DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Usher syndrome type 1 — screening already-approved drugs against its 7-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleUsher syndrome type 1 maps to a 7-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 usher syndrome type 1 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
Seventy patients with Usher's syndrome were studied in 1983, leading to the description of two distinct clinical types based on differences in hearing impairment, vestibular sensitivity, and retinal photoreceptor deterioration. A 2017 study using next-generation sequencing of 112 genes in 138 patients clinically diagnosed with Usher syndrome achieved a molecular diagnosis in 97% of both USH1 and USH2 patients. Biallelic mutations were found in 97% of USH1 and 90% of USH2 cases. Copy number variations accounted for 10% of identified USH2A alleles, often appearing in trans to seemingly monoallelic point mutations. The common p.Trp3955* nonsense mutation, found on 13% of detected USH2A alleles, was shown in vitro to be amenable to PTC124-induced read-through, a potential therapy target. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, linking that gene to Heimler syndrome for the first time.
A 2013 study of 18 subjects from nine families with Usher syndrome type IIA examined the relationship between identical USH2A mutations and hearing loss. Among affected siblings carrying the same mutations, hearing loss ranged from mild to profound, showing both similarities and differences within families. No significant differences in hearing thresholds were found between groups of subjects with different pathological mutations. The authors concluded that the USH2A genotype-phenotype relationship is probably modulated by other variables such as modifying genes, epigenetics, or environmental factors.
The 2017 study noted that targeted next-generation sequencing not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome. In some patients the diagnosis was adjusted, for example in cases of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and retinitis pigmentosa respectively. The 1983 study emphasised that distinguishing the two clinical types has relevance for diagnosis and genetic counselling.
What is still missing is a clear understanding of the modifying variables that cause variable hearing loss even with identical USH2A mutations, and whether PTC124-induced read-through of the p.Trp3955* nonsense mutation translates into clinical benefit in patients. No trial has yet tested this in Usher syndrome patients. Patient stratification by mutation type and modifier genes remains incomplete, and funding for such trials is not secured.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Ophthalmology · 1983 · 148 citations
Usher's Syndrome
AbstractThe conditions of 70 patients with Usher's syndrome were studied by ophthalmic and neuro-otologic examinations. Two distinct clinical and presumed genetic types were discernible on the basis of differences in hearing impairment, vestibular sensitivity, and, to a lesser extent, deterioration in retinal photoreceptor function. Distinguishing these two types has relevance for both diagnosis and genetic counseling of patients with Usher's syndrome.
Molecular Genetics & Genomic Medicine · 2017 · 66 citations · open access
Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and<i>PEX26</i>mutated in Heimler syndrome
AbstractBackground Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). Methods Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. Results A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. Conclusion Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
International Journal of Audiology · 2013 · 29 citations
Expressivity of hearing loss in cases with Usher syndrome type IIA
AbstractOBJECTIVE: The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DESIGN: DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype-phenotype correlations. STUDY SAMPLE: Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. RESULTS: Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. CONCLUSIONS: Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome.
Usher′s syndrome: Can primarily be a primary ciliary disorder?
AbstractSir, Usher's syndrome is a genetically heterogeneous disorder. It mainly consists of auditory and visual disturbances. Manifestations include sensory neural hearing loss, vestibular system involvement and progressive loss of vision due to retinitis pigmentosa. Primary ciliary disorder is an inherited disorder which affects the structure and function of cilia. Bronchiectasis can be due to various conditions, primary ciliary disorder is one of them. Here we would like to present a rare case of Usher's syndrome that had clinical and radiological features of bronchiectasis, thereby opening avenues to suggest a possible link between Usher's syndrome and primary ciliary disorder. A 20-year-old male patient symptomatic since childhood was presented with history of postural dependant cough with copious expectoration and recurrent rhinosinusitis. For these complaints he had received multiple courses of empirical antituberculous therapy and operated for left lower lobectomy in the past. Further history-taking elicited a progressive loss of vision and hearing with scholastic backwardness. The patient was born of non-consanguineous marriage without any significant family history. Clinical examination and chest radiograph suggested bronchiectasis. Routine blood and biochemistry parameters were normal. High resolution computed tomography-HRCT [Figure 1a and b] confirmed the presence of bronchiectasis in the right middle lobe and lingula with left lower lobectomy status. Audiometry reported bilateral moderately severe mixed hearing loss with normal vestibular function. Ophthalmologic evaluation revealed retinitis pigmentosa [Figure 2]. Mental testing showed social quotient of 38 suggesting moderate retardation in social maturity.Figure 1a: and b. HRCT thorax showing presence of bronchiectasisFigure 2: Fundoscopic findings suggestive of retinitis pigmentosaOn the basis of clinical history, chest radiography, audiometry and ophthalmoscopy findings patient was diagnosed as a case of Usher syndrome (Type II or III) with bronchiectasis. Usher syndrome is an autosomal recessive disease characterized by congenital deafness, involvement of the vestibular system, and progressive visual loss owing to retinitis pigmentosa. It is also known as Hallgren syndrome, Usher-Hallgren syndrome, Retinitis pigmentosa-dysacusis syndrome and Dystrophia retinae dysacusis syndrome . It was first described by Von Graefe[1] in 1858 but Usher[2] was the first to recognize its hereditary nature in his report of 41 families in 1914. It is considered to be the most common cause of congenital deaf-blind ness. It was further divided by Davenport and Omenn into three clinical sub-types Usher type I (USH1), Usher type II (USH2) and Usher type III (USH3) in order of decreasing severity of deafness and involvement of the vestibular system.[3] Vestibular function is absent in USH1 and normal in USH2 and USH3. Differential diagnoses include Alport syndrome, Bardet-Biedl syndrome, Friedreich ataxia, Hurler syndrome, Kearns-Sayre syndrome, Refsum's disease. In addition to congenital deaf-blindness our patient also had bronchiectasis, recurrent rhinosinusitis. Very few cases have been reported in the literature suggesting an association between bronchiectasis, rhinosinusitis and Usher syndrome. Bronchiectasis has been first reported in siblings suffering from USH1.[4] Later impaired nasal ciliary beat frequency with no clinical consequences was demonstrated on nasal mucosal brush biopsy in four cases of USH2.[5] Our case is USH2/USH3 with presence of bronchiectasis. In these cases defective development of both the immotile (present in ear and eye) and motile (present in the respiratory epithelium) cilia has been hypothesized. The combined involvement of three sensory systems in Usher can be explained by the shared origin of photoreceptors, the auditory and vestibular hair cells from ciliated progenitor cells.[4] The ultrastructurally defective cilia in the respiratory tract cause impaired mucociliary clearance leading to repeated infections and bronchiectasis as is seen in primary ciliary dyskinesia. This association suggests that Usher syndrome could be a primary ciliary disorder.
[Clinical phenotype and genotype analysis of the family with the Usher syndrome].
AbstractOBJECTIVE: To detect potential variants in a family affected with Usher syndrome type I, and analyze its genotype-phenotype correlation. METHODS: Clinical data of the family was collected. Potential variants in the proband were detected by high-throughput sequencing. Suspected variants were verified by Sanger sequencing. RESULTS: The proband developed night blindness at 10 year old, in addition with bilateral cataract and retinal degeneration. Hearing loss occurred along with increase of age. High-throughput sequencing and Sanger sequencing revealed that she has carried compound heterozygous variants of the MYO7A gene, namely c.2694+2T>G and c.6028G>A. Her sister carried the same variants with similar clinical phenotypes. Her daughter was heterozygous for the c.6028G>A variant but was phenotypically normal. CONCLUSION: The clinical features and genetic variants were delineated in this family with Usher syndrome type I. The results have enriched the phenotype and genotype data of the disease and provided a basis for genetic counseling.
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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