2015

10 projects receive grants in 2015

A total of 1 600 000 SEK was awarded in grants from the Swedish Fund for Research without Animal Experiments in 2015. It was divided between 10 projects. Se recipients and project titles below. More information about the projects will be added shortly.

 

Anders Backlund, Uppsala University, receives SEK 100 000 for the project ”Using computer modeling to decrease the number of animal experiments

“In modern drug discovery, numerous compounds are discovered with a broad variety of biological activities. As a result of this, the pharmaceutical industry tends to face a data-overload, which as a result, unfortunately tends to produce more experimental animal testing. Initial high throughput in silico evaluation of compounds has the ability to transform random screenings into more focused targets and thus considerably impact the success rate of screening programs.

At Uppsala University, the web application ChemGPS-NP (http://chemgps.bmc.uu.se), has been developed for exploration of biologically relevant chemical space using an eight-dimensional (8D) map. The assignment of compounds on the map is based on computed structure derived physico-chemical characteristics. Applying ChemGPS-NP as a tool in such an initial evaluation would assist in compound selection, prioritization and interpretation. A major advantage of this model is the ability to handle very large datasets in determining the extent of similarity for better compound prioritization. In addition, as the system develops, unlimited primary compound toxicity profiling can be done with increasing precision and in a very short time.

The support from Forska Utan Djurförsök will be used initially to build a reference database by charting libraries of compounds with known toxicity, by defining their positions on the chemical 8D map. Once this database is established it will be straightforward to use this tool to exclude compounds that are similar to known toxins and potentially harmful. This will ultimately provide a method to reduce unnecessary animal testing at the earliest stages of drug development.”

Kristina Blom, Medibiome AB, receives SEK 100 000 for the project ”A novel alternative method to study wound healing in infected human living skin exposed to substances and biomaterials.”

“A unique method to analyze how different products affect wound healing in presence of bacteria has been developed where human living skin tissue is cultured in a bioreactor invented by Medibiome (PCT/EP2014/050899). This bioreactor allows the culture of explanted tissue for prolonged period owing to a continuous flow of nutrients which causes minimal stress to the cells. To confirm our preliminary promising results, verification studies have been run. Wound healing processes can be analyzed in presence of bacteria in the Medibiome bioreactor but not in a static system. Critical parameters have been identified and evaluated and are under the progress to be optimized. Furthermore, a validation plan and a validation protocol have been developed.”

Anna Forsby, Stockholm University, receives SEK 200 000 for the project “Further development of the Vitro NociOcular Assay for prediction of irritation potential of chemicals

Martin Hallbäck, Linköping University, receives SEK 200 000 for the project ”Development of a platform to test compounds that may be candidates for stopping Alzheimer’s disease“.

“The goal of the project is to develop an animal independent platform for testing substances that may be candidates for slowing the continuous deterioration in Alzheimer’s and other neurodegenerative diseases.

Alzheimer’s disease is the most common cause of dementia. Despite the best efforts we still do not understand the disease and we lack a cure. The patient suffers a gradual deterioration of brain function leading to complete dependence on caregivers and finally a premature death. In the brain there is a gradual spread of the disease from area to area, but the messenger for this spread has remained elusive. We are finally starting to understand that the spread is caused by the spread of small, toxic, aggregates of misfolded proteins.

Because the living human brain is difficult to access, we depend on good models if we are to understand and combat brain diseases. We work with human cells as a model system and we have developed a model to study how Alzheimer’s and other neurodegenerative diseases can spread between neurons. We now want to develop this method further to use human induced pluripotent stem cells (iPSC) based on mature skin cells reprogrammed into stem cells which we can then mature into different cells, e.g. neurons. The large animal saving effect of this would be to establish a platform that replaces animal models to search for ways to slow or stop the spread of Alzheimer’s disease. By showing that this platform can be used both for large-scale screening of chemical libraries and to investigate specific candidates, we have good hopes to establish the platform as the primary way to investigate this kind of problems within the Alzheimer’s field, but also in similar studies of other dementias with similar pathology.”

Anna Herland, Karolinska Institutet, receives SEK 200 000 for the project ”Stem cell derived cholinergic neurons as in vitro models to reduce animal experiments within neurodegeneration and analgesia

“The aim of our research is to create better model systems of human neuronal tissue. Such models are essential to increase knowledge in basic scientific questions as well as to facilitate pharmaceutical development. We are focused on research within analgesia, drugs that relieve pain, and neurodegeneration. These disease conditions are prevalent, for example it is estimated that one in five Europeans suffer from chronic pain and that about 5.4 million Americans are diagnosed with Alzheimer’s disease.

The available models systems for neuronal tissue used today are animals, especially rodents, and human, cancer derived, cell lines. Both systems are strikingly bad at predicting both effects and side effects of drugs. The guiding hypothesis of this project is that neural differentiation of stem cells in combination with three-dimensional cell culture systems can provide highly relevant models of the human brain. We are using human induced pluripotent cells (iPS cells) originating from human skin biopsies. These cells can be differentiated to virtually any specialized cell in the human body; we have developed efficient methods to make them into neurons. By culturing the differentiated neurons in three-dimensional, gel like systems we can recapitulate disease specific phenomena that can not be seen in conventional cell culture systems.

We have furthermore derived iPS cells from skin biopsies from Alzheimer’s patients and when we generate neurons from these cells they show signature of the disease. The Alzheimer specific neurons we generate are easily used multi-parallell screening applications and could be valuable for drug development.  Ultimately our systems could decrease the demand to use animals or animal derived cells both in academic and industrial settings.”

Maria Karlgren, Uppsala University, receives SEK 200 000 for the project  ”A humanized cell model for accurate assessment of molecular transport across the blood-brain barrier

“Developing drugs for treatment of CNS diseases is more difficult as compared to development of drugs for other therapeutic areas. This is due to the blood-brain barrier (BBB) which protects the brain from entry of drugs and other xenobiotics. In drug development in vitro and in vivo animal models are used for prediction of BBB permeability. However, these models don’t translate very well to humans. The reason for this is that the drug transport proteins, which are present in the BBB and are important for the barrier function, differs between species. Hence, today the role of human drug transporters in the BBB is often overlooked. This project aims to solve the problem by developing predictive models that take the human transporters expressed at the BBB into account. With these novel models we will be able to both estimate drug delivery to the human brain and to identify the mechanisms involved. After validation, the models will be used for quantification of delivery to the brain of CNS drug candidates for selection of compounds with desired BBB permeability. We are convinced that these refined models will expand the technical platform and provide more predictive and high-throughput BBB models than currently available and thereby reduce the number of animal based experiments in CNS drug development.”

Vesa Loitto, Linköping University, receives SEK 100 000 for the project ”Quantification of ER-stress in immortalized cells refines in vitro toxicity screening/prediction

“In depth understanding and early recognition of cellular and whole organism cytotoxicity in the development of new drugs is essential for the wellbeing of humans and animals. To achieve these goals a large number of animals are sacrificed to identify failures among drug candidates. It is therefore both essential and urgent to find new tools that reduce and replace animal testing.

I have recently developed a live cell-compatible, novel fluorescent biosensor for the assessment of endoplasmic reticulum (ER) stress. The biosensor is currently being tested in cells exposed to various stressors. The goal is to use the sensor during in vitro screening of chemicals and drug candidates, but also to gain deeper understanding of ER stress dynamics in cellular responses. The long-term in this project is to set up an entire battery of several in vitro assays to replace animal testing.”

Pär Matsson, Uppsala University, receives SEK 200 000 for the project ”Models for predicting intracellular drug exposure

“For a pharmaceutical drug to give the desired effect it must reach the organ and the cells that need treatment. In most cases, the pharmacological effect results from that the drug molecule binds to a specific protein inside the target cell. To predict if a new drug will give the desired effect it is thus necessary to determine the amount of drug that is distributed into the different cells of the body.

We have developed a novel experimental method for measuring intracellular exposure to unbound drug – i.e., the concentration that can interact with intracellular targets and metabolizing enzymes. We have shown that our method accurately predicts drug binding in the human liver, and preliminary results indicate equally good predictivity for other human tissues.

We will now establish a unique database of high quality intracellular drug accumulation data. This will be used to develop computational models that will allow prediction of intracellular concentrations directly from a drug’s chemical structure. Drug-like molecules that do not reach their targets in sufficient amounts, or which result in dangerously high concentrations, can thereby be filtered out in the early stages of the drug development process, avoiding unnecessary experiments in laboratory animals and patients.

The developed models can be used to prioritize candidate drugs for further development, ultimately leading to significantly fewer animal experiments in the pharmacological and toxicological evaluation of new drugs.”

Lena Palmberg, Karolinska Institutet, receives SEK 100 000 for the project ”A three-dimensional model based on human cells from the airways to replace animals for controlled nanoparticles aerosol exposures”.

“Good reliable human airway wall models will most likely replace animal models in the study of nanoparticle exposures, a research field under intense growth. Our studies will evaluate unique and relevant airway wall models, both normal and chronic bronchitis-like with primary human bronchial epithelial cells from healthy subjects and smokers with and without COPD. The combination of these sophisticated models with primary human cells and the addition of innate effector cells from different patient groups mimic the in vivo-situation better than animal models where species differences always is an issue. These models with multiple cell types enable us to study cell- to cell interactions and cross-talk between the cells. Our advanced exposure systems allow aerosol exposures of cell cultures to respirable particles. Our chosen test substances of different ambient air pollutants like biodiesel particles and nanoparticles contribute to the development of asthma, chronic bronchitis, COPD and cardiovascular diseases and trigger symptoms in subjects suffering from those diseases. Therefore, with further development and validation, these models could form part of an in vitro testing strategy to reduce the requirement for animal inhalation studies.”

Lena Svensson, Lund University, receives SEK 200 000 for the project ”Replacing animal models by microfluidic vascular models to study cell migration

“We plan to use “lab on a chip”-devices, to create a more physiologically relevant models of the vascular system, thereby creating a better replacement for today’s studies using animals. We will, in short, culture endothelial cells in microchannels, covering an extra cellular matrix mimic, creating a model interior blood vessel wall. This system will enable us to perform microscopy based mechanistic studies of cell migration, on and through the vessel wall, and other cell functions, something which animal models do not readily lend themselves to.

Cell migration through the blood vessels is key function in the immune system whereby leukocytes can spread to a site of infection to deal with foreign threats. Dysfunctional leukocyte migration is of importance in several diseases such as autoimmune diseases. Cellular transmigration is also a key aspect in cancer progression: cancer metastasis is the process during which cancer cells leave their original tumour, move through the surrounding tissue and enter the vascular system. The cancer cells travel through the vascular system and eventually cross the vessel walls (extravasation) and establish new tumours, with detrimental consequences to the patients, causing more than 80% of cancer related deaths. The mechanisms involved in this process are poorly understood and current knowledge relies heavily on animal experiments, either as an end point assay or as highly invasive intravital microscopy.

The development of a more relevant and advanced human physiological model will increase the number of researchers who will choose to go from animal models to human in vitro models. This will not only lead to reduced unnecessary use of animals in the academic setting and pharmacology industry research community but also lead to refined experimental control, giving the user control over several parameters not possible in an in vivo setting.”

Senast uppdaterad: 7 mars 2016