DeCure for Mitochondrial DNA depletion syndrome 18
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 18 — 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 18 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 18 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
No disease-modifying therapies exist for single large-scale mitochondrial DNA deletion syndromes (SLSMDs), which include Pearson syndrome and Kearns-Sayre syndrome. In a compassionate-use programme, six patients with SLSMDs received autologous CD34+ hematopoietic cells augmented with maternally derived healthy mitochondria, a procedure called mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease at baseline, including neurologic, endocrine, or renal impairment. The procedure was well tolerated; all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in peripheral blood in four of six patients, and mtDNA content of peripheral blood cells increased in all six patients 6 to 12 months after treatment compared to baseline. Some clinical improvement in aerobic function was noted in two patients, measured by sit-to-stand or six-minute walk testing, and five of six patients with very low body weight before treatment gained weight. Quality-of-life measurements by caregiver assessment and physical examination showed improvement in some parameters.
Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) are defined by dysfunctional mtDNA replication and maintenance, and treatment options remain limited. Aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for some forms of MDDS. Experimental strategies under investigation include small molecule substrate enhancement, lentiviral or adenoassociated vector-mediated gene therapy. Some of these have reached the clinical phase with very promising results, but patient recruitment for clinical trials is very limited because these are rare disorders. No clear consensus on an effective therapeutic approach for mtDNA disorders exists; current treatment is largely supportive rather than curative, partly because there are virtually no defined genotype-phenotype relationships — an identical mutation may cause multiple phenotypes, and the same phenotype may arise from different mutations.
Gene therapy approaches for mtDNA disorders have shown promising proof-of-principle developments, but a successful therapeutic strategy has not yet been realised. Key hurdles include the need for efficient mitochondrial targeting and an effective therapeutic molecule. It remains unknown whether mtDNA mutations significantly contribute to the aging process, though some have speculated that gene therapy approaches developed for mitochondrial disease might one day be applied to aging. The understanding of mitochondrial pathology in human disease has increased substantially, and attention has shifted to treating mitochondrially based disorders, including neurodegenerative conditions where mitochondrial dysfunction appears to play a pivotal role.
What is still missing: adequately powered clinical trials that can recruit enough patients with these rare disorders; a clear understanding of genotype-phenotype relationships to guide patient stratification; and proven methods for efficient mitochondrial targeting and delivery of therapeutic molecules in gene therapy approaches.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science Translational Medicine · 2022 · 72 citations
Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes
AbstractPatients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34 + hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.
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.
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.
Mitochondrial Gene Therapy: An Evaluation of Strategies for the Treatment of Mitochondrial DNA Disorders
AbstractMitochondrial DNA (mtDNA) disorders include a vast range of pathological conditions, despite each sharing a mutual inability to produce ATP efficiently as a result of defective oxidative phosphorylation. There is no clear consensus regarding an effective therapeutic approach, and consequently the current treatment strategies are largely supportive rather than curative. This is almost certainly the result of there being virtually no defined genotype-phenotype relationships among the mtDNA disorders; hence an identical mutation may be responsible for multiple phenotypes, or the same phenotype may be produced by different mutations. In light of this, the development of gene therapy to treat mtDNA disorders offers a promising approach, as it potentially circumvents the complication of the aforementioned genotype-phenotype inconsistency and ultimately the current inability to treat individual disorders with sufficient efficacy. Such an approach will ultimately require the combination of efficient mitochondrial targeting, and an effective therapeutic molecule. Although promising proof-of-principle developments in this field have been demonstrated, the realization of a successful therapeutic mitochondrial gene therapy strategy has not come to fruition. This review critiques the key approaches under development by discussing the theory underlying each strategy, and detailing the current progress made. We also emphasize the potential hurdles that must be acknowledged and overcome if the potential of a therapeutic gene therapy to treat mitochondrial DNA disorders is to be realized.
Mitochondrial DNA Gene Therapy: A Gene Therapy for Aging?
AbstractMutations in mitochondrial DNA cause a group of diverse diseases that affect an estimated half a million people worldwide. These disorders are remarkably resistant to conventional treatments, and thus several gene therapy approaches are being explored. As some of these approaches develop towards maturity, one can't help thinking that some day they may be used against a much more common health problem currently affecting about 6 billion people- aging, which also has been quite resistant to treatment. Unfortunately, we still do not know whether mtDNA mutations significantly contribute to the aging process or not. The prospect of success in mtDNA gene therapy makes getting the answer a high priority.
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.
