RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

O’Brien, John; Chouliaras, Leonidas; Sultana, Janet; Taylor, John-Paul; Ballard, Clive; Aarsland, Dag; Blanc, F.; Boeve, Bradley F.; Brooks, David J.; Chaudhuri, K. Ray; Cummings, Jeffrey L.; Feldman, Howard; Flicker, Leon; Galvin, James E.; Grosset, Donald; Ikeda, Manabu; Kohlhaas, Susan; Lawlor, Brian A.; Lemstra, Afina W.; Leroi, Iracema; Londos, Elisabet; Leverenz, James B.; Lewis, Simon J.G.; McKeith, Ian; Mills, Roger; Oakley, Richard T.; Richardson, Jill C.; Sabbagh, Marwan; Skidmore, John; Svennigsson, Per; Tiraboschi, Pietro; Weintraub, Daniel; Walker, Zuzana; Watson, Rosie; Weil, Rimona S; Williams‐Gray, Caroline H.; Yarnall, Alison

doi:10.1186/s13195-022-01103-7

Cited by 7 publications

(8 citation statements)

References 193 publications

(162 reference statements)

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“…A few limitations were evident in the landscape of clinical trials for DLB. In contrast with PD and AD where novel therapies dominate clinical trials [12,13], most of the clinical trials in DLB investigate repurposed agents and there are very few agents in Phase 1 trials [14]. This is largely because drugs are often developed initially for AD or PD and later directed towards DLB.…”

Section: Discussionmentioning

confidence: 99%

“…Disease stage classification included the following categories: prodromal, dementia stages (mild, moderate, and severe), and combination of prodromal and dementia stages. Repurposed drugs were defined when an established compound was investigated for a new therapeutic indication [14]. Approved indication was defined searching in PubMed and using FDA, and EMA databases.…”

Section: Synthesis and Analysis Of The Datamentioning

confidence: 99%

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Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

et al. 2023

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Introduction: Reviews of randomized clinical trials (RCTs) in dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease-modifying therapies (DMTs).Methods: We performed a systematic review of all clinical trials conducted until September 27, 2022, by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB. Results: We found 25 agents in 40 trials assessing symptomatic treatments and DMTs for DLB: 7 phase 3, 31 phase 2, and 2 phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend

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Section: Discussionmentioning

confidence: 99%

Section: Synthesis and Analysis Of The Datamentioning

confidence: 99%

Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

et al. 2023

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“…Elemental diet also reverses the gut permeability increase seen in Crohn's disease 122 . Metformin reduces gut permeability in mice, 123 and has other effects which may potentially be beneficial in PD 124 …”

Section: Potential Treatments Based On the Endotoxin Hypothesismentioning

confidence: 97%

“…Candesartan, an existing drug licensed for the treatment of hypertension, has been shown to reduce TLR4 expression and activity, is expected to cross the BBB, and has a good safety profile, making it an attractive candidate for repurposing in Parkinson's disease. 124,128 TAK242 is a potent small molecule inhibitor of TLR4, which has previously been used in a clinical trial for treatment of sepsis and shown to be well tolerated in the short term. 129 (5) Blocking the microglial response to LPS.…”

Section: Potential Treatments Based On the Endotoxin Hypothesismentioning

confidence: 99%

The Endotoxin Hypothesis of Parkinson's Disease

2023

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The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram‐negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α‐synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut–brain axis leads to neuroinflammation and spreading of α‐synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α‐synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…Biomarkers for a-synuclein, as described above, are also needed in LBD trials and would be of particular use as diagnostic biomarkers for recruiting participants in the prodromal or preclinical stages. Clinical trials are ongoing for tyrosine kinase inhibitors and CT1812, which in preclinical studies increased clearance of a-synuclein, amyloid and hyperphosphorylated tau [132]. In these clinical trials, plasma and CSF biomarkers have been included as outcome measures to assess target engagement and delineate the effect on comorbid pathologies.…”

Section: Biomarkers In Clinical Trialsmentioning

confidence: 99%

Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers

Gibson

Abdelnour

Chong

et al. 2023

Current Opinion in Neurology

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Purpose of review Currently, no disease modifying therapies (DMTs) have been approved for use in dementia with Lewy bodies (DLB). Clinical trials face difficulties due to the clinical and neuropathological heterogeneity of the condition with a diverse array of neuropathogenic mechanisms contributing to the clinical phenotype. The purpose of this review is to describe how recent advances in the development of biofluid biomarkers may be used in clinical trials to tackle some of these challenges. Recent findings Biomarkers are essential both to support the accurate diagnosis of DLB and to delineate the influence of coexisting pathologies. Recent advances in the development of α-synuclein seeding amplification assays (SAA) allow accurate identification of α-synuclein from the prodromal stages in DLB. Additionally, validation of plasma phosphorylated tau assays in DLB is ongoing and offers an accessible biomarker to indicate the existence of AD co-pathology. Use of biomarkers for diagnosis and group stratification in clinical trials of DLB is growing and likely to be of increasing importance in the future. Summary In vivo biomarkers can enhance patient selection in clinical trials allowing greater diagnostic accuracy, a more homogeneous trial population, and stratification by co-pathology to create subgroups most likely to derive therapeutic benefit from DMTs.

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RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

Cited by 7 publications

References 193 publications

Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

The Endotoxin Hypothesis of Parkinson's Disease

Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers

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