DeCure for Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 3 (hepatocerebral type) — 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 3 (hepatocerebral type) 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 3 (hepatocerebral type) 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
deoxyguanosine kinase (DGUOK) — DGUOK 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 dtpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2OCP · 2.8 Å · ligand 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE (DTP). Experimental structure, not a prediction.
What the evidence adds up to
Mutations in the nuclear gene DGUOK, which encodes deoxyguanosine kinase, cause an infantile hepatocerebral type of mitochondrial depletion syndrome. In a 2018 report of six Austrian patients with bi-allelic DGUOK mutations, three of the mutations were novel, including a large intragenic founder deletion. One patient was diagnosed with hepatocellular carcinoma at six months of age, and liver transplantation in that case proved beneficial for both tumour treatment and psychomotor development. The underlying problem is that mitochondrial DNA depends on a constant supply of deoxyribonucleoside triphosphates for its maintenance and replication; disturbed homeostasis of these pools is thought to be the cause of the depletion.
All known nuclear genes that produce mtDNA alterations and cause mitochondrial depletion syndrome fall into two categories: those whose products function directly at the mtDNA replication fork (POLG, POLG2, TWINKLE) and those whose products supply mitochondria with deoxynucleotide triphosphate pools (TK2, DGUOK, TP, SUCLA2, ANT1, and possibly MPV17). The syndrome is a heterogeneous group of progressive disorders characterised by low mtDNA copy number. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial disease. A 1999 review noted that as understanding of mitochondrial pathology increased, attention had begun to shift to possibilities for treating mitochondrially based disorders, but that review predates any specific clinical trial data for DGUOK deficiency.
No drug treatment is described in these abstracts for DGUOK-related mitochondrial depletion syndrome. The only intervention reported is liver transplantation in a single patient with hepatocellular carcinoma. What is still missing is any clinical trial of a pharmacological agent, any attempt to stratify patients by residual enzyme activity or mutation type, and the funding to move from biochemical understanding to a tested therapy.
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 Pediatric Gastroenterology and Nutrition · 2018 · 15 citations
Severe Deoxyguanosine Kinase Deficiency in Austria
AbstractMutations in the nuclear gene DGUOK, encoding deoxyguanosine kinase, cause an infantile hepatocerebral type of mitochondrial depletion syndrome (MDS). We report 6 MDS patients harboring bi-allelic DGUOK mutations, of which 3 are novel, including a large intragenic Austrian founder deletion. One patient was diagnosed with hepatocellular carcinoma aged 6 months, supporting a link between mitochondrial DNA depletion and tumorigenesis; liver transplantation proved beneficial with regard to both tumor treatment and psychomotor development.
BMC Medical Genetics · 2019 · 14 citations · open access
Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series
AbstractBACKGROUND: Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. CASE PRESENTATION: In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706-707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)). CONCLUSIONS: These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.
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.
Entrevista a Juan José Azcárate, Consejero delegado de Centro para la Cultura y el Conocimiento(CCC)
AbstractMitochondria is a ubiquitous, energy-supplying (ATP-based) organelle found in nearly all eukaryotes. It acts as a "power plant" by producing ATP through oxidative phosphorylation, providing energy for the cell. The bioenergetic functions of mitochondria are regulated by nuclear genes (nDNA). Mitochondrial DNA (mtDNA) and respiratory enzymes lose normal structure and function when nuclear genes encoding the related mitochondrial factors are impaired, resulting in deficiency in energy production. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial diseases. The mitochondrial depletion syndrome (MDS) is associated with the mutations of mitochondrial genes in the nucleus. It is a heterogeneous group of progressive disorders characterized by the low mtDNA copy number. <i>TK2, FBXL4, TYPM</i>, and <i>AGK</i> are genes known to be related to MDS. More recent studies identified new mutation loci associated with this disease. Herein, we first summarize the structure and function of mitochondria, and then discuss the characteristics of various types of MDS and its association with cardiac diseases.
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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