Fraunhofer Project Center for Drug Discovery and Delivery @ Hebrew University of Jerusalem, Israel

Translational Research on Infection, Inflammation, and Innate Immunity

The Fraunhofer Project Center for Drug Discovery and Delivery at the Hebrew University in Jerusalem, Israel, (FPC_DD@HUJI) is a joint research institution of Fraunhofer IGB and the Institute for Drug Research of the Hebrew University. The focus of the project center is on discovery and validation of new antiinfective and anti-inflammatory compounds as well as targeted nanoparticle based delivery systems for virual infections and autoimmune diseases.

The FPC_DD@HUJI is the continuation of the joint project "JRHDD – Joint Research Hub for Drug Discovery and Delivery". It started in October 2018 and will initially be funded for a period of three years. The Project Center is jointly headed by Prof. Dr. Steffen Rupp (Fraunhofer IGB) and Prof. Dr. Gershon Golomb (HUJI).

Range of services

The Fraunhofer Project Center combines several innovative technologies to support pharmaceutical companies in the development of new active substances at the preclinical phase. Main activities are in drug discovery and targeted delivery:

  • Drug discovery/screening
    • Combination of in silico-based methods and cell-based test systems for the identification of anti-infectives and immune modulators
  • Identification and validation of lead structures
    • Complex human-based 3D infection and tissue models with components of the immune system for validation of immune modulators and anti-infectives
  • Drug transport and release
    • Targeted liposomal nanocarriers for the transport of active substances into the target cells

 

Advantages

  • Highly specific in-silico screening for agonists and antagonists of immune receptors using powerful algorithms
  • Complex human-based multicellular 3D in-vitro models for validation of drug candidates and nanocarriers
  • Development of nanocarriers for efficient drug transport and controlled drug release

Identification of immunomodulating agents

A combination of computational chemistry (on the part of HU) and a patented reporter gene assay (from IGB) is used with the aim of finding new Toll-like receptor antagonists (TLR) for modulation of the innate immune response.

During the preceding project “JRHDD – Joint Research Hub for Drug Discovery and Delivery”, 17 potential antagonists with high IC50 value were identified from 1.8 million commercially available molecules, and these were registered for patent [2].

RNA-based drugs against HSV1

TEM image of a cell infected with HSV-1 on a co-culture carrier.

Another focal point is the development of new therapeutic strategies against herpes simplex viruses (HSV). Herpes viruses cause lifelong latent infections in neuronal cells and cannot be eliminated at present. Substances such as antimicrobial peptides kill the virus but are also highly toxic to eukaryotic cells. RNA-based drugs represent a possible alternative to the antiviral drugs used to date. The use of RNA interference (RNAi) makes it possible to switch off the genes involved in the proliferation of HSV-1.

Current challenges in the application of the RNAi method arise from the fact that the inhibitory RNA is rapidly degraded by the body's enzymes and, due to its negative charge, has extremely low membrane permeability. To overcome these problems, the Project Center uses liposomal formulations for the targeted transport of RNA molecules into the infected cell.

Nanocarriers for targeted drug transport

Skin model for in-vitro testing of HSV infections.

For encapsulation and targeted transport of active substances, e.g. siRNAs which block virus replication, liposomal formulations with optimal physico-chemical properties [3] are being developed at the Project Center. Liposomes are efficient drug delivery systems that protect the active ingredient from degradation, improve its pharmacokinetic properties and release a high concentration of active ingredient at the site of action. Targeting is performed using special navigator ligands that bind specifically to cell-type-specific receptors.

The drug-loaded liposomal transport systems (HU) are investigated and analyzed for drug release and activity using 2D and 3D cell-based test systems (IGB) [4, 5]. Various navigator peptide phospholipid formulations have shown an improved delivery of different drug candidates and their activity in 2D and 3D test systems.

Literature

  1. Burger-Kentischer, A., Abele, I. S., Finkelmeier, D., Wiesmuller, K. H., Rupp, S. (2010) A new cell-based innate immune receptor assay for the examination of receptor activity, ligand specificity, signalling pathways and the detection of pyrogens. Journal of Immunological Methods 358: 93-103
  2. Zatsepin, M., Mattes, A., Rupp, S., Finkelmeier, D., Basu, A., Burger-Kentischer, A., Goldblum, A. (2016) Computational discovery and experimental confirmation of TLR9 receptor antagonist leads. J Chem Inf Model 56: 1835-1846
  3. Ron-Doitch, S., Sawodny, B., Kühbacher, A., David, MM., Samanta, A., Phopase, J., Burger-Kentischer, A., Griffith, M., Golomb, G., Rupp, S. (2016) Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV. J Control Release 229:163-71.
  4. Hogk, I., Kaufmann, M., Finkelmeier, D., Rupp, S., Burger-Kentischer, A. (2013) An in vitro HSV-1 reactivation model containing quiescently infected PC12 cells. BioResearch open access 2, 250-257
  5. Kuhbacher, A., Sohn, K., Burger-Kentischer, A., Rupp, S. (2017) Immune cell-supplemented human skin model for studying fungal infections. Methods in Molecular Biology 1508: 439-449

Successful cooperation

The Institute for Drug Research at Hebrew University and Fraunhofer IGB have been working together in various projects. The main topics were on the one hand drug screening by combining in-silico and in-vitro methods for immunomodulating substances and on the other hand the development of new nanotransporters for RNA-based drugs against HSV1.

JRHDD – Joint Research Hub for Drug Discovery and Delivery

Duration: July 2017 – September 2018

The central objective of the JRHDD project was to exploit mechanisms of innate immunity in combination with targeted drug delivery for therapy of infections as well as autoimmune and inflammatory diseases.  Targeting these compounds directly to the site of infection or inflammation will support the healing process significantly. The JRHDD is continued as FPC_DD@HUJI from October 2018.

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Novel drug/gene delivery systems for Herpes Simplex Virus (HSV) therapy

Duration: November 2012 – October 2016

More than 90 percent of the world’s population is infected with Type 1 Herpes simplex (HSV-1). Until now, there is still no effective treatment for herpes infections available. HSV infections have been exclusively treated with antivirals so far, mainly nucleoside analogues. One aim is therefore to develop an alternative therapy approach for the treatment of HSV-1 infection.

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Discovery and delivery of PRR antagonists and agonists to regulate innate immune reaction

Duration: November 2012 – October 2016

Agonists and antagonists of TLRs are a promising new therapeutic approach for immunotherapy by using them as immunomodulators. The possible spectrum of indications ranges from allergies, infections and tumors, up to autoimmune diseases. It is the aim of this international project at Fraunhofer IGB to seek out new TLR antagonists/agonists, in order to be able to treat inflammatory reactions and allergies.

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Funding

The Project Center is supported on the German side with funds from the PROFIL program of Fraunhofer-Gesellschaft and from Fraunhofer IGB. PROFIL supports institute initiatives abroad with a long-term perspective and strategic importance. On the Israeli side, the Project Center is supported by  the Hebrew University of Jerusalem.