DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 9 — 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 9 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 9 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
succinate-CoA ligase GDP/ADP-forming subunit alpha (SUCLG1) — SUCLG1 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 3s,5s,9r,20r,21rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6WCV · 1.52 Å · ligand (3S,5S,9R,20R,21R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9,20,
21-pentahydroxy-8,8-dimethyl-10,14,19-trioxo-2,4,6-trioxa-18-thia-11,15-diaza-3,5-diphosphadocosan-22-oic acid 3,5-dioxide (non-preferred name) (TUY). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial DNA depletion syndrome 9 is one of the inherited mitochondrial diseases of DNA replication. The nuclear gene mutations that cause these syndromes fall into two categories: genes whose products work directly at the mtDNA replication fork (POLG, POLG2, TWINKLE) and genes whose products supply mitochondria with deoxynucleotide triphosphate pools (TK2, DGUOK, TP, SUCLA2, ANT1, and possibly MPV17). The underlying mechanism in many cases is disturbed homeostasis of mitochondrial dNTP pools. The exact mechanism by which nucleoside accumulation causes mtDNA depletion or deletion abnormalities remains unknown.
For mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a related disorder caused by thymidine phosphorylase deficiency, allogeneic hematopoietic stem cell transplantation can restore normal enzyme activity and improve clinical manifestations, but transplant-related complications and disease progression result in a high mortality rate. Dialysis and enzyme replacement therapy only transiently reverse the biochemical imbalance. Adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in a murine model (Tymp -/- Upp1 -/- mice). For mitochondrial DNA depletion and multiple deletions syndromes more broadly, treatment options remain limited. Liver transplantation or allogeneic stem cell transplantation are among the few available options for some forms. Current experimental strategies under investigation range from small molecule substrate enhancement to lentiviral or adeno-associated vector-mediated gene therapy.
Some experimental therapies have reached the clinical phase with very promising results, but these are all rare disorders and patient recruitment for clinical trials is very limited. The development of therapies has been difficult because mitochondrial diseases are heterogeneous, can affect different tissues and organs, and can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. What is still missing is sufficient patient numbers to power clinical trials, adequate funding to develop therapies for each specific genetic defect, and better stratification of patients by the precise nuclear gene mutation causing their mtDNA depletion.
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.
AbstractA revolution in chemical pathology occurred about 40 years ago with the discovery of a patient with mitochondrial dysfunction. The field of mitochondrial medicine has experienced explosive growth during the last decade. More than 50 mtDNA mutations and several nuclear gene mutations have been identified in affected patients. The recent development of animal models will continue the revolution in mitochondrial medicine by facilitating in depth studies of the molecular pathogenesis and development of novel drug and gene therapy strategies for mitochondrial dysfunction. As we enter the next millennium, we can expect mitochondrial medicine to remain a dynamic and rapidly developing field.
Journal of Inherited Metabolic Disease · 2008 · 70 citations
Disorders caused by deficiency of succinate‐CoA ligase
AbstractSuccinate-CoA ligase catalyses the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP. It is a mitochondrial matrix enzyme and at least the ADP-forming enzyme is part of the Krebs cycle. The substrate specificity is determined by the beta subunit of succinate-CoA ligase, which is encoded by either SUCLA2 or SUCLG2. In patients with severe hypotonia, deafness and Leigh-like syndrome, mutations have been found in SUCLA2. Mutations have also been reported in SUCLG1, which encodes the alpha subunit found in both enzymes, in patients with severe infantile acidosis and lactic aciduria. Elevated methylmalonate and methylcitrate and severe mtDNA depletion were found in both disorders. The mtDNA depletion may be explained by the interaction of succinate-CoA ligase with nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide metabolism.
Frontiers in Cellular Neuroscience · 2017 · 52 citations · open access
Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options
AbstractMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp -/-Upp1 -/-mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.
Deoxyribonucleotides and Disorders of Mitochondrial DNA Integrity
AbstractMitochondrial DNA (mtDNA) depends on numerous nuclear encoded factors and a constant supply of deoxyribonucleoside triphosphates (dNTP), for its maintenance and replication. The function of proteins involved in nucleotide metabolism is perturbed in a heterogeneous group of disorders associated with depletion, multiple deletions, and mutations of the mitochondrial genome. Disturbed homeostasis of the mitochondrial dNTP pools are likely the underlying cause. Understanding of the biochemical and molecular basis of these disorders will promote the development of new therapeutic approaches. This article reviews the current knowledge of deoxyribonucleotide metabolism in relation to disorders affecting mtDNA integrity.
Developmental Disabilities Research Reviews · 2010 · 39 citations
Emerging therapeutic approaches to mitochondrial diseases
AbstractMitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to the therapy of mitochondrial disorders, some of which are targeted to specific conditions whereas others may be applicable to a more diverse group of patients.
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.
Deoxyribonucleotides and Disorders of Mitochondrial DNA Integrity
AbstractMitochondrial DNA (mtDNA) depends on numerous nuclear encoded factors and a constant supply of deoxyribonucleoside triphosphates (dNTP), for its maintenance and replication. The function of proteins involved in nucleotide metabolism is perturbed in a heterogeneous group of disorders associated with depletion, multiple deletions, and mutations of the mitochondrial genome. Disturbed homeostasis of the mitochondrial dNTP pools are likely the underlying cause. Understanding of the biochemical and molecular basis of these disorders will promote the development of new therapeutic approaches. This article reviews the current knowledge of deoxyribonucleotide metabolism in relation to disorders affecting mtDNA integrity.
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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