DeCure for Mitochondrial DNA depletion syndrome 16 (hepatic type)
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 16 (hepatic 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 16 (hepatic 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 16 (hepatic 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
DNA polymerase gamma 2, accessory subunit (POLG2) — POLG2 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 dcpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8D33 · 2.46 Å · ligand 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE (DCP). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial DNA depletion syndrome 16 (hepatic type) is one of the hepatocerebral mitochondrial DNA depletion syndromes (MTDPS), a group of autosomal recessive disorders defined by a systemic reduction of mtDNA copy number due to mutations in nuclear genes involved in mtDNA synthesis. In a Japanese cohort of 23 hepatocerebral MTDPS patients identified from 999 patients diagnosed with mitochondrial diseases between 2007 and 2019, the most common causative gene was MPV17 (13 of 23 patients), followed by DGUOK (4 patients), POLG (1), MICOS13 (1), and TWNK (1). The most frequent initial manifestation was failure to thrive (56.5%) and the most common liver symptom was cholestasis (91.3%). A separate histopathological study of 13 children with hepatocerebral MDS who died, harbouring mutations in DGUOK, MPV17, and POLG, found a moderately reproducible pattern of parenchymal damage in liver specimens that may aid diagnosis.
Liver transplantation (LT) has been performed for hepatocerebral MTDPS but outcomes are not favourable. In the Japanese cohort, LT was performed on 11 or 12 patients (depending on the report version). Among these, four or five survived, while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors carried either the c.149G>A or c.293C>T mutations, which are associated with milder phenotypes. The authors concluded that patients with these MPV17 mutations and no marked neurologic manifestations before LT had a better prognosis, but overall the outcome of LT for MTDPS was not favourable.
For the broader group of mitochondrial DNA maintenance disorders, including MTDPS, current treatment options are limited. Allogeneic haematopoietic stem cell transplantation can restore enzyme activity in MNGIE (a related thymidine phosphorylase deficiency) but carries high mortality from transplant complications and disease progression. Experimental strategies under investigation include small molecule substrate enhancement, lentiviral and adeno-associated viral vector gene therapy, and haematopoietic stem cell gene therapy, some of which have reached early clinical phases with promising results. However, these are all rare disorders, and patient recruitment for clinical trials is severely limited. What remains missing is not a candidate therapy but the funding and infrastructure to run adequately powered trials, and the ability to stratify patients by genotype and neurological status before any intervention is attempted.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
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.
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.
Research Square · 2020 · 2 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 the outcomes of 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 19 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three 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 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while 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, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G>A or c.293C>T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.
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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