The future of Parkinson’s disease research: A new paradigm of human-specific investigation is necessary… and possible

Cassotta, Manuela; Geerts, Hugo; Harbom, Lise J; Outeiro, Tiago F.; Pediaditakis, Iosif; Reiner, Orly; Schildknecht, Stefan; Schwamborn, Jens Christian; Bailey, Jarrod; Herrmann, Kathrin; Högberg, Helena T.

doi:10.14573/altex.2203161

Cited by 9 publications

(9 citation statements)

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“…Additionally, a recent workshop invited experts in non-animal approaches for neurodegenerative diseases to explore the potential and limitations of NAMs, as applied to PD. 89 The participants put forward several key recommendations required to advance PD research, including the need for collaboration across a broad range of stakeholders (including clinicians and funders), to help support a shift away from animal use, and to follow the lead of the toxicology field, where non-animal approaches have more traction. As we explore elsewhere throughout this review, these non-animal human-relevant tools offer a more realistic picture of disease initiation and progression than do chemically-damaged rodents or non-human primates.…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Marshall

Bailey

Cassotta³

et al. 2023

Altern Lab Anim

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The failure rate for the translation of drugs from animal testing to human treatments remains at over 92%, where it has been for the past few decades. The majority of these failures are due to unexpected toxicity — that is, safety issues revealed in human trials that were not apparent in animal tests — or lack of efficacy. However, the use of more innovative tools, such as organs-on-chips, in the preclinical pipeline for drug testing, has revealed that these tools are more able to predict unexpected safety events prior to clinical trials and so can be used for this, as well as for efficacy testing. Here, we review several disease areas, and consider how the use of animal models has failed to offer effective new treatments. We also make some suggestions as to how the more human-relevant new approach methodologies might be applied to address this.

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Section: Parkinson’s Diseasementioning

confidence: 99%

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Marshall

Bailey

Cassotta³

et al. 2023

Altern Lab Anim

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“…Current studies focus on the applicability of in vitro molecular-level mechanistic studies to living systems and the related modeling limitations and opportunities, as extensively discussed in Meisl et al [108]. Molecular models combining the kinetic of αsyn aggregation and multiple biological pathways underlying PD neurodegeneration can assist in vitro to in vivo translation [109].…”

Section: In Vitro/in Vivo Translationmentioning

confidence: 99%

Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Righetti

Antonello

Marchetti

et al. 2022

Front. Appl. Math. Stat.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, yet there is no disease-modifying therapy up to this date. The biological complexity underlying PD hampers the investigation of the principal contributors to its pathogenesis. In this context, mechanistic models grounded in molecular-level knowledge provide virtual labs to uncover the primary events triggering PD onset and progression and suggest promising therapeutic targets. Multiple modeling efforts in PD research have focused on the pathological role of α-synuclein (αsyn), a presynaptic protein that emerges from the intricate molecular network as a crucial driver of neurodegeneration. Here, we collect the advances in mathematical modeling of αsyn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design.

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“…[11][12][13] Parkinson's disease was chosen as an example of a neurodegenerative systemic disease, which are believed to be generally less amenable to the application of non-animal alternative approaches. 14 Using 3Ranker, we efficiently identified papers featuring potential Three Rs alternatives among the thousands of abstracts that were retrieved for these topics. The algorithm and a user-friendly web interface for searching are available via www.open3r.org.…”

Section: Introductionmentioning

confidence: 99%

The 3Ranker: An AI-based Algorithm for Finding Non-animal Alternative Methods

van Beuningen,

Alkema,

Hijlkema

et al. 2023

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The search for existing non-animal alternative methods for use in experiments is currently challenging because of the lack of both comprehensive structured databases and balanced keyword-based search strategies to mine unstructured textual databases. In this paper we describe 3Ranker, which is a fast, keyword-independent algorithm for finding non-animal alternative methods for use in biomedical research. The 3Ranker algorithm was created by using a machine learning approach, consisting of a Random Forest model built on a dataset of 35 million abstracts and constructed with weak supervision, followed by iterative model improvement with expert curated data. We found a satisfactory trade-off between sensitivity and specificity, with Area Under the Curve (AUC) values ranging from 0.85–0.95. Trials showed that the AI-based classifier was able to identify articles that describe potential alternatives to animal use, among the thousands of articles returned by generic PubMed queries on dermatitis and Parkinson’s disease. Application of the classification models on time series data showed the earlier implementation and acceptance of Three Rs principles in the area of cosmetics and skin research, as compared to the area of neurodegenerative disease research. The 3Ranker algorithm is freely available at www.open3r.org ; the future goal is to expand this framework to cover multiple research domains and to enable its broad use by researchers, policymakers, funders and ethical review boards, in order to promote the replacement of animal use in research wherever possible.

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The future of Parkinson’s disease research: A new paradigm of human-specific investigation is necessary… and possible

Cited by 9 publications

References 0 publications

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

The 3Ranker: An AI-based Algorithm for Finding Non-animal Alternative Methods

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