Disease Models

Viele Arzneimittelkandidaten fallen in der klinischen Prüfung aufgrund zu geringer Wirkung, Toxizität oder pharmakokinetischer Mängel durch. Daher sind prädiktive präklinische und klinische Krankheitsmodelle zur Evaluierung von Krankheitshypothesen und zur differenzierten Validierung der Aktivitätsprofile von Wirkstoffen notwendig.

Das Institut besitzt langjährige Erfahrung in der Entwicklung von »Krankheitsmodellen«, die zur Charakterisierung von Wirkstoffkandidaten hinsichtlich ihrer Pharmakodynamik und -kinetik verwendet werden können.

In vitro Testsysteme können eingesetzt werden, um neue therapeutische »Targets« zu identifizieren bzw. zu validieren und um die Wirksamkeit, Bioverfügbarkeit und »off-Target«-Effekte von Wirkstoffkandidaten zu prüfen, damit nicht geeignete Wirkstoffkandidaten sehr früh identifiziert bzw. aussortiert werden können.

Hochprädiktive, nah an der klinischen Krankheitssituation ausgerichtete Tiermodelle ermöglichen die Prüfung von Krankheitshypothesen, die Validierung von Krankheitstargets und die Evaluierung von Wirksubstanzen.

Ein umfangreiches Spektrum an humanexperimentellen Modellen kann den Brückenschlag von der Grundlagenforschung zur Klinik bilden, wie z. B. in der Schmerz- und Analgetikaforschung. Des Weiteren existiert ein Humanmodell, das zur Früherkennung der Psoriasis Arthritis durch den Einsatz einer bildgebenden Methode dient.

 

Kernkompetenzen:

  • In vitro Testsyteme zur Charakterisierung der Bioverfügbarkeit, »off-Target«-Effekten und der Wirksamkeit von Substanzen
  • Zelluläre, krankheitsrelevante Testsysteme mit primären Zellen von Patienten oder gesunden Spendern
  • Pharmakodynamische und -kinetische Testung von Wirkstoffkandidaten in krankheitsrelevanten Tiermodellen
  • Erfassung von krankheitsrelevanten Parametern im Tiermodell (z. B. kognitive Read-Outs, klinische Scores, bildgebende Methoden, Blut- und Gewebeanalysen)   
  • Durchführung und Entwicklung von humanen Schmerzmodellen
  • Durchführung und Entwicklung von klinischen Modellen zur Krankheitsfrüherkennung und zum Therapiemonitoring

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.

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

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.