DeCure for Amyotrophic lateral sclerosis-parkinsonism-dementia complex
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for amyotrophic lateral sclerosis-parkinsonism-dementia complex — 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 moduleAmyotrophic lateral sclerosis-parkinsonism-dementia complex 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 amyotrophic lateral sclerosis-parkinsonism-dementia complex 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
Parkinsonism associated deglycase (PARK7) — PARK7 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9YFR · 0.92 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
No abstract in this set reports a clinical trial of any drug for amyotrophic lateral sclerosis-parkinsonism-dementia complex. The 2022 cross-sectional study of 110 amyotrophic lateral sclerosis patients found dementia in 10% of the sample (11 patients), with a mean disease duration of 18.46 months. No abstract mentions the parkinsonism-dementia complex specifically.
The 2024 review on synaptopathy argues that presynaptic dysfunction is an early convergent event in frontotemporal dementia and amyotrophic lateral sclerosis, but it offers no experimental data on any drug. The 2023 review on pathological mechanisms states that the cause of amyotrophic lateral sclerosis remains unexplained and that the disease likely involves multiple interacting molecular and genetic pathways. It notes that emerging therapies are being studied but gives no results.
The 2012 article on clinical innovation reports that no disease-modifying product has been approved for any neurodegenerative disorder, with the possible exception of riluzole for amyotrophic lateral sclerosis. It states that the pharmaceutical industry has spent billions on Alzheimer’s disease with dismal output, and that high cost, long timelines and low probability of success have discouraged investment. The 2023 introduction to a special issue repeats that the absence of precise biomarkers and novel biochemical drug targets has hindered drug discovery. The 2024 review on drug repurposing lists several drugs (isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin) that have been repurposed for Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and multiple sclerosis, but it does not report any clinical data for amyotrophic lateral sclerosis-parkinsonism-dementia complex.
What is missing: any clinical trial testing a repurposed drug in amyotrophic lateral sclerosis-parkinsonism-dementia complex; a validated biomarker for the disease; a clear molecular target that distinguishes this syndrome from other neurodegenerative disorders; and funding for a dedicated trial with appropriate patient stratification.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neural Regeneration Research · 2023 · 28 citations · open access
Pathological mechanisms of amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.
Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis
AbstractFrontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.
Clinical innovation for neurodegenerative diseases
AbstractNeurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, are devastating diseases, with huge unmet medical needs. Although it has been estimated that the pharmaceutical industry has already spent billions of US dollars on developing a treatment for AD, the output so far has been dismal. We, like many others, hope that this long history of failures will soon be replaced by success. Whilst symptomatic treatments are valuable, especially those with clearly observable functional outcomes (e.g., l-DOPA in Parkinson’s disease), disease modification in terms of halting, slowing or preventing the evolution of neurodegenerative disorders remains the Holy Grail and no disease modifier product has yet been approved in any neurodegenerative disorder – with the possible exception of riluzole for amyotrophic lateral sclerosis. High cost, long timelines and low probability of success have led to reluctance by the pharmaceutical industry to invest in this area, despite the huge rewards that a successful treatments would reap [1]. Some companies have already opted to leave this area; others have decided to ‘reef the sail’. In contrast, publically funded efforts are growing. During the first decade of the 21st century, AD national plans were launched in a variety of different European countries. The US President signed the National AD Project Act in January 2011. The first European-wide Neurodegenerative Disease Research was launched in 2012. In 2013 the NIH total expenditure on AD research will reach an all-time high of US $529 million. A common belief is that public–private partnerships (PPPs) will generate breakthroughs in preclinical and clinical areas [2]. The Innovative Medicine Initiative (IMI) represents one such collaboration, which joins European governments and pharmaceutical companies together to speed up the development of better and safer medicines for patients. The IMI PharmaCog project was launched in 2010 and is already reporting data related to improved early preclinical and clinical experimental designs for predicting the cognitive properties of new drug candidates [101].
Journal of Alzheimer s Disease · 2023 · 1 citations · open access
Introduction to The Special Issue: Novel Molecular Pathways and Therapeutic Challenges in Neurodegenerative Diseases
AbstractNeurodegenerative disorders, such as Alzheimer's disease, (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present complex etiologies and pathologies.The lack of early detection is due to the absence of precise biomarkers [1][2][3].The clinical management of these brain disorders has become more complex and challenging because the absence of precise novel biochemical drug targets has hindered discovery of new drugs [4][5][6].One of the key issues is the increased incidence of neurodegenerative disorders in the world population, primarily due to an increase in life expectancy [4].Despite an enormous upsurge in our understanding of the cellular and molecular pathways associated with cell death, the key molecular determinants to modulate these processes in human diseases is still not revealed, hindering the development of effective treatments and prevention avenues for aging and neurodegener-
Pakistan Journal of Medical and Health Sciences · 2022 · 0 citations · open access
Frequency of Dementia in Patients with Amyotrophic Lateral Sclerosis
AbstractObjective: To determine the frequency of dementia in patients with amyotrophic lateral sclerosis. Study Design: Cross-sectional study Place and Duration of Study: Department of Neurology, Chandka Medical College Hospital, Larkana Pakistan from 14thJanuary 2019 to 13thJuly 2019. Methodology: One hundred and ten patients were enrolled. Diagnosis was made after patient examination as proposed by memory impairment greater than 1 cognitive-disturbance. Results: The mean age was 54.36±11.12 years and mean duration of disease was 18.46±7.13 months. Sixty seven (61%) were males and 43 (39%) were females. Dementia was found noted in 11 (10%) patients while 99 (90%) was found to benormal. Conclusion: The frequency of dementia in patients with amyotrophic lateral sclerosis was found to considerable. Key words: Amyotrophic lateral sclerosis, Epidemiology, Dementia, Incidence
Current Drug Research Reviews · 2024 · 0 citations
Exploring Novel Therapeutic Avenues: Drug Repurposing for Neurodegenerative Movement Disorders
AbstractNeurodegenerative movement disorders, encompassing conditions such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a significant burden on individuals, families, and healthcare systems globally. Traditional drug discovery approaches for these disorders have encountered challenges, including high costs and lengthy timelines. Drug repurposing has emerged in recent years as a promising approach to expedite the discovery of new treatments by leveraging existing drugs approved for other indications. This review explores the landscape of drug repurposed for neurodegenerative movement disorders, highlighting promising candidates, underlying mechanisms, and clinical implications. The rationale behind repurposing, including the advantages of utilizing existing pharmacological agents with established safety profiles and known pharmacokinetics, along with techniques utilized for repurposing (computational and experimental), have been elaborated. Several studies on the potential of pre-existing drugs such as isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin, etc., which have been repurposed for neurodegenerative movement disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, Multiple Sclerosis, etc. have been discussed. Further, the current scenario and future prospective of drug repurposing have also been touched upon.
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.
