DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for cone dystrophy 3 — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCone dystrophy 3 maps to a 4-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
approvedVardenafilApproved drug
Structures already discussed alongside cone dystrophy 3 in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Catalytic Domain Of Human Phosphodiesterase 5A — Vardenafil has a real, experimentally solved structure in complex with this target (PDB 1XP0, 1.79 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet vdndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1XP0 · 1.79 Å · ligand Vardenafil (VDN). Experimental structure, not a prediction.
What the evidence adds up to
In a 1993 prospective study of 33 patients with cone-rod dystrophy from 25 families, plus a retrospective review of 150 additional patients, electroretinography distinguished two major types. In type 1, cone amplitudes were reduced more than rod amplitudes; in type 2, cone and rod amplitudes were reduced in equal proportion. Each type was further divided into two subtypes based on visual field loss and threshold profiles. Among the 95 retrospective patients with sufficient data, all but two fit one of these four subtypes. The study did not test any drug.
A 2005 immunohistochemical study examined donor eyes from one affected member of a family with autosomal dominant cone dystrophy. Three years before death, the patient’s electroretinogram showed normal rod function but a cone b-wave amplitude reduced 40% below the lower limit of normal. Fundus exam showed only isolated drusen within the macula. In the affected retina, red/green cone opsins were distributed along the entire plasma membrane of cones, from the outer segment tip to the synaptic base, rather than being restricted to the outer segments. Blue cone opsin remained confined to outer segments. Rhodopsin staining appeared normal. Cone pedicles appeared larger than normal. This is a single-case descriptive finding, not a therapeutic trial.
Two other abstracts discuss myotonic dystrophy and Duchenne muscular dystrophy, not cone dystrophy. One from 2000 describes a mouse model of myotonic dystrophy; the other from 2016 reviews downstream pharmacological targets for Duchenne muscular dystrophy, noting that for 30 years only corticosteroids have been available and that no cure exists. Neither abstract reports any drug tested in cone dystrophy.
No drug has been tested in any clinical trial for cone dystrophy 3 in these abstracts. The available literature describes phenotypic subtypes and a single postmortem finding of mislocalised cone opsins. What is missing is any funded clinical trial, any drug candidate tested in patients, and any understanding of whether the opsin mislocalisation is a druggable target or a secondary effect. Patient stratification by electroretinographic subtype exists but has not been linked to any therapeutic strategy.
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 · 1993 · 87 citations
Clinical Subtypes of Cone-Rod Dystrophy
AbstractOBJECTIVE: To determine possible distinct phenotypic subtypes of cone-rod dystrophy. PATIENTS: Thirty-three patients with cone-rod dystrophy (from 25 families) were assessed prospectively on electroretinography, visual field testing, psychophysical threshold profiles, and fundus features. The clinical records of an additional 150 patients with cone-rod dystrophy were examined retrospectively in terms of the classification schema derived from the prospective study. RESULTS: Based on electroretinographic recordings, two major types of cone-rod dystrophy were differentiated. In type 1, cone amplitudes were reduced to a greater degree than were rod amplitudes on electroretinography, while in type 2, cone and rod electroretinographic amplitudes were reduced in equal proportion. These two types were further subdivided on the basis of patterns of visual field loss and threshold elevation. In type 1a, there was a central or paracentral scotoma, and cone thresholds were more elevated centrally than peripherally. In type 1b, there was no central scotoma, and cone thresholds were more elevated peripherally than centrally. In type 2a, there was a central scotoma, cone thresholds were more elevated centrally than peripherally, and rod thresholds were more elevated peripherally than centrally. In type 2b, a partial or complete ring scotoma was present, cone thresholds were more elevated peripherally than centrally, and rod thresholds were more elevated in the midperipheral than in either the central or far peripheral region of the retina. Of the 150 additional patients with cone-rod dystrophy, data sufficient for classification were available for 95 patients, and all but two had findings that were consistent with classification into one of these four subtypes. CONCLUSION: Our results identify four functionally distinct subtypes of cone-rod dystrophy that may be useful for patient counseling and future molecular genetic studies.
AbstractTriplet repeat diseases are disorders in which there is expansion of a repeat sequence of three nucleotides in the affected gene. Although the pathology usually results from production of a defective protein, myotonic dystrophy (DM) has proved to be a puzzle because the expanded repeats appear in a non-coding region of the affected DMPK gene. In a Perspective, Tapscott explains how findings from a new mouse model of DM (Mankodi et al.) could solve this paradox.
Expert Opinion on Orphan Drugs · 2016 · 42 citations
Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy
AbstractINTRODUCTION: Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. AREAS COVERED: In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. EXPERT OPINION: For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.
Abnormal Distribution of Red/Green Cone Opsins in a Patient with an Autosomal Dominant Cone Dystrophy
AbstractPURPOSE: To define the distribution of the red/green and blue opsins in cones from donor eyes from an affected member of a clinically well-characterized family with an autosomal dominant form of cone dystrophy. METHODS: Tissue was fixed and processed for immunohistochemistry. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin, and cone opsins. The cone-associated matrix was also labeled with the lectin PNA. The affected donor eyes were compared to a postmortem matched normal eye. RESULTS: Electroretinogram (ERG) testing three years prior to the affected member's death showed normal rod function, while the cone b-wave amplitude was reduced 40% below the lower limit of normal. Fundus exam showed only isolated drusen within the macula. Either a normal-appearing or only nonspecific macular findings were noted in the other affected family members who were examined. Immunofluorescence studies showed that blue cone opsin was restricted to the outer segments of blue cones in the affected retina. Red/green opsins were distributed along the entire plasma membrane of these cone types, from the tip of the outer segment to the synaptic base. Cone-associated matrix displayed a heterogeneous distribution. These patterns were observed both in the macula and in the periphery of the affected retina. Cone pedicles appeared larger than normal. In contrast, rhodopsin staining appeared normal. CONCLUSIONS: The immunocytochemical data obtained suggest that the clinical manifestation of this dystrophy is associated with an abnormal distribution of cone red/green opsins. Additionally, changes in the cone pedicles could have contributed to the abnormal cone ERG in this patient.
International braz j urol · 2015 · 0 citations · open access
Is There a Space to Improve the Treatment of Erectile Dysfunction in the Next Years? Opinion: Yes
AbstractPrior to the US approval of sildenafil in 1998, the available treatment options for erectile dyfunction (ED) included: intraurethral alprostadil (MUSE), intracavernosal injections (tri mix, alprostadil), vacuum pump therapy, placement of a penile prosthesis, hormone replacement therapy and individual or couples psychotherapy (1-7). The appro-val of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), dramatically changed the treatment and research landscape. By utilizing sildenafil millions of men with ED could reliably and safely restore their erectile function. In addition to sildenafil, three other PDE5i medications have been approved in the US for the treatment of ED; they are: ta-dalafil (daily and as needed), vardenafil and avanafil. While the PDE5i medications are successful in restoring erectile function in the majority of men, they are not as effective in men whose cavernous nerve has been damaged from a radical prostatectomy or in men with diabetes mellitus. Additionally, some men may not respond to PDE5i’s because their vascular disease is too severe, they take concomitant medications that interfere with ED restoration, or they harbor severe psychological and/or interpersonal issues that overwhelm the prosexual effect of the drug. For men who utilize nitrate medications, PDE5i’s are contraindicated because of their synergistic hypotensive effects, therefore these men must find other treatment op-tions. For all the above reasons clinicians would welcome new agents that could overco-me the limitations of the current PDE5i drugs. I am certain that we will see new and better options for men suffering from ED. The introduction of the PDE5i’s drugs revolutionized the manner in which we currently treat ED patients and opened the pathway for further research into the biological under-pinnings of ED. One important limitation of the PED5i’s is that they only provide short--term solutions to the chronic vascular issues that cause the ED. Treatments that would cure or reverse the underlying precipitating and maintaining factors would move us beyond the current standard of care. Stem cell therapy is an exciting new treatment option that in theory offers the potential to reverse the underlying causes of ED and reduce patient reliance on the tran-
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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