DeCure for Mitochondrial DNA depletion syndrome 4a
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 4a — screening already-approved drugs against its 6-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 4a maps to a 6-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 4a 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
retinaldehyde binding protein 1 (RLBP1) — RLBP1 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 retdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4CJ6 · 1.896 Å · ligand RETINAL (RET). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial DNA depletion syndrome 4a is a form of mtDNA depletion syndrome, a group of autosomal recessive disorders characterised by a significant reduction in mtDNA content. The nuclear gene FBXL4, located on chromosome 6, encodes a protein involved in mitochondrial bioenergetics, mtDNA maintenance, and mitochondrial dynamics. Pathogenic variants in FBXL4 reduce mtDNA synthesis, causing a large decrease in mtDNA content in cells. These variants are associated with encephalomyopathy MTDPS type 13, a rare and severe multisystem disorder with infant-onset encephalomyopathy, lactic acidosis, developmental delay, hypotonia, feeding difficulties, and failure to thrive. Other features can involve the central nervous system, ophthalmologic, cardiac, gastrointestinal, genitourinary, and immunological systems.
A 2024 case report describes an infant born to consanguineous Pakistani parents with early onset severe lactic acidosis, hypotonia, feeding difficulties, hypertrophic cardiomyopathy, supraventricular tachycardia, and transient neutropenia. The infant harboured a homozygous variant in FBXL4 (c.370C>T [p.Q124*]), identified in heterozygosity in both parents. Medical treatment included coenzyme Q10, propranolol, and sodium bicarbonate, alongside multidisciplinary support. A progressive improvement in postural tone and feeding autonomy was observed during the first months of life. No other treated cases or controlled data are reported in these abstracts.
The broader literature on mitochondrial disease therapy, from 1999 and 2010 reviews, notes that development of therapies has been difficult due to heterogeneity in genetics, tissues affected, and environmental factors. Some emerging approaches are targeted to specific conditions, others may be applicable to more diverse groups, but no specific drug or gene therapy is validated for FBXL4-related depletion. The 1999 review of neuroprotection and the 2010 review of emerging therapies do not provide survival or response rates for any intervention in this syndrome.
What is still missing: no controlled trial data, no validated animal model for FBXL4 specifically, no patient stratification by variant type, and no dedicated funding for a clinical trial in this ultra-rare disorder. The single case report cannot establish efficacy of the combination therapy used.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Methods in molecular biology · 2011 · 152 citations
Measurement of Mitochondrial DNA Copy Number
AbstractMitochondrial disorders are complex and heterogeneous diseases that may be caused by molecular defects in either the nuclear or mitochondrial genome. The biosynthesis and maintenance of the integrity of the mitochondrial genome is solely dependent on a number of nuclear proteins. Defects in these nuclear genes can lead to mitochondrial DNA (mtDNA) depletion (Spinazzola et al. Biosci Rep 27:39-51, 2007). The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a significant reduction in mtDNA content. These genes include POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B, and C10orf2, all nine genes have mutations reported to cause various forms of MDDSs. In this chapter, we outline the real-time quantitative polymerase chain reaction (qPCR) analysis of mtDNA content in muscle or liver tissues.
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.
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.
Reductions in Stavudine Dose Might Ameliorate Mitochondrial-Associated Complications Without Compromising Antiviral Activity
AbstractBACKGROUND: Stavudine (d4T) is a nucleoside analogue approved for the treatment of HIV infection. Concern has risen due to its association with mitochondrial toxicity. Given that the toxicity might be dose-dependent, we explored prospectively whether lowering d4T doses might improve the safety profile of the drug without compromising its antiviral activity. METHOD: All HIV-infected patients seen at our institution during the first semester of year 2003 who were receiving a d4T-containing regimen and had plasma HIV RNA below 50 copies/mL for the previous 3 months were invited to participate in a trial in which half of patients reduced the dose of d4T from 40 to 30 mg bid (cases) and the other half continued with the same d4T dose (controls). RESULTS: A total of 92 patients were recruited in the study: 47 cases and 45 controls. A total of 9 patients experienced virological failure during the following 12 months: 4 cases and 5 controls. No significant differences between groups were recognized for mean transaminase levels, cholesterol, triglycerides, and lactate at baseline nor over the 12-month follow-up period. Lipodystrophy was recognized in 20% of patients at baseline, without significant differences between groups, and no significant improvements were recognized in the d4T 30 mg bid arm after 12 months follow-up. However, a median significant increase of 2.23-fold in the mitochondrial DNA content in peripheral blood mononuclear cells (PBMCs) was recognized in a subset of 11 patients who reduced the d4T dose, whereas it remained unchanged in 10 controls. CONCLUSION: A reduction in the d4T dose from 40 to 30 mg bid may ameliorate mtDNA depletion in PBMCs without compromising the antiviral activity of the drug. However, significant improvements on surrogate laboratory markers of mitochondrial toxicity or in lipoatrophy could not be recognized over 12 months follow-up.
Mitochondrial DNA Depletion Associated With Partial Complex II and IV Deficiencies and 3-Methylglutaconic Aciduria
AbstractWe report a patient with mitochondrial DNA depletion, partial complex II and IV deficiencies, and 3-methylglutaconic aciduria. Complex II deficiency has not been previously observed in mitochondrial DNA depletion syndromes. The observation of 3-methylglutaconic and 3-methylglutaric acidurias may be a useful indicator of a defect in respiratory chain function caused by mitochondrial DNA depletion.
International Journal of Molecular Sciences · 2025 · 3 citations · open access
Advances in Management of Mitochondrial Myopathies
AbstractMitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.
DOAJ (DOAJ: Directory of Open Access Journals) · 2024 · 0 citations · open access
New variant in the FBXL4 gene – leading to mitochondrial DNA depletion syndrome
AbstractDefects in the mitochondrial DNA (mtDNA) cause mtDNA depletion syndrome (MTDPS), a subclass of mitochondrial disorders that are genetically and phenotypically heterogeneous. MTDPS is a rare autosomal recessive disease caused by a mutation of a nuclear gene named FBXL4 (F-box and leucine-rich repeat protein 4), located on chromosome 6. This nuclear-encoded mitochondrial protein plays a vital role in mitochondrial bioenergetics, mtDNA maintenance, and mitochondrial dynamics. Pathogenic variants in the FBXL4 gene reduce mtDNA synthesis, resulting in a large decrease in the mtDNA content in cells, which is essential for normal energy production. These pathogenic variants in the FBXL4 gene are associated with an encephalomyopathy MTDPS type 13 (MTDPS13), a rare and severe multisystemic disorder mainly characterized by infant-onset encephalomyopathy and lactic acidosis, developmental delay, hypotonia with feeding difficulties and failure to thrive. Other features may include the central nervous system and the ophthalmologic, cardiac, gastrointestinal, genitourinary, and immunological systems. Herein, we report the case of an infant born to consanguineous Pakistani parents with an early onset of severe lactic acidosis, hypotonia, feeding difficulties, hypertrophic cardiomyopathy, supraventricular tachycardia, and transient neutropenia harboring a homozygous variant in the FBXL4 (c.370C>T [p.Q124*]) gene. This variant was identified in the patient’s parents in heterozygosity. He started medical treatment (with coenzyme Q10, propranolol, and sodium bicarbonate) and multidisciplinary support. As a result, a progressive improvement in postural tone and feeding autonomy was observed during the first months of life. Therefore, encephalomyopathy MTDPS13 should be suspected when dealing with patients with severe congenital lactic acidosis and developmental impairment.
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.
