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ePaper created 2013-09-24, 11:56:35 | version 1.25.20
78 Initial situation Herpes simplex virus infections are among the most common skin diseases. More than 90 percent of the world’s population is infected with Type 1 Herpes simplex (HSV-1). Aside from the characteristic skin lesions, HS viruses can also cause seri- ous conditions involving other organs (ocular herpes), as well as the central nervous system (herpes encephalitis, herpes meningitis), which may prove fatal. Until now, there is still no effective treatment for herpes infections available. HSV infec- tions have been exclusively treated with antivirals so far, main- ly nucleoside analogues. These are merely able to alleviate the symptoms and to shorten the duration of the infection but cannot prevent reactivation of the virus. One aim is therefore to develop an alternative therapy approach for the treatment of HSV-1 infection. RNA interference-mediated therapy approach RNA-based drugs represent a possible alternative to the anti- viral drugs used to date. The use of RNA interference (RNAi) enables the targeted knockdown of individual genes, for ex- ample, those involved in the proliferation of HSV-1. For this purpose, small ribonucleic acid (RNA) molecules (siRNA or miRNA) are introduced into the cells, allowing the targeted in- hibition of the key proteins decisive for viral reactivation, pro- liferation or replication, thereby achieving long-term inhibition of the outbreak of a latent herpes infection. Nanotechnology for targeted drug administration One of the main problems in the application of the RNAi method is the targeted transport of the RNA molecules into the cells and the form of administration. RNA is a naturally unstable molecule, which is rapidly degraded by the body’s enzymes. Furthermore, the negative charge of RNA molecules results in an extremely limited membrane permeability. In or- der to overcome these problems and enable the use of RNA molecules as active agents in herpes treatment, we, in cooper- ation with the Hebrew University of Jerusalem, are developing a formulation of specific RNAs and a biodegradable polymer with nanometer-scale dimensions – also referred to as RNA nano-carrier system. Such a formulation can protect the non- membrane permeable, unstable RNA molecules against deg- radation from the immune system and enable their absorption through the skin. This targeted drug delivery is to be achieved by coupling the nanoparticles to viral envelope protein frag- ments or specific antibody fragments, which are targeted to a specific epitope of neural cells. Thus, the nanoparticles are specifically targeted to neural cells, which are potentially in- fected with HSV-1. Whereas, the coupling of viral envelope protein fragments to nanoparticles enables targeted delivery for all cell types. Competencies and technology Complex, cell-based test systems have been developed at the Fraunhofer IGB for many years. This expertise will be em- ployed to prove the effectiveness and compatibility of the oligonucleotide-based drug and its formulation. The Activity- Selectivity (AS) assay allows the effectiveness and simultane- ously the compatibility of the RNA nano-carrier formulation to be examined [1]. Accompanying examinations of the im- munomodulatory effects of the carrier are performed with the cell-based pyrogen assay developed and patented at the IGB [2]. Cell or membrane permeability, as well as continu- ing efficacy studies of the nano-carriers loaded with specific miRNA are carried out in an established co-culture system. TARGETED DRUG DELIVERY – RNA- MEDIATED TREATMENT OF HSV-1 INFECTIONS Dipl.-Biol. (t. o.) Ina Hogk, Dr. rer. nat. Anke Burger-Kentischer PHARMACY 1 2 3