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GARDair Report Summary

Project ID: 756014
Funded under: H2020-EU.3.1.3.

Periodic Reporting for period 1 - GARDair (The first predictive in vitro assay for the identification of respiratory sensitizers.)

Reporting period: 2017-03-01 to 2018-02-28

Summary of the context and overall objectives of the project

Chemical sensitization, also referred to as chemical allergy, is a disease state induced by the human immune system in response to chemical sensitizers. Sensitized individuals that are subsequently exposed to such chemicals will suffer from disease-associated symptoms, such as itching, blistering and tissue damage in case of skin contact, and coughing, wheezing and asthma-like symptoms in case of inhalation.

It is well recognized that the route of exposure may have an impact on the observed symptoms. However, it is also becoming increasingly clear that chemical compounds may have intrinsic properties that preferentially lead to sensitization of the skin or the respiratory tract, also referred to as allergic contact dermatitis (ACD) and occupational asthma (OA), respectively. This understanding has an impact on how chemicals are safety tested and labeled for potentially hazardous effects.

In both cases, these kinds of safety assessments have historically been carried out using animal experiments. However, public opinion, concern for human environmental health and economic interests have lead to legislations within the EU that prohibits the use of animal experiments to perform safety assessments on cosmetics and any ingredients thereof, a trend that is currently spreading both globally and across market and industry segments. Thus, there is an urgent need to develop animal-free methods for assessment of chemical sensitizers. While several animal-free, so called in vitro assays for assessment of skin sensitizers have been proposed, the demand for an assay that accurately and specifically predicts and classifies chemical respiratory sensitizers remains unfulfilled.

SenzaGen AB, the beneficiary of this Horizon 2020 grant, specializes in the development of in vitro methods for assessment of immunotoxicological endpoints. To this end, SenzaGen AB has developed the proprietary GARD platform. GARD – Genomic Allergen Rapid Detection – is a state of the art assay for assessment of chemical sensitizers. It is based on measuring the activation state of human immune cells, by quantifying the gene regulation mechanisms induced in the cells following chemical exposure. By using state-of-the-art gene expression technologies, high informational content data is generated, that allows the user to get a holistic view of the cellular response induced by the test substance.

Based on the GARD platform, GARDskin was the first application described and is consequently the most advanced in terms of regulatory acceptance. A blinded ring trial was conducted in 2017 and a full validation report was recently submitted to ECVAM and OECD scientific advisory boards for review. The data demonstrates that GARDskin is a powerful tool for assessment of chemical skin sensitizers, with a predictive accuracy of 93,8% and excellent reproducibility between laboratories. Consecutively, GARDskin is currently the most accurate test for assessment of skin sensitizers on the market.

Of certain interest in the current context, however, is the GARDair application. It is a novel assay that has demonstrated the capacity to accurately classify respiratory sensitizers. Furthermore, recent research has aimed to broaden the applicability of GARDair for specific assessment of chemical respiratory irritants. Thus, GARDair has the capacity to be the first test method that specifically classifies chemicals as respiratory sensitizers or irritants, two endpoints to which validated prediction models currently do not exist.

While proof-of-concept studies have been presented, industrial implementation of the proposed methodologies will require further resources, which have been granted by Horizon 2020. In this context, the specific objectives of this project are I) to confirm the scientific validity of proposed biomarkers for respiratory sensitization, as well as explore novel biomarkers for respiratory irritation, and II) to transfer any established genomic biomarker-based assa

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The period has comprised a large focus on R&D activities. The overall goal has been to identify and confirm the validity of genomic biomarkers for respiratory sensitization and irritation, and the application of such genomic biomarkers in the design of predictive assays for the respective biological endpoints. Whole genome analysis has been conducted on data generated by both genomic microarrays and next-generation sequencing technologies. Data was analyzed using state-of-the-art bioinformatics techniques. Based on the bioinformatical findings, gene signatures have been identified and draft predictive models based on machine-learning techniques have been designed, both considered key milestones for the further progression of the project.

The period has also comprised an upscaling of the SenzaGen commercial organization. Exploitation plans for the project are being developed and implemented. Project results were continuously reported to the scientific community, clients, partners and investors through written reports, presence at conferences and social media activities. Marketing material has been created, aimed for various target groups and key opinion leaders. Potential leads to future licensing of the technology to partner laboratories have been secured.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

According to current legislations within the EU, testing of a chemical’s ability to induce respiratory sensitization is to be performed if relevant and possible, with methods approved for the specific purpose. However, no such methods exist. Still, while not approved for regulatory use and registration, various assays based on animal experimentation have been proposed. However, the usage of such methods conflicts with current recommendations to use primarily in vitro methods to assess sensitization. Thus, the current state of the art is considered to be at baseline level.

It is expected that the GARDair project will advance the current state of the art by I) demonstratating the functionality and applicability of a novel technology for assessment of respiratory sensitizers, thus fulfilling European legislations and recommendations previously not achieved, and II) advancing said legislations to better reflect the current technological state of the art.

The proposed technology has the potential to not only save thousands of animal lives, but also to provide a broad spectrum of industries with an affordable and more accurate alternative to current animal-based methods. Ultimately, the GARD technology will contribute to technical and regulatory progress in this domain.

In conclusion, the project is expected to have a profound impact on various aspects of society. Examples include, but are not limited to, the technological advancement of the state of the art, allowing for safe and resource effective product development in chemical- and pharma-associated industries, animal welfare, increased environmental health and quality of life in sensitized individuals, which in turn contributes to the alleviation of economic burdens associated with disease.

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