Disease Models

Many drug candidates fail clinical trials due to insufficient efficacy, toxicity or pharmacokinetic deficiencies. Predictive preclinical and clinical disease models are therefore necessary for evaluating disease hypotheses and for the differentiated validation of the activity profiles of active substances.
The Institute has many years of experience in the development of »disease models« that can be used to characterise drug candidates with regard to their pharmacodynamics and kinetics.
In vitro test systems can be used to identify or validate new therapeutic targets and to test the efficacy, bioavailability and "off-target" effects of drug candidates so that unsuitable drug candidates can be identified or eliminated at a very early stage.
Highly predictive animal models that are closely aligned to the clinical disease situation enable the testing of disease hypotheses, the validation of disease targets and the evaluation of active substances.
An extensive range of human experimental models can bridge the gap between basic research and the clinic, e.g. in pain and analgesic research. There is also a human model for the early detection of psoriatic arthritis using an imaging method.

Core competences:

In vitro test systems to characterise the bioavailability, »off-target« effects and efficacy of substances
Cellular, disease-relevant test systems with primary cells from patients or healthy donors
Pharmacodynamic and kinetic testing of drug candidates in disease-relevant animal models
Recording of disease-relevant parameters in animal models (e.g. cognitive read-outs, clinical scores, imaging methods, blood and tissue analyses)
Implementation and development of human pain models
Implementation and development of clinical models for early disease detection and therapy monitoring

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Services

Bioavailability tests

Compounds can be evaluated with regard to their bioavailability both in vitro and in vivo:

Biodissolution
In vitro cell barrier model (transport rate)
Stability tests (liver microsomes, CYP450)
Pharmacokinetic studies in animals and healthy volunteers (clinical phase I study)

Investigation of drug safety profiles

Safety profiles of drug candidates can be investigated:

Mutagenicity test
In vitro cytotoxicity test
Off-target tests
Safety pharmacology studies such as modified Irwin / primary observation tests in animals
Examination of the safety of the drug candidates in healthy volunteers (clinical phase I study)

Effectiveness tests – in vitro

Disease-relevant cell-based test systems can be used to study the effectiveness of compounds and to identify mechanism of action or new targets. Various models with suitable readouts as well as primary cells generated from healthy volunteers or patients are available:

Functional immune cell tests (readout: e.g. cytokines, surface markers, ROS, metabolic activity)
Cell-cell interaction tests (e.g. dendritic cells: T cells; primary immune cells: hepatocytes)
Protein-drug interaction tests (surface plasmon resonance technology, FACS-FRET)
Cellular test systems (e.g. migration, Ca / cAMP / IP3 / PGE2 / NO / ROS signaling)

In addition, new customer-specific in vitro models can be established.

Effectiveness tests – in vivo

With disease-relevant in vivo models, the effectiveness of compounds or the identify mechanism of action or new targets can be evaluated. Validated animal models are available for a wide variety of diseases, including:

Pain (readout: Dynamic Plantar, Hargreaves, optical imaging)
Multiple sclerosis (read-out: clinical scores, motoric behavior)
Rheumatoid arthritis (read-out: clinical scores, optical imaging)
Alzheimer's disease (read-out: plaque IHC, cognition)
Sepsis (read-out: liver values, survival, telemetry)
Dermatitis, Psoriasis, Scleroderma (read-out: skin thickness, optical imaging)

In addition, new customer-specific in vivo models can be established.

Human pain models

Human experimental pain models can be used to predict the effectiveness of potential pain relieving agents at an early stage (Proof-of-Concept). Since different types of pain are represented by different models, a large portfolio of different pain models and readout methods is existing:

Heat and cold pain stimuli
Electrical pain
Pressures (sharp and dull)
Induction of hyperalgesia (capsaicin, menthol, freeze Lesion, UVB)
Numerical Rating Scale (NRS), electroencephalogram (EEG), functional magnetic resonance imaging (fMRI)

The human pain lab is a DFNS-certified laboratory for creating somatosensory profiles using QST (Quantitative Sensory Testing).

Clinical Models for early diagnosis and treatment monitoring

Close networking with the clinics and institutes of the Frankfurt University Hospital enables direct access to relevant clinical samples and patient populations. A special focus of the research group is to develop and validate clinical models for early disease detection and therapy monitoring in the areas of early indifferent arthritis and psoriatic arthritis through innovative imaging processes and clinical assessments as well as biomarker development for use in clinical routine care.

Selected Projects

XCITING

Approx. 30% of patients with plaque type psoriasis also develop a musculoskeletal manifestation of the disease manifest as psoriatic arthritis as the disease progresses. Risk groups affected by this have so far only been insufficiently classified. Innovative imaging methods such as fluorescence optical imaging could detect musculoskeletal inflammatory changes of the hands at an early stage and improve the prediction of the development of psoriatic arthritis. This is being investigated in a prospective Germany-wide observational study.

ImSAVAR

The EU-funded project Immune Safety Avatar (imSAVAR) focuses on developing a platform for integrated non-clinical assessments of the safety and effectiveness of immunomodulatory therapies. The imSAVAR platform is being set up in cooperation with other Fraunhofer institutes, universities, pharmaceutical companies and regulatory authorities. In the context of ImSAVAR, preclinical models will be developed that improve the prediction of the transferability of the safety and effectiveness of immunomodulators to humans.

For this platform, ITMP develops functional immune cell test systems with primary immune cells (e.g. NK cells, CD8 +, Treg cells, TH1 / TH2 cells) and cell-cell interaction models. Furthermore, hepatotoxicity test systems are set up in co-culture with immune cells and validated with biologics that have already been approved. The cytokine level, surface markers, bilirubin release / transport and proliferation are used as disease-relevant measurement parameters.

Partners: 28 partners (academia, EFPIA companies, SME, non-profit organizations)

Additional information

Selected Publications

Blum L., Gul S., Ulshöfer T., Henke M., Krieg R., Berneburg I., Thomas D, Trautmann S., Kurz J., Geyer J., Geisslinger G., Becker K., Parnham M.J., Schiffmann S.
In-vitro safety and off-target profile of the anti-parasitic arylmethylaminosteroid 1o.
Sci Rep. 2020 May 5;10(1):7534
doi: 10.1038/s41598-020-64382-w

Blum L., Geisslinger G., Parnham M. J., Grünweller A., Schiffmann S.
Natural antiviral compound silvestrol modulates human monocyte-derived macrophages and dendritic cells.
J Cell Mol Med. 2020 Jun;24(12):6988-6999
doi: 10.1111/jcmm.15360.

Nieraad, H., de Bruin, N., Arne, O., Hofmann, M.C.J., Schmidt, M., Saito, T., Saido, T.C., Gurke, R., Schmidt, D., Till, U., Parnham, M.J., Geisslinger, G.
Impact of hyperhomocysteinemia and different dietary interventions on cognitive performance in a knock-in mouse model for Alzheimer’s disease.
Nutrients. 2020 Oct 23;12(11):3248
doi: 10.3390/nu12113248

Walter C, Oertel BG, Felden L, Nöth U, Deichmann R, Lötsch J.
Delta-9-tetrahydrocannabinol reduces the performance in sensory delayed discrimination tasks. A pharmacological-fMRI study in healthy volunteers.
IBRO Rep. 2019 Nov 13;7:117-128
doi: 10.1016/j.ibror.2019.11.004.

Köhm M, Zerweck L, Ngyuen PH, Burkhardt H, Behrens F.
Innovative Imaging Technique for Visualization of Vascularization and Established Methods for Detection of Musculoskeletal Inflammation in Psoriasis Patients.
Front Med (Lausanne). 2020 Sep 2;7:468
doi: 10.3389/fmed.2020.00468.