Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: Expert opinions on the state of affairs and the way forward

Schiffelers, Marie-Jeanne; Blaauboer, Bas J.; Bakker, Wieger; Beken, Sonja; Hendriksen, Coenraad; Koëter, H.B.W.M.; Krul, Cyrille

doi:10.1016/j.yrtph.2014.02.007

Cited by 25 publications

(11 citation statements)

References 16 publications

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“… 18 Animals treated in this manner developed a severe, disseminated hAd5 infection, which was accompanied by high mortality of about 50%. 18 Applying the replace, reduce, or refine animal experiments (3R) principle 42 aiming to specifically reduce the burden on experimental animals, we investigated whether immunosuppressed Syrian hamsters could also be infected with lower doses of hAd5. Therefore, the animals were immunosuppressed with CP, injected with 4 × 10 11 vp/kg hAd5, and analyzed 3, 7, and 14 days later for hAd5 infection ( Figure S2 A).…”

Section: Resultsmentioning

confidence: 99%

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters

Schaar

Geisler

Kraus

et al. 2017

Molecular Therapy - Nucleic Acids

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Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters. In vitro evaluation of amiRs targeting the E1A, pTP, IVa2, and hexon genes of hAd5 revealed that two scAAV vectors containing three copies of amiR-pTP and three copies of amiR-E1A, or six copies of amiR-pTP, efficiently inhibited hAd5 replication and improved the viability of hAd5-infected cells. Prophylactic application of amiR-pTP/amiR-E1A- and amiR-pTP-expressing scAAV9 vectors, respectively, to immunosuppressed Syrian hamsters resulted in the reduction of hAd5 levels in the liver of up to two orders of magnitude and in reduction of liver damage. Concomitant application of the vectors also resulted in a decrease of hepatic hAd5 infection. No side effects were observed. These data demonstrate anti-adenoviral RNAi as a promising new approach to combat hAd5 infection.

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Section: Resultsmentioning

confidence: 99%

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters

Schaar

Geisler

Kraus

et al. 2017

Molecular Therapy - Nucleic Acids

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“…As a consequence, not only is more testing of potential EDCs needed, but a better understanding of endocrine function and disruption is also required. A solution that is appropriate and in keeping with the three R’s (replacement, refinement and reduction) ethos of animal research [ 14 ], is to exploit the use of invertebrate organisms which may offer a simplified model for research, as well as providing a faster, cheaper and more ethically acceptable alternative to mammalian testing, at least during initial chemical screening [ 15 ]. As NRs play key roles in endocrine and metabolic functions [ 16 ], cross-species comparative studies of the conservation of these genes within invertebrate genomes may identify new model systems for the testing of chemicals with endocrine disrupting potential without using vertebrates.…”

Section: Introductionmentioning

confidence: 99%

The Nuclear Receptors of Biomphalaria glabrata and Lottia gigantea: Implications for Developing New Model Organisms

et al. 2015

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Nuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.

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“…Thus, changes are required to achieve regulatory acceptance in a more efficient way. Some potential improvement paths are described below 199,200,201,202 :…”

Section: Animal Testing Alternatives and 3rs Principlementioning

confidence: 99%

Medical Devices Biological Safety Assessment: Towards Animal-free Testing

Sachot¹,

Vitale

2019

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Animals have been used since a very long time as experimental subjects to support scientific progress and medical advances. Currently, various testing procedures implying animals are still being conducted within a broad range of scientific fields and applications, as for example the assessment of medical devices safety. The aim of this assessment is to investigate whether a medical device is safe for human use or poses a risk for patients' health. Animal testing for that purpose is especially encouraged by regulatory requirements, which prerequisite however that the use of such testing is deemed necessary and justified in the context of a risk management process. Thus, animal models are no longer systematically used as in the past, but they remain a cornerstone within the delicate decision-making process related to the marketing of medical devices. Though, animal testing has some critical limitations, such as ethical concerns and relevance of animal data, which challenge its further use to that objective. A particular attention is therefore currently given to the development of animal-free alternatives to better support the application of the 3Rs Principle (replacement, reduction, refining) within this field. Unfortunately, the highlyadvanced methods and technologies being developed face barriers (e.g. validation and standardization) which hinder and slow down their implementation as regulatory-accepted alternatives. To overcome these difficulties, the process of regulatory acceptance of these alternatives may be optimized. This may be achieved for example by improving the cooperation, coordination and communication between the different stakeholders, i.e. researchers, regulatory approval bodies and industries. Mostly, a special focus may be set on commitment and shared effort to enhance the efficiency of that process and to establish a regulatory testing framework that no longer relies on animal models.

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Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: Expert opinions on the state of affairs and the way forward

Cited by 25 publications

References 16 publications

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters

The Nuclear Receptors of Biomphalaria glabrata and Lottia gigantea: Implications for Developing New Model Organisms

Medical Devices Biological Safety Assessment: Towards Animal-free Testing

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