DeCure for Mitochondrial dna depletion syndrome 21
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial dna depletion syndrome 21 — 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 depletion syndrome 21 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 depletion syndrome 21 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
guanylate kinase 1 (GUK1) — GUK1 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 5gpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9JAC · 1.47 Å · ligand GUANOSINE-5'-MONOPHOSPHATE (5GP). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial DNA depletion syndrome 21 is one of a group of autosomal recessive disorders in which affected tissues show profoundly decreased mitochondrial DNA copy numbers. A 2008 review of 32 patients with mitochondrial DNA depletion syndromes identified eight associated genes — TK2, RRM2B, SUCLA2, SUCLG1, PEO1, POLG1, DGUOK and MPV17 — and reported that five of those patients carried previously unreported mutations in one of those eight genes. A 2011 methods paper listed nine genes — POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B and C10orf2 — in which mutations had been reported to cause various forms of mitochondrial DNA depletion syndromes.
No abstract in this set describes a drug treatment specifically tested in patients with mitochondrial DNA depletion syndrome 21. A 2010 review of mitochondrially targeted therapeutics for neurodegenerative disease stated that the drugs that had reached clinical trials had produced encouraging but largely inconclusive results. A 2014 review of mitochondrial disease generally stated that there is no cure, that treatment goals are slowing progression and maximising quality of life, and that effective care includes energy management, nutritional support, physical therapy and emotional support.
A 2022 compassionate-use study treated six patients with single large-scale mitochondrial DNA deletion syndromes — a different group of disorders from the depletion syndromes — using mitochondrial augmentation therapy, in which autologous CD34+ haematopoietic cells were enriched with maternally derived healthy mitochondria. The procedure was well tolerated; all study-related severe adverse events were linked to leukapheresis or the baseline disorder. After treatment, heteroplasmy decreased in peripheral blood in four of six patients, and mtDNA content in peripheral blood cells increased in all six patients at 6 to 12 months compared with baseline. Some clinical improvement in aerobic function was noted in two patients, and body weight increased in five of six patients who had very low body weight before treatment. Quality-of-life measures and physical examination showed improvement in some parameters. A 2018 review of mitochondrial replacement therapy noted that despite supporting safety and efficacy data, social and legal barriers remain to its clinical use.
What is still missing for mitochondrial DNA depletion syndrome 21 specifically: no drug has been tested in a controlled trial for this exact disorder; no abstract reports a patient cohort with the syndrome 21 genotype; no data exist on whether any existing compound alters mtDNA copy number in these patients; and the heterogeneity of mitochondrial diseases means that results from other syndromes — such as the single large-scale deletion syndromes — cannot be assumed to apply. A dedicated trial would require patient stratification by the specific nuclear gene mutated, a validated biomarker for mtDNA content in the relevant tissue, and funding for a disease that affects a very small number of individuals.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2008 · 187 citations
Clinical and molecular features of mitochondrial DNA depletion syndromes
AbstractMitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-gammaA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype-phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.
Methods in molecular biology · 2011 · 152 citations
Measurement of Mitochondrial DNA Copy Number
AbstractMitochondrial disorders are complex and heterogeneous diseases that may be caused by molecular defects in either the nuclear or mitochondrial genome. The biosynthesis and maintenance of the integrity of the mitochondrial genome is solely dependent on a number of nuclear proteins. Defects in these nuclear genes can lead to mitochondrial DNA (mtDNA) depletion (Spinazzola et al. Biosci Rep 27:39-51, 2007). The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a significant reduction in mtDNA content. These genes include POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B, and C10orf2, all nine genes have mutations reported to cause various forms of MDDSs. In this chapter, we outline the real-time quantitative polymerase chain reaction (qPCR) analysis of mtDNA content in muscle or liver tissues.
Expert Opinion on Therapeutic Targets · 2010 · 82 citations
Targeting mitochondrial dysfunction in neurodegenerative disease: Part II
AbstractIMPORTANCE OF THE FIELD: With improvements in life expectancy over the past decades, the incidence of neurodegenerative disease has dramatically increased and new therapeutic strategies are urgently needed. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders. AREAS COVERED IN THIS REVIEW: This review examines the role of mitochondrial dysfunction in neurodegeneration, drawing examples from common diseases such as Alzheimer's disease and rarer familial disorders such as Charcot-Marie-Tooth. The review is provided in two parts. In part I we discussed the mitochondrial defects which have been most extensively researched (oxidative stress, bioenergetic dysfunction, calcium mishandling). We focus now on those defects which have more recently been implicated in neurodegeneration; in mitochondrial fusion/fission, protein import, protein quality control, kinase signalling and opening of the permeability transition pore. WHAT THE READER WILL GAIN: An examination of mitochondrial defects observed in neurodegeneration, and existing and possible future therapies to target these defects. TAKE HOME MESSAGE: The mitochondrially-targeted therapeutics that have reached clinical trials so far have produced encouraging but largely inconclusive results. Increasing understanding of mitochondrial dysfunction has, however, led to preclinical work focusing on novel approaches, which has generated exciting preliminary data.
Science Translational Medicine · 2022 · 72 citations
Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes
AbstractPatients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34 + hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.
Understanding mitochondrial disease and goals for its treatment
AbstractMitochondrial disease is a progressive, debilitating, incurable illness that results from mutation of genes that regulate mitochondrial function. The disease can manifest in utero or at birth, during childhood, or have a delayed onset in adulthood. Mitochondrial disease can be transmitted as a genetically carried mutation or develop as a spontaneous genetic mutation later in life. As a multisystem disease with a highly variable clinical presentation, mitochondrial disease can present as 'any disease with any symptoms at any age'. Consequently, all patients with progressive, unexplained multisystem illness should be evaluated for mitochondrial disease. Treatment goals include slowing of disease progression and maximising quality of life. There is no cure for this illness. Effective interdisciplinary care includes energy management, nutritional support, physical therapy and emotional support for the patient and their family.
Current Opinion in Obstetrics & Gynecology · 2018 · 8 citations
Mitochondrial replacement therapy
AbstractPURPOSE OF REVIEW: The present study briefly reviews the history of mitochondrial replacement therapy (MRT); however, the focus is on recent advancements and future directions of the field. Specifically addressing societal and legal concerns and advances in MRT. RECENT FINDINGS: There continue to be new ethical debates surrounding MRT. In addition, there have been advancements in MRT techniques which could improve potential outcomes. Furthermore, advances in genetics continue to provide alternative approaches to treatment of many diseases, including alternatives to MRT. SUMMARY: MRT may be beneficial to eradicate a severely debilitating and often fatal disease. Despite significant supporting safety and efficacy, there are still many social and legal barriers to instituting MRT to clinical practice.
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.
