DeCure for Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 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 moduleProgressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 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 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 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
DNA polymerase gamma 2, accessory subunit (POLG2) — POLG2 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 dcpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8D33 · 2.46 Å · ligand 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE (DCP). Experimental structure, not a prediction.
What the evidence adds up to
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, is a mitochondrial disorder for which the published evidence consists of case series and genetic analyses, not controlled trials. In a 2025 retrospective cohort of 36 chronic progressive external ophthalmoplegia patients (mean age of onset 41.2 years), all had single mtDNA deletions; the common 4977 base-pair deletion was found in 11 patients (30.6%), with higher incidence in those aged 51 or older (36.36%) than in younger patients (18.18%), and the mean age of onset in common-deletion carriers was 27 years. Ptosis affected 56% of that cohort. A separate 2023 series of 8 adult patients with ophthalmologic and muscle disease found multiple mtDNA deletions in muscle in 7 patients and a single deletion in one; heteroplasmy was below 15% for all but one deletion (50–60%), and no nuclear gene variant known to affect mtDNA maintenance was identified.
Earlier work from 1989 and 1990 established that the deletions in these patients are flanked by directly repeated sequences of 13–18 base pairs, with a consensus 11-nucleotide motif resembling recombination signals, and that heteroplasmic mtDNA populations are present before primary cell layers diverge, with no direct maternal transmission of heteroplasmy. A 2023 case report of a 16-year-old female notes that the ptosis and ophthalmoplegia are unresponsive to anticholinergics and that no effective treatment exists, only palliative ptosis surgery. The most common enzyme defect cited is combined deficiency of complexes I and IV.
No drug intervention is tested in any of these abstracts. No therapy is shown to alter the course of the disease. What is missing is any randomised trial, any drug candidate tested in patients, any biomarker that predicts progression, and any stratification by deletion type or heteroplasmy level that might guide future treatment attempts. Funding for natural history studies and for preclinical work on mtDNA maintenance pathways is absent from the record.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Neurology · 1990 · 98 citations
Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies
AbstractBy using a combination of Southern blot hybridization analysis, polymerase-chain reaction amplification, and direct nucleotide sequencing, we studied deletions of mitochondrial DNA (mtDNA) in several nonfamilial patients with progressive external ophthalmoplegia and Kearns-Sayre syndrome, and in some of their direct relatives. Results suggest that the heteroplasmic mtDNA populations are already present at a very early stage of development, and that there is no direct transmission of mtDNA heteroplasmy by maternal inheritance.
Proceedings of the National Academy of Sciences · 1989 · 83 citations · open access
Directly repeated sequences associated with pathogenic mitochondrial DNA deletions.
AbstractWe determined the nucleotide sequences of junctional regions associated with large deletions of mitochondrial DNA found in four unrelated individuals with a phenotype of chronic progressive external ophthalmoplegia. In each patient, the deletion breakpoint occurred within a directly repeated sequence of 13-18 base pairs, present in different regions of the normal mitochondrial genome-separated by 4.5-7.7 kilobases. In two patients, the deletions were identical. When all four repeated sequences are compared, a consensus sequence of 11 nucleotides emerges, similar to putative recombination signals, suggesting the involvement of a recombinational event. Partially deleted and normal mitochondrial DNAs were found in all tissues examined, but in very different proportions, indicating that these mutations originated before the primary cell layers diverged.
Journal of Neuro-Ophthalmology · 2023 · 2 citations
Myopathy and Ophthalmologic Abnormalities in Association With Multiple Skeletal Muscle Mitochondrial DNA Deletions
AbstractBACKGROUND: Establishing a molecular diagnosis of mitochondrial diseases due to pathogenic mitochondrial DNA (mtDNA) variants can be difficult because of varying levels of tissue heteroplasmy, and identifying these variants is important for clinical management. Here, we present clinical and molecular findings in 8 adult patients with classical features of mitochondrial ophthalmologic and/or muscle disease and multiple mtDNA deletions isolated to muscle. METHODS: The patients were identified via a retrospective review of patients seen in both a tertiary ophthalmology center and a genetics clinic with a clinical diagnosis of chronic progressive external ophthalmoplegia, optic nerve abnormalities, and/or mitochondrial myopathy. Age at onset of symptoms ranged from 18 to 61 years. Ocular manifestations included bilateral optic neuropathy in one patient, bilateral optic disc cupping without optic neuropathy in 2 patients, ptosis in 4 patients, and ocular motility deficits in 2 patients. Five patients had generalized weakness. RESULTS: Pathogenic variants in mtDNA were not found in the blood or buccal sample from any patient, but 7 of 8 patients had multiple mtDNA deletions identified in muscle tissue. One patient had a single mtDNA deletion identified in the muscle. Heteroplasmy was less than 15% for all of the identified deletions, with the exception of one deletion that had a heteroplasmy of 50%-60%. None of the patients were found to have a nuclear gene variant known to be associated with mitochondrial DNA maintenance. CONCLUSIONS: mtDNA deletions were identified in adult patients with ophthalmologic and/or musle abnormalities and may underlie their clinical presentations.
Acta Ophthalmologica · 2020 · 1 citations · open access
Strabismus in chronic progressive external ophthalmoplegia
AbstractPURPOSE: To elucidate the patterns of strabismus and ophthalmoplegia associated with chronic progressive external ophthalmoplegia (CPEO) confirmed by mitochondrial DNA (mtDNA) deletions in Asians. METHODS: A total of 10 patients confirmed to have mtDNA deletion associated with CPEO were included. Long-range PCR encompassing the entire mtDNA was carried out. In the cases with mtDNA deletion, the exact deletion ranges of mtDNA were identified by sequencing. A full ophthalmologic examination including prism and alternate cover test in the primary position, evaluation of ductions and versions, and binocularity was performed in 10 patients with confirmed mtDNA deletions associated with CPEO. RESULTS: All of the patients showed ophthalmoplegia as well as ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%) while one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four patients (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and the remaining two patients (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 prism diopters (PD) to 50 PD. CONCLUSIONS: Exotropia with/without vertical deviation is the most common form of strabismus in Asian patients with CPEO and only one of them showed a small angle of esotropia. Ophthalmoplegia could be asymmetric in 10% of CPEO patients.
Indian Journal of Pathology and Microbiology · 2023 · 0 citations · open access
Progressive external ophthalmoplegia – A case report
AbstractProgressive external ophthalmoplegia is a slowly progressive hereditary mitochondrial myopathy. Most mitochondrial disorders overlap clinically, enzymatically, and genetically. The most common enzyme defect is the combined deficit of complexes I and IV. Progressive external ophthalmoplegia particularly affects the extraocular muscles and is characterised by ophthalmoplegia, and bilateral ptosis. The ptosis and ophthalmoplegia is unresponsive to anticholinergics, with no effective treatment, but corrective surgery for ptosis as a palliative one. In this article, we report a rare case of a 16-year-old female with characterstic histological features consistent with progressive external ophthalmoplegia.
Journal of Clinical Medicine · 2025 · 0 citations · open access
Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions
AbstractIntroduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the ‘common’ 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
Digitalen Hochschulbibliothek Sachsen-Anhalt (Universitäts- und Landesbibliothek Sachsen-Anhalt) · 2025 · 0 citations · open access
Clinical ophthalmic outcomes and impact of single large-scale mitochondrial DNA deletions
AbstractIntroduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the ‘common’ 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
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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