DeCure for Mitochondrial DNA depletion syndrome 19
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 19 — 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 19 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 19 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
Mitochondrial DNA depletion syndrome 19 is one of the mitochondrial DNA depletion and multiple deletions syndromes, a group defined by dysfunctional mtDNA replication and maintenance. As of 2021, treatment options for these disorders were described as rather limited. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation were among the few available options for some forms of the syndrome. A 2014 review stated that mitochondrial disease is a progressive, debilitating, incurable illness, that there is no cure, and that treatment goals are limited to slowing disease progression and maximising quality of life through energy management, nutritional support, physical therapy and emotional support.
Experimental strategies under investigation by 2021 included small molecule substrate enhancement approaches and more complex treatments such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies had reached the clinical phase with very promising results, but the review noted that patient recruitment for clinical trials is very limited because these are all rare disorders. A 2008 review of mitochondrial gene therapy concluded that no effective therapeutic approach had a clear consensus, that current treatment strategies were largely supportive rather than curative, and that a successful therapeutic mitochondrial gene therapy strategy had not come to fruition. That review emphasised the potential hurdles that must be acknowledged and overcome.
The nuclear genes known to cause mtDNA depletion syndromes fall into two categories: genes whose products function directly at the mtDNA replication fork (POLG, POLG2, TWINKLE) and genes whose products supply deoxynucleotide triphosphate pools (TK2, DGUOK, TP, SUCLA2, ANT1, MPV17). A 2008 study of 32 MDS patients aimed to define mutation frequency and genotype-phenotype correlations, and five of those patients carried previously unreported mutations in one of the eight known MDS genes. The clinical presentations are myopathic, encephalomyopathic and hepatocerebral, with the hepatocerebral form linked to mutations in Twinkle, POLG1, DGUOK and MPV17.
What is still missing is the patient recruitment potential for clinical trials, which is very limited because these are all rare disorders. The genotype-phenotype relationships among mtDNA disorders remain poorly defined, with an identical mutation capable of producing multiple phenotypes or the same phenotype produced by different mutations. No defined therapeutic molecule has been successfully delivered to mitochondria in patients, and the hurdles for gene therapy have not been overcome.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annual Review of Medicine · 2007 · 280 citations · open access
Inherited Mitochondrial Diseases of DNA Replication
AbstractMitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.
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.
Human Molecular Genetics · 2013 · 81 citations · open access
Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome
AbstractMitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the dN or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.
International Journal of Molecular Sciences · 2021 · 28 citations · open access
Therapy Prospects for Mitochondrial DNA Maintenance Disorders
AbstractMitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.
Mitochondrial Gene Therapy: An Evaluation of Strategies for the Treatment of Mitochondrial DNA Disorders
AbstractMitochondrial DNA (mtDNA) disorders include a vast range of pathological conditions, despite each sharing a mutual inability to produce ATP efficiently as a result of defective oxidative phosphorylation. There is no clear consensus regarding an effective therapeutic approach, and consequently the current treatment strategies are largely supportive rather than curative. This is almost certainly the result of there being virtually no defined genotype-phenotype relationships among the mtDNA disorders; hence an identical mutation may be responsible for multiple phenotypes, or the same phenotype may be produced by different mutations. In light of this, the development of gene therapy to treat mtDNA disorders offers a promising approach, as it potentially circumvents the complication of the aforementioned genotype-phenotype inconsistency and ultimately the current inability to treat individual disorders with sufficient efficacy. Such an approach will ultimately require the combination of efficient mitochondrial targeting, and an effective therapeutic molecule. Although promising proof-of-principle developments in this field have been demonstrated, the realization of a successful therapeutic mitochondrial gene therapy strategy has not come to fruition. This review critiques the key approaches under development by discussing the theory underlying each strategy, and detailing the current progress made. We also emphasize the potential hurdles that must be acknowledged and overcome if the potential of a therapeutic gene therapy to treat mitochondrial DNA disorders is to be realized.
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.
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.
