DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Usher syndrome type 2A — screening already-approved drugs against its 3-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 2A maps to a 3-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 2a 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
PDZ domain containing 7 (PDZD7) — PDZD7 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7PC5 · 1.7 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
The Usher syndromes are genetically distinct disorders that share specific phenotypic characteristics. Clinical criteria for diagnosing Usher syndrome type I and type II were recommended in 1994 and adopted by the Usher Syndrome Consortium. In a 2014 cross-sectional study of 433 patients (297 unrelated families), molecular studies were performed for 304 patients (256 unrelated families). The comparison between type I and type II patients showed P < .001 for most items analysed. The most frequent mutations in the USH2A gene were p.Glu767Serfs*21 and p.Cys759Phe, with allelic frequencies of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. None of the p.Cys759Phe patients exhibited severe hearing loss, and more than 60% had only mild hearing loss. Most patients carrying p.Glu767Serfs*21 (72.1%) were moderately deaf.
A 2017 report on a Saudi family with Usher syndrome type 1B and a homozygous splice site mutation in MYO7A (c.470+1G>A in intron 5) described advanced retinal degeneration at a young age. Visual acuity was more reduced in older siblings (age >30 years, range 20/300–20/40) than in younger siblings (age <30 years, range 20/70–20/25). OCT scans showed macular atrophy in all but one case, which had cystoid macular edema. Full-field electroretinogram was flat in all cases. The authors noted this may have implications for future gene therapy in cases with this genotype.
A 2020 study of one family with Usher syndrome type I found a proband who developed night blindness at age 10, with bilateral cataract and retinal degeneration, and hearing loss increasing with age. High-throughput and Sanger sequencing revealed compound heterozygous variants of MYO7A: c.2694+2T>G and c.6028G>A. Her sister carried the same variants with similar clinical phenotypes. Her daughter was heterozygous for c.6028G>A but phenotypically normal. The authors stated the results enriched phenotype and genotype data and provided a basis for genetic counselling.
No drug treatment, no intervention, and no repurposing candidate is mentioned in any of these abstracts. What is still missing for any potential therapy in Usher syndrome type 2A is a clear molecular target for drug repurposing, any preclinical or clinical trial data testing a specific compound, and patient stratification beyond the known genotype-phenotype correlations described here. Funding for drug screening or gene therapy development, and trial designs that account for the slow, variable progression of retinal and hearing loss, are also absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics · 1994 · 344 citations
Clinical diagnosis of the Usher syndromes
AbstractThe Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.
Journal of Medical Genetics · 1993 · 85 citations · open access
Usher syndrome type I associated with bronchiectasis and immotile nasal cilia in two brothers.
AbstractUsher syndrome type I is an autosomal recessive disease characterised by congenital sensorineural deafness, involvement of the vestibular system, and progressive visual loss owing to retinitis pigmentosa. Here we report the association of this disease with bronchiectasis, chronic sinusitis, and reduced nasal mucociliary clearance in two sibs and we suggest Usher syndrome type I could be a primary ciliary disorder.
JAMA Ophthalmology · 2014 · 76 citations · open access
Clinical Aspects of Usher Syndrome and the<i>USH2A</i>Gene in a Cohort of 433 Patients
AbstractIMPORTANCE: A new statistical approach is needed to describe the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES: To describe the primary phenotypic characteristics and differences between type I and type II Usher syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES: Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS: The comparison between patients with type I Usher syndrome and those with type II Usher syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs*21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs*21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf. CONCLUSIONS AND RELEVANCE: Our study presents the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher syndrome because an estimated prognosis of their disease can be made.
Saudi Journal of Ophthalmology · 2017 · 13 citations · open access
Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene
AbstractUsher syndrome is the most common cause of deafness associated with visual loss of a genetic origin. The purpose of this paper is to report very severe phenotypic features of type 1B Usher syndrome in a Saudi family affected by positive homozygous splice site mutation in MYO7A gene. Affected siblings went through detailed history. Complete ophthalmic examination was done. Imaging with colour fundus photography, fundus autofluorescence (AF), and optical coherence tomography (OCT) scans was performed. Full field electroretinogram (ffERG) was recorded. Molecular genetic testing was done using next-generation sequencing. Visual acuity was more reduced (range 20/300–20/40) in older siblings (age>30 years), than in younger (age <30 years) siblings (range 20/70–20/25). OCT scans showed macular atrophy in all but one case that has cystoid macular edema (CME). AF demonstrated atrophy outside a small foveal area showing high signal. FfERG was flat in all cases. The homozygous splice site mutation c.470+1G>A in intron 5 of the MYO7A gene was detected in all affected siblings. This mutation manifested with advanced retinal degeneration at a young age. This may have implications regarding future gene therapy in Usher syndrome cases with this genotype.
Ophthalmic Paediatrics and Genetics · 1991 · 4 citations
A hereditary syndrome with retinopathy and ataxia or deafness in two consanguineous brothers
AbstractOf two brothers born of Sephardic first cousin parents one presented with congenital neural deafness, nyctalopia, visual field loss, flat ERG, unintelligible speech and a shuffling gait, and the other with severe ataxia, severe decreased visual acuity, mild field loss, decreased ERG, dysarthric speech and high grade myopia. The diagnosis of Usher syndrome type 1 or 2 is discussed as well as the possibility that both brothers have different genetic disorders.
[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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