DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for late-onset Parkinson disease — screening already-approved drugs against its 24-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLate-onset Parkinson disease maps to a 24-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 late-onset parkinson disease 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
alcohol dehydrogenase 1C (class I), gamma polypeptide (ADH1C) — ADH1C 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 naddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1U3W · 1.45 Å · ligand NICOTINAMIDE-ADENINE-DINUCLEOTIDE (NAD). Experimental structure, not a prediction.
What the evidence adds up to
A 1981 study of 58 patients treated with levodopa found that disease duration, not duration of levodopa therapy, determined disability scores over six years. Patients matched for disease duration had similar disability scores regardless of how long they had been on levodopa. Those with longer disease duration had consistently higher disability scores when matched for therapy duration. Side effects did not differ between groups and did not increase over time. The authors concluded that delaying levodopa therapy fails to improve disability in early disease and confers no benefit in later years.
A 2014 meta-analysis of 49 published studies including 709 participants examined the age-dependent penetrance of mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 in late-onset familial parkinsonism. All assessed autosomal dominant mutations had significantly different age-dependent cumulative incidences. Penetrance of SNCA duplications was comparable to point mutations, driven by inclusion of the p.A53T mutation (mean age at onset 45.9 years). For LRRK2 p.G2019S, Israeli Ashkenazi Jewish carriers (mean onset 57.9 years) were comparable to Tunisian Arab Berber carriers (mean onset 57.1 years), while Norwegian carriers (mean onset 63 years) were significantly different from both other groups. The authors concluded that penetrance may be modified by genetic or environmental factors across populations.
A 2022 review described drug repurposing strategies for Parkinson's disease, noting that repurposing is most promising when a drug has already been tested for safety. The review discussed obstacles faced by the repurposing community and suggested new approaches, but provided no new clinical data. A 2019 review summarised molecular mechanisms of sporadic Parkinson's disease and their connection to aging, focusing on protein conformational control and degradation. It evaluated the need for reliable non-motor markers for preclinical identification and early correction of integrative brain dysfunction, particularly sleep and behaviour disorders. It mentioned endogenous neuroprotective factors capable of inhibiting neurodegeneration but gave no specific drug data. A 2008 review noted that several genes have been linked to Parkinson's pathogenesis but account for only a minority of cases, and that the interplay between genes, environment, and aging remains unclear.
What is still missing is large-scale, adequately funded clinical trials that test repurposed drugs in well-stratified patient populations, using reliable early biomarkers to identify candidates before substantial dopamine neuron loss has occurred. No current study provides the randomised controlled evidence needed to change clinical practice for late-onset Parkinson disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 1981 · 126 citations
Evidence to support early levodopa therapy in Parkinson disease
AbstractTo see whether duration of disease or of levodopa treatment was responsible for gradual worsening of parkinsonian patients, 58 persons treated with levodopa were classified into three groups based on predopa disease duration. Data over 6 years of treatment showed that disease duration was the determining factor. Patients matched for disease duration had similar disability scores regardless of duration of therapy. Matched for therapy duration, patients with longer disease duration had consistently higher disability scores. Side effects showed no differences between groups and did not increase over time. In sum, delaying therapy fails to improve disability in the early years of disease and does not confer any benefit in later years.
AbstractIMPORTANCE: Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely. OBJECTIVE: To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism. DATA SOURCES: Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014. STUDY SELECTION: Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study. DATA EXTRACTION AND SYNTHESIS: The age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death. MAIN OUTCOMES AND MEASURES: Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals. RESULTS: All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001). CONCLUSIONS AND RELEVANCE: Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.
Movement Disorders · 1993 · 43 citations · open access
Early combination therapy with bromocriptine and levodopa in parkinson's disease
AbstractThe use of early combination therapy with bromocriptine (Br) and levodopa (LD) in Parkinson's disease is controversial. It has been suggested that treatment with this regimen would prevent or delay the onset of motor fluctuations and dyskinesia. Thus, some have recommended it as a standard of care. This recommendation is based on the theory that LD may accelerate the progression of PD and clinical experience using Br monotherapy in early Parkinson's disease, which suggested that Br causes fewer late complications. This article reviews these arguments and shows that the theories are unproven. A single, uncontrolled trial is often referred to as evidence for efficacy of early combination therapy. We critically review this and five other studies which have evaluated the treatment strategy. We show that the literature is often misleading and that these trials do not support the efficacy of early combination therapy. We conclude that there is no justifiable reason to use a combination of Br and LD in early parkinsonian patients.
A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer
AbstractBACKGROUND: Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC. OBJECTIVES: This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC. DATA SOURCES: Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science. SYNTHESIS METHODS: Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies. RESULTS: Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61-0.75) and 0.83 (95% CI 0.75-0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41-2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69-1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57-0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28-0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14-0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors. CONCLUSION: The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel.
Frontiers in Pharmacology · 2022 · 18 citations · open access
Drug reprofiling history and potential therapies against Parkinson’s disease
AbstractGiven the high whittling down rates, high costs, and moderate pace of new medication, revelation, and improvement, repurposing "old" drugs to treat typical and uncommon illnesses is progressively becoming an appealing proposition. Drug repurposing is the way toward utilizing existing medications in treating diseases other than the purposes they were initially designed for. Faced with scientific and economic challenges, the prospect of discovering new medication indications is enticing to the pharmaceutical sector. Medication repurposing can be used at various stages of drug development, although it has shown to be most promising when the drug has previously been tested for safety. We describe strategies of drug repurposing for Parkinson's disease, which is a neurodegenerative condition that primarily affects dopaminergic neurons in the substantia nigra. We also discuss the obstacles faced by the repurposing community and suggest new approaches to solve these challenges so that medicine repurposing can reach its full potential.
Neurology Clinical Practice · 2020 · 14 citations · open access
Treatment of Dementia With Bosutinib
AbstractOBJECTIVE: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib. METHODS: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline. RESULTS: < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances. CONCLUSIONS: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.
AbstractParkinson's disease (PD) is one of the most severe human neurodegenerative diseases that is mainly represented by sporadic form with multifactorial nature and commonly diagnosed in persons over 65 years of age. Current data on molecular mechanisms of PD development and their connection with processes of aging have been given in the review. Mechanisms of conformational control and selective degradation of proteins in the cell, possible trigger factors initiating the cascade of pathological reactions have been analyzed. Perspectives to solve the problem of elimination of basic causes of PD incurability (late diagnosis, and ineffective treatment) related to determination of reliable non-motor markers of the preclinical identification and early disorder correction of integrative brain functions have been evaluated. The basic attention is paid to an analysis of early sleep and behavior disorders in PD and aging. Known at the present moment endogenous neuroprotective factors capable to inhibit the neurodegenerative process in this disease have been considered.
Hyperechogenicity of substantia nigra in Parkinson's disease – Searching for genetic predictors
AbstractIn spite of extensive research the cause of Parkinson's disease, the second most common neurodegenerative disorder, is still unclear. Several genes have been indentified in the last years to be related to the pathogenesis of PD, and a complex interplay between genes, environment and aging has been suggested. However, these genes are only associated with a minority of PD cases and the exact gene – environment interaction still remains to be elucidated.
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.
