DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Leber congenital amaurosis 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 moduleLeber congenital amaurosis 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 leber congenital amaurosis 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
TUB like protein 1 (TULP1) — TULP1 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 n,n-dimethyloctylammoniodrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2FIM · 1.9 Å · ligand 3-(N,N-DIMETHYLOCTYLAMMONIO)PROPANESULFONATE (3DP). Experimental structure, not a prediction.
What the evidence adds up to
In 100 consecutive Leber congenital amaurosis patients, mutations were identified in only 11%: GUCY2D accounted for 6%, RPE65 for 3%, and CRX for 2%. Visual evolution in patients with GUCY2D and CRX mutations remained stable, while individuals with RPE65 mutations showed progressive visual loss. The clinical presentation was variable overall. A 2008 case report from Kaduna State, Nigeria, described three siblings with this irreversible blinding condition and discussed genetic issues, clinical presentation, counselling, and treatment, but provided no quantitative outcome data.
A 2019 study using whole exome sequencing and targeted gene panels identified three novel pathogenic variants in the CRB1 gene (p.Glu703*, c.2128+1G>A, and p.Ser758SerfsX33) in LCA patients. The authors concluded that next-generation sequencing is efficient for identifying causative variants in disorders with locus heterogeneity, but they reported no treatment outcomes. A 2017 Spanish case report of a girl with RPE65-mutation-confirmed LCA, followed from age 4 to 11, noted that electroretinogram was not measurable in all phases and that gene therapy had been researched with good functional outcomes up to that point, without providing specific numbers.
A 2009 commentary recalled that in 2001 a team led by Jean Bennett restored vision to three dogs with LCA, a result that electrified families and spread like wildfire. The same commentary noted that Bennett received hundreds of inquiries from expectant parents. No human trial results from that work were reported in the abstracts provided. What remains missing is large-scale, long-term human trial data with clearly reported response rates and survival outcomes, adequate funding for definitive clinical studies, and patient stratification by specific genetic mutation, given the heterogeneity of the disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Ophthalmic Genetics · 2000 · 111 citations
Mutational analysis and clinical correlation in Leber congenital amaurosis
AbstractUNLABELLED: Leber congenital amaurosis (LCA, MIM 204001) is a clinically and genetically heterogeneous retinal disorder characterized by severe visual loss from birth, nystagmus, poor pupillary reflexes, retinal pigmentary or atrophic changes, and a markedly diminished electroretinogram (ERG). PURPOSE: To examine 100 consecutive patients with LCA in order to assess the relative burden of the three known genes involved in LCA, namely retinal guanylyl cyclase (GUCY2D), retinal pigment epithelium protein ( RPE65), and the cone-rod homeobox (CRX), and to define their clinical correlates. METHODS: Mutational analysis and detailed clinical examinations were performed in patients diagnosed with LCA at the Johns Hopkins Center for Hereditary Eye Diseases and the Montreal Children's Hospital. RESULTS: Mutations were identified in 11% of our patients: GUCY2D mutations accounted for 6%, while RPE65 and CRX gene mutations accounted for 3% and 2%, respectively. The clinical presentation was variable; however, the visual evolution in patients with mutations in GUCY2D and CRX remained stable, while individuals with mutations in the RPE65 gene showed progressive visual loss. CONCLUSIONS: This study suggests that molecular diagnosis of Leber congenital amaurosis could provide important information concerning prognosis and course of treatment.
Long-term Preservation of Cone Photoreceptors and Restoration of Cone Function by Gene Therapy in the Guanylate Cyclase-1 Knockout (GC1KO) Mouse
AbstractPURPOSE: The authors previously showed that subretinal delivery of AAV5 vectors containing murine guanylate cyclase-1 (GC1) cDNA driven by either photoreceptor-specific (hGRK1) or ubiquitous (smCBA) promoters was capable of restoring cone-mediated function and visual behavior and preserving cone photoreceptors in the GC1 knockout (GC1KO) mouse for 3 months. Here, the authors compared therapy conferred by the aforementioned vectors to that achieved with the highly efficient capsid tyrosine mutant AAV8(Y733F) and asked whether long-term therapy is achievable in this model. METHODS: AAV5-hGRK1-mGC1, AAV5-smCBA-mGC1, or AAV8(Y733F)-hGRK1-mGC1 was delivered subretinally to GC1KO mice between postnatal day (P)14 and P25. Retinal function was assayed by electroretinography. Localization of AAV-mediated GC1 expression and cone survival were assayed with immunohistochemistry, and the spread of vector genomes beyond the retina was quantified by PCR of optic nerve and brain tissue. RESULTS: Cone function was restored with all vectors tested, with AAV8(Y733F) being the most efficient. Electroretinographic responses were clearly measurable out to 1 year after treatment. AAV-mediated expression of GC1 was found exclusively in photoreceptors out to 15 months after injection. Cones were preserved for at least 11 months after treatment. AAV5- and AAV8(733)-delivered vector genomes were recovered primarily from optic nerve of the treated eye and, in only instance, from brain (1 of 20 samples). CONCLUSIONS: The authors demonstrate for the first time that long-term therapy (∼1 year) is achievable in a mammalian model of GC1 deficiency. These data provide additional justification for the development of an AAV-based gene therapy vector for the clinical treatment of Leber congenital amaurosis-1.
CRB1-Related Leber Congenital Amaurosis: Reporting Novel Pathogenic Variants and a Brief Review on Mutations Spectrum
AbstractBackground: Leber congenital amaurosis (LCA) is a rare inherited retinal disease causing severe visual impairment in infancy. It has been reported that 9-15% of LCA cases have mutations in CRB1 gene. The complex of CRB1 protein with other associated proteins affects the determination of cell polarity, orientation, and morphogenesis of photoreceptors. Here, we report three novel pathogenic variants in CRB1 gene and then briefly review the types, prevalence, and correlation of reported mutations in CRB1 gene. Methods: Whole exome sequencing and targeted gene panel were employed. Then validation in the patient and segregation analysis in affected and unaffected members was performed. Results: Our detected novel pathogenic variants (p.Glu703*, c.2128+1G>A and p.Ser758SerfsX33) in CRB1 gene were validated by Sanger sequencing. Segregation analysis confirmed the inheritance pattern of the pathogenic variants. Conclusion: Our findings show that emerging the next-generation sequencing-based techniques is very efficient in identifying causative variants in disorders with locus heterogeneity.
Klinische Monatsblätter für Augenheilkunde · 2016 · 7 citations · open access
A Novel Recessive RPGRIP1 Mutation Causing Leber Congenital Amaurosis
AbstractBACKGROUND: Leber congenital amaurosis is an early-onset childhood severe retinal dystrophy, of significant genetic heterogeneity. RPGRIP1 is ubiquitously expressed, but mutations in RPGRIP1 lead to a retina-restricted phenotype, such as Leber congenital amaurosis and cone-rod dystrophy. PATIENT AND METHODS: We analysed a consanguineous family from Egypt in which one individual, a four-year-old girl, was affected with Leber congenital amaurosis. IROme, a proprietary enrichment system for retinal dystrophy genes, was applied and high throughput sequencing was performed. RESULTS: Severe visual impairment was reported during infancy. The fundus of the affected patient exhibited disc pallor and attenuated vessels. Neurodevelopmental delay and brain atrophy in the CT scan were reported. Genomic sequencing identified a novel homozygous deletion, c.[420delG], in RPGRIP1. This mutation was not detected in 80 ethnically matched controls and has not been reported elsewhere. CONCLUSIONS: Identifying new mutations in Leber congenital amaurosis-related genes and their clinical manifestations can improve our understanding of the disease and could help to stratify the population for potential therapies.
Nigerian Journal of Ophthalmology · 2008 · 1 citations · open access
Lebers Amaurosis in Three Siblings: A case report
AbstractThis case report appears to be first reported incident of Lebers congenital amaurosis in three siblings in Kaduna State. Genetic issues, clinical presentation, counselling, treatment and future progression of this irreversible blinding condition are discussed. Keywords: Lebers amaurosis, retinitis pigmentosa, Kaduna, NigeriaNigerian Journal of Ophthalmology Vol. 16 (1) 2008: pp. 26-29
Gaceta Médica de México · 2017 · 1 citations · open access
Amaurosis congénita de Leber RPE-65, seguimiento a 7 años
AbstractLeber congenital amaurosis is a retinal dystrophy with several forms of presentation due to its genetic variability. Case of a female girl followed up from 4 to 11 years old is presented, with positive clinical data of nyctalopia, myopia and choroid ocular fundus. Electroretinogram was not measurable in all phases but diagnostic was confirmed by RPE65 mutation genetic study. RPE65 Leber congenital amaurosis is particularly important as it has been researched for a gene therapy treatment with good functional outcomes up to now, awaiting to offer hope and a better quality of life to people with this disease.
Cambridge University Press eBooks · 2009 · 0 citations
Great Expectations and Hard Times: expectation management in gene transfer
AbstractIn 2001, a report in Nature Genetics raised the possibility that a rare, hereditary form of blindness, Leber's congenital amaurosis (LCA), might soon have a cure. A team of researchers led by Jean Bennett of the University of Pennsylvania's Scheie Eye Institute had successfully restored vision to three dogs with LCA. According to news stories, the report “electrified” families with the disease; said one mother of an LCA child, “we are bursting at the seams.” Word spread like “wildfire,” according to Bennett, who received hundreds of inquiries from expectant parents.
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.
