of Psychiatric Disorders in Otosclerosis Patients: A Systematic Review
AbstractObjective: The primary objective of this research is to conduct a systematic review of the available studies and evidence to determine if there is a significant relationship between otosclerosis and psychiatric disorders. By critically evaluating the existing data, this study aims to provide insights into the potential interplay between these medical conditions. Data Sources: PubMed, Embase, Ebsco, Proquest, and Web of Science Review Methods: PubMed, Embase, Ebsco, Proquest, and Web of Science databases were queried for original English articles from 1950 to 2023. This review was conducted in accordance with the 2020 PRISMA guidelines. The publications were screened by two independent viewers. The Newcastle–Ottawa Scale quality instrument was used to assess the quality of studies. Results: Initially, 153 abstracts were screened for eligibility. After a rigorous selection process, five studies met the criteria, collectively encompassing 262 patients diagnosed with otosclerosis. The reported mean ages ranged from 25 to 52 years. A combined assessment of psychiatric disorder rates among otosclerosis patients revealed a rate of 36%. Depression, anxiety, and schizophrenia were the most common mental illnesses reported in all six studies. One of the studies specifically examined psychiatric disorder rates before and after stapedectomy, revealing a statistically significant decrease in depressive and anxiety-related symptoms following the surgical intervention. Conclusions: This systematic review emphasizes the emerging evidence connecting otosclerosis with psychiatric disorders and underscores the importance of adopting a multidisciplinary approach to assess and manage otosclerosis patients.
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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