DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Leber congenital amaurosis 3 — screening already-approved drugs against its 1-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 3 maps to a 1-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 3 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.
What the evidence adds up to
In a mouse model of guanylate cyclase-1 deficiency (GC1KO), which corresponds to LCA1, subretinal delivery of AAV vectors carrying murine GC1 cDNA restored cone function and preserved cone photoreceptors for at least 11 months. Electroretinographic responses were measurable out to one year after treatment. The AAV8(Y733F) capsid mutant was the most efficient vector tested. AAV-mediated GC1 expression was found exclusively in photoreceptors up to 15 months after injection. Vector genomes were recovered primarily from optic nerve of the treated eye, and from brain in only one of 20 samples. These data come from a 2011 study and represent the first demonstration of long-term therapy in a mammalian model of GC1 deficiency.
A 2010 re-examination of Leber’s original papers concluded that what Leber described as congenital amaurosis is roughly the same as what is now known as neuronal ceroid lipofuscinosis, and that the present diagnosis of Leber congenital amaurosis is not a clinical syndrome but an aspecific symptom complex. A 1968 report described a family in which Leber congenital amaurosis coexisted with the cutaneous form of Ehlers-Danlos syndrome, both following an autosomal recessive inheritance pattern. A 2008 case report from Kaduna State, Nigeria, described three siblings with Leber congenital amaurosis and discussed the irreversible nature of the condition.
Genetic heterogeneity is substantial. A 2019 study reported three novel pathogenic variants in the CRB1 gene, which accounts for 9-15% of LCA cases. A 2016 study identified a novel homozygous deletion in RPGRIP1 in a consanguineous Egyptian family, with the affected child showing severe visual impairment, neurodevelopmental delay, and brain atrophy on CT scan. The mutation was not detected in 80 ethnically matched controls. A 2009 commentary noted that after a 2001 report of restored vision in three dogs with LCA, news spread rapidly among families, generating intense expectations that a cure was imminent.
What is still missing are completed human trials for most genetic subtypes, long-term safety data in patients, and a clear understanding of which patients might benefit from gene therapy given the disease’s genetic and clinical heterogeneity. Stratification by specific mutation and residual photoreceptor structure remains a prerequisite that is not yet met for most forms of LCA.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
Leber's Congenital Amaurosis as Conceived by Leber
AbstractNot being satisfied with the present-day diagnosis of Leber's congenital amaurosis, the original papers written by Leber were studied. It gradually became clear that what Leber had in mind with congenital amaurosis is roughly the same as what we know as neuronal ceroid lipofuscinosis. The present diagnosis of Leber's congenital amaurosis is not a clinical syndrome but an aspecific symptom complex.
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.
Leber's Congenital Amaurosis With an Ehlers-Danlos-like Syndrome
AbstractA report is given of a family in which Leber's congenital amaurosis is coexistent with the cutaneous form of the Ehlers-Danlos syndrome. The former is quite rare and the latter probably more common than known. Both disorders appear to follow an autosomal, recessive inheritance pattern. The characteristics, brief review of the literature, and postulated pathogenesis are presented. To our knowledge this paper represents the first example of the coexistence of Leber's congenital amaurosis and an Ehlers-Danlos-like syndrome.
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
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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