DeCure for Mitochondrial DNA deletion syndrome with progressive myopathy
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA deletion syndrome with progressive myopathy — 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 moduleMitochondrial DNA deletion syndrome with progressive myopathy 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 mitochondrial dna deletion syndrome with progressive myopathy 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
Three adult patients with TK2 mutations presented with slowly progressive myopathy compatible with a fairly normal life over decades. Their residual muscle mitochondrial DNA content was higher than in paediatric cases, but this difference was not explained by the type of TK2 mutation or by the residual TK2 enzyme activity. The phenotype otherwise closely resembled paediatric cases: early onset, absence of central nervous system symptoms, generalised muscle weakness predominating in axial and proximal muscles but affecting facial, ocular and respiratory muscles, a mosaic pattern of COX-negative and ragged-red fibres, combined mitochondrial DNA-dependent respiratory complex deficiencies, and mitochondrial DNA depletion.
Seven further adult cases presented with a mild myopathy compatible with a relatively normal life for decades and were associated with multiple mitochondrial DNA deletions and no marked depletion in skeletal muscle. TK2 activity was drastically reduced in cultured fibroblasts of two of these patients. The authors suggest that redundant or complementary biochemical mechanisms could bypass the defect in some individuals, in contrast with severely affected infantile patients. No treatment was tested in either study.
What is still missing is any clinical trial of a drug in this adult population, any understanding of why some patients with very low TK2 activity have mild disease while others with similar mutations die in infancy, and any funding or trial design that stratifies patients by residual mitochondrial DNA content or compensatory pathway activity.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2012 · 53 citations
Adult cases of mitochondrial DNA depletion due to <i>TK2</i> defect
AbstractOBJECTIVE: In this study we aim to demonstrate the occurrence of adult forms of TK2 mutations causing progressive mitochondrial myopathy with significant muscle mitochondrial DNA (mtDNA) depletion. METHODS: Patients' investigations included serum creatine kinase, blood lactate, electromyographic, echocardiographic, and functional respiratory analyses as well as TK2 gene sequencing and TK2 activity measurement. Mitochondrial activities and mtDNA were analyzed in the patients' muscle biopsy. RESULTS: The 3 adult patients with TK2 mutations presented with slowly progressive myopathy compatible with a fairly normal life during decades. Apart from its much slower progression, these patients' phenotype closely resembled that of pediatric cases including early onset, absence of CNS symptoms, generalized muscle weakness predominating on axial and proximal muscles but affecting facial, ocular, and respiratory muscles, typical mitochondrial myopathy with a mosaic pattern of COX-negative and ragged-red fibers, combined mtDNA-dependent respiratory complexes deficiency and mtDNA depletion. In accordance with the disease's relatively slow progression, the residual mtDNA content was higher than that observed in pediatric cases. That difference was not explained by the type of the TK2 mutations or by the residual TK2 activity. CONCLUSION: TK2 mutations can cause mitochondrial myopathy with a slow progression. Comparison of patients with similar mutations but different disease progression might address potential mechanisms of mtDNA maintenance modulation.
Severe TK2 enzyme activity deficiency in patients with mild forms of myopathy
AbstractThymidine kinase 2 (TK2) is a mitochondrial enzyme participating in the salvage of deoxyribonucleotides needed for mitochondrial DNA (mtDNA) replication. TK2 catalyzes the first and rate-limiting step of the deoxypyrimidine salvage pathway. Mutations in TK2 were typically associated with a severe myopathic form of mtDNA depletion syndrome (MDS) characterized by a dramatic decrease in mtDNA copy number in muscle that manifests during infancy and leads to the early death of most patients.1 Recently, several patients have been diagnosed with a late-onset or slow-progressing form of the disease manifesting as a milder myopathy with mtDNA multiple deletions.2–5 Here we describe 7 adult cases presenting with a mild myopathy compatible with a relatively normal life for decades and associated with multiple mtDNA deletions and no marked depletion in skeletal muscle. TK2 activity was drastically reduced in cultured fibroblasts of 2 of these patients, suggesting that redundant or complementary biochemical mechanisms could bypass the defect in some individuals, in contrast with severely affected infantile patients. Acknowledgment: The authors thank Michael Terry for English language assistance and Laura Rufian and Sara Jiménez for technical support.
AbstractOne of the great challenges in molecular biology is to understand the mechanisms by which a particular genetic defect gives rise to the disease or diseases associated with it. Mitochondrial myopathies are no exception. This review emphasizes some of the important mechanisms that can modify the phenotypic expression of the genetic disorders seen in mitochondrial myopathies.
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.
