DeCure for Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 15 (hepatocerebral type) — screening already-approved drugs against its 2-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 15 (hepatocerebral type) maps to a 2-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 15 (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
transcription factor A, mitochondrial (TFAM) — TFAM 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 +drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6HC3 · 3.1 Å · ligand L(+)-TARTARIC ACID (TLA). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) is caused by mutations in nuclear genes that maintain mitochondrial DNA copy number. In a Japanese cohort of 23 hepatocerebral MTDPS patients identified among 999 mitochondrial disease patients between 2007 and 2019, the most common genetic cause was MPV17 (13 patients), followed by DGUOK (4 patients), with single cases of POLG, MICOS13, and TWNK. Eight MPV17-deficient patients carried the c.451dupC mutation and all four DGUOK-deficient patients carried a founder deletion c.143-307_170del335. The most frequent initial symptom was failure to thrive (56.5%) and the most common liver symptom was cholestasis (91.3%). An Austrian report of six DGUOK patients described three novel mutations including a large intragenic founder deletion; one patient was diagnosed with hepatocellular carcinoma at six months of age, and liver transplantation was reported as beneficial for both tumour treatment and psychomotor development in that case.
Liver transplantation outcomes in the Japanese cohort were not favourable. Of 11 transplanted patients (eight MPV17-deficient, two DGUOK-deficient), only four survived, while seven who had marked neurological symptoms before transplantation died. The four survivors included patients with MPV17 mutations c.149G>A or c.293C>T, which were associated with milder phenotypes and only mild intellectual disability. The authors concluded that patients with these specific MPV17 mutations and no severe pre-transplant neurological involvement had moderately better outcomes, but overall the prognosis after transplantation remained poor. A histopathological study of liver tissue from 13 children who died from hepatocerebral MDS (with confirmed DGUOK, MPV17, or POLG mutations) found a moderately reproducible pattern of parenchymal damage that might aid differential diagnosis in families with early-onset acute liver failure and encephalopathy.
Experimental therapies for mitochondrial DNA maintenance disorders are under investigation, including small molecule substrate enhancement, lentiviral and adeno-associated vector gene therapy, and some have reached clinical testing with what the authors describe as very promising results. However, these are all rare disorders, and patient recruitment for clinical trials is severely limited. What remains missing is sufficient funding and infrastructure to conduct adequately powered trials, the ability to stratify patients by specific genotype and neurological status before treatment, and any proven therapy that consistently alters the course of the disease beyond the modest, genotype-restricted benefit seen with liver transplantation.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
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.
Polish Journal of Pathology · 2018 · 6 citations · open access
Histopathological liver findings in patients with hepatocerebral mitochondrial depletion syndrome with defined molecular basis
AbstractMitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of <i>DGUOK</i>, <i>MPV17</i>, and <i>POLG </i>genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy.
Research Square · 2020 · 3 citations · open access
Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: Evaluation of outcomes after liver transplantation
AbstractAbstract Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate outcomes LT in MTDPS patients in Japan. Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 20 of 23 patients: MPV17 (n=13), DGUOK (n=4), POLG (n=1), MICOS13 (n=1), and TWNK (n=1). Eight MPV17-deficient patients harbored c.451dupC and all four DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n=13, 56.5%). The most frequent liver symptom was cholestasis (n=21, 91.3%). LT was performed on 11 patients, including eight MPV17-deficient and two DGUOK-deficient patients. Four patients, including one with mild intellectual disability, survived; seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G>A or c.293C>T. Conclusions MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, but patients who had MPV17 mutations associated with mild phenotypes such as c.149G>A or c.293C>T and no marked neurologic manifestations before LT, had moderately better outcomes.
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.
THE CLINICAL SPECTRUM OF MTDNA DEPLETION DUE TO MUTATIONS IN THE THYMIDINE KINASE (TK2) GENE
AbstractBackground : Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder characterized by decreased mtDNA copy number in affected tissues. MDS has been linked to four genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the â -subunit of the ADP-forming succinyl CoA synthetase ligase. Children with TK2 mutations have a predominantly myopathic syndrome.
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.
