DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Leber congenital amaurosis 4 — 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 moduleLeber congenital amaurosis 4 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 leber congenital amaurosis 4 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
AIP like 1 HSP90 co-chaperone (AIPL1) — AIPL1 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…
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RCSB Protein Data Bank · entry 5U9J · 2.1 Å · ligand GERAN-8-YL GERAN (GER). Experimental structure, not a prediction.
What the evidence adds up to
In a 2000 study of 100 consecutive Leber congenital amaurosis patients, mutations were identified in only 11%: GUCY2D in 6%, RPE65 in 3%, and CRX in 2%. Visual evolution in patients with GUCY2D and CRX mutations remained stable, while those with RPE65 mutations showed progressive visual loss. The authors concluded that molecular diagnosis could provide information on prognosis and course of treatment, but the vast majority of patients in that cohort had no identifiable mutation in the three known genes.
A 2011 study in the GC1 knockout mouse, a model of GUCY2D deficiency (LCA1), delivered AAV vectors containing murine guanylate cyclase-1 cDNA subretinally between postnatal day 14 and 25. Cone function was restored with all vectors tested, with AAV8(Y733F) being the most efficient. Electroretinographic responses were measurable out to one year after treatment, and cones were preserved for at least 11 months. Vector genomes were recovered primarily from optic nerve of the treated eye and from brain in only one of 20 samples. The authors stated this was the first demonstration of long-term therapy (about one year) in a mammalian model of GC1 deficiency.
A 2017 case report described a single female patient with RPE65-confirmed Leber congenital amaurosis followed from age 4 to 11. The electroretinogram was not measurable in all phases. The report noted that gene therapy for RPE65 LCA had been researched with good functional outcomes up to that point, but presented no new data from the patient.
A 2009 commentary on expectation management in gene transfer recalled that a 2001 report of restored vision in three dogs with LCA had electrified families and generated hundreds of inquiries from expectant parents. The commentary did not report any new trial results. What remains missing is evidence from adequately powered human trials that can confirm durable visual improvement, and a clear understanding of which genetic subtypes and patient ages are most likely to benefit.
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.
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.
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