DeCure for Mitochondrial complex IV deficiency, nuclear-type
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex IV deficiency, nuclear-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 complex IV deficiency, nuclear-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 complex iv deficiency, nuclear-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.
What the evidence adds up to
The abstracts provided do not contain any clinical trial results, survival data, or response rates for mitochondrial complex IV deficiency, nuclear-type. They are review articles and a methods paper focused on complex I and III deficiencies, not complex IV. One 2004 abstract on mitochondrial gene therapy notes that for the vast majority of patients with mitochondrial genome defects, there is no satisfactory treatment available, and that objective limitations of conventional biochemical treatment warrant exploration of gene therapy. That abstract describes a proposed method for direct mitochondrial transfection using DQAsomes, but provides no patient outcomes.
The 2010 and 2013 reviews on complex I deficiency mention that the first successful treatment trials were carried out in patient-derived cell lines, using chemical compounds that target cellular aberrations induced by complex I dysfunction. They state that before human clinical trials can be entered, it is necessary to study toxicity, pharmacokinetics, and therapeutic potential in suitable animal models. The 2024 review on complex III deficiency notes that these disorders are the least common among mitochondrial diseases and summarises genetic knowledge without reporting any therapeutic results.
No abstract in this set reports any treatment tested in patients with mitochondrial complex IV deficiency, nuclear-type. There are no numbers for survival, response, or sample size because no human studies are described. What is missing is any clinical trial data, any patient-derived evidence for this specific nuclear-type complex IV deficiency, and any validated animal model for this particular subtype. The field still lacks funded clinical trials, proper patient stratification for this rare condition, and a trial design that could test the gene therapy approaches mentioned in the 2004 abstract.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
IUBMB Life · 2013 · 48 citations · open access
Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit
AbstractTo allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.
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.
Journal of Inherited Metabolic Disease · 2010 · 31 citations · open access
Mouse models for nuclear DNA‐encoded mitochondrial complex I deficiency
AbstractMitochondrial diseases are a group of heterogeneous pathologies with decreased cellular energy production as a common denominator. Defects in the oxidative phosphorylation (OXPHOS) system, the most frequent one in humans being isolated complex I deficiency (OMIM 252010), underlie this disturbed-energy generation. As biogenesis of OXPHOS complexes is under dual genetic control, with complex II being the sole exception, mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) are found. Increasing knowledge is becoming available with respect to the pathophysiology and cellular consequences of OXPHOS dysfunction. This aids the rational design of new treatment strategies. Recently, the first successful treatment trials were carried out in patient-derived cell lines. In these studies chemical compounds were used that target cellular aberrations induced by complex I dysfunction. Before the field of human clinical trials is entered, it is necessary to study the effects of these compounds with respect to toxicity, pharmacokinetics and therapeutic potential in suitable animal models. Here, we discuss two recent mouse models for nDNA-encoded complex I deficiency and their tissue-specific knock-outs.
AbstractMitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.
Molecular Therapy · 2004 · 2 citations · open access
683. Cationic Mitochondriotropic Vesicles for DNA Delivery to Mitochondria
AbstractThe number of diseases found to be associated with defects of the mitochondrial genome has grown significantly since 1988. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment available for a vast majority of patients. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. Two different strategies for mitochondrial gene therapy are imaginable1 The first involves expressing a wild-type copy of the defective gene in the nucleus, with cytoplasmic synthesis and subsequent targeting of the gene product to the mitochondria (“allotopic expression”). Besides the different codon usage in mitochondria, however, there are possibly four major difficulties in adapting this nuclear-cytosolic approach for mitochondrial gene therapy to mammalian cells2. First, the majority of mtDNA defects involve tRNAs and to date, no natural mechanism has been reported for the mitochondrial uptake of cytosolic tRNAs in mammalian cells. Second, it is generally agreed that the thirteen proteins encoded for by mtDNA are very hydrophobic peptides, which would not be readily imported by the mitochondrial protein import machinery. However, since the 13 mitochondrial coded proteins are not equally hydrophobic, the allotopic expression of at least some of the peptides appears as possible3. Third, it has been hypothesized that some of the proteins encoded by the mitochondrion may potentially be toxic if synthesized in the cytosol4. Fourth, according to a hypothesis termed co-location for redox regulation5, the co-location of mtDNA and its products may be essential for the rapid control of gene expression by the redox state in the mitochondrial matrix. Considering all problems associated with the nuclear-cytosolic approach the development of methods for the direct transfection of mitochondria6 as an alternative approach towards mitochondrial gene therapy seems highly warranted. We have developed a strategy for mitochondrial gene therapy which involves the transport of a DNA-mitochondrial leader sequence peptide conjugate to mitochondria using cationic mitochondriotropic vesicles, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. For the design of cationic mitochondriotropic vesicles we have utilized the self-assembly behavior of dequalinium, a cationic single-chain bola-amphiphile which is known to selectively accumulate in mitochondria. We found that such bola-amphiphiles are able to form liposome-like cationic vesicles (“bolasomes”), which we termed “DQAsomes” when prepared from dequalinium7,8. Data will be presented showing that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system.
Mitochondrial Disorders: From Pathophysiology to Acquired Defects
AbstractMitochondrial Disorders: From Pathophysiology to Acquired Defects Editors: Claude Desnuelle; Salvatore DiMauro Bibliographic Data: Springer-Verlag, 2002. ISBN: 2-287-59759-x, 325 pp, hard cover, $85.00. Reviewer's Expert Opinion: Description: This book provides a carefully considered overview of important topics in mitochondrial disease. Purpose: This original book broadly surveys mitochondrial medicine by synthesizing a great deal of information succinctly. There are 26 contributing authors who offer a variety of perspectives on this expanding field. Audience: A concentrated readership of physicians and scientists interested in learning about recent advances in primary or secondary dysfunction of the mitochondrial respiratory chain is anticipated. Although the book is clearly written and accessible to nonspecialists, detail is sufficient to interest researchers in the field. The editors and authors are preeminent authorities in mitochondrial disease. Features: The chapters are informative reviews on topics ranging from biochemical and molecular aspects of mitochondrial biology to apoptosis and aging. The importance of the interaction between the nuclear and mitochondrial genomes is emphasized. Several chapters that illustrate specific points are written in the form of scientific articles and are interspersed with the more general reviews. The book is divided into four major sections: Part I describes mitochondrial biology; Part II is devoted to iatrogenic causes of mitochondrial dysfunction, especially antiretroviral agents, but other drugs with potential to harm mitochondria are also discussed; Part III gives an overview of mitochondrial medicine, with an emphasis on neurological features; and Part IV provides perspective on potential therapies for mitochondrial disease. Overall, the book successfully highlights the central role that mitochondria play in diverse disease processes, including cancer, diabetes, drug sensitivity, and neurodegenerative, gastrointestinal, kidney, and hematopoietic disorders. The book is very well organized. Illustrations are helpful and clear. References are current and authoritative. This book is unique in providing a truly comprehensive review of a vast and rapidly expanding field. Assessment: This book is an outstanding contribution to the field of mitochondrial medicine. This comprehensive yet concise review should be available in any medical library.
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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