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esearchers from the Paul-Ehrlich-Institut, together with a research group from the Hannover Medical School, have developed a laboratory model based on lentiviral gene transfer in which therapeutic proteins are targeted to platelets and released in the body. With this newly developed technology, platelets can be used as a transport vehicle for the storage and targeted delivery of therapeutic proteins. The technology opens up a wide range of new therapeutic applications. Molecular Therapy Nucleic Acids reports on the results in its online issue from 3 January 2022.
Platelets are small, anucleate blood cells that are released from their progenitor cells, the megakaryocytes (MK), into the bone marrow. They circulate in the blood and carry numerous bioactive substances in their storage vesicles (granules). The platelets then release these substances after activation. Alpha granules (αG) are the most abundant platelet granules. They store more than 300 different proteins, such as growth factors and cytokines (the messengers of the immune system).
Platelet activation is triggered by the environment, e.g. by vascular injuries, inflammation, or directly by pathogens during an infection. This makes platelets attractive targets for cell therapy. The use of platelets and platelet membrane-coated nanoparticles as drug delivery tools is already being explored, in the treatment of tumours or cardiovascular diseases, for example, or in platelet-directed gene therapy for haemophilia. In order to restrict transgene expression to thrombocytes, lentiviral vectors equipped with switches (promoters) are generally used. These promoters are specific to MKs. Lentiviral vectors are virus-derived gene carriers that cannot replicate and are harmless in this regard.
A research group from the Paul-Ehrlich-Institut, headed by Professor Ute Modlich, Paul-Ehrlich-Institut, in cooperation with a group from the Hannover Medical School, headed by Professor Thomas Moritz, focused on loading platelets with therapeutic proteins and releasing the proteins in a targeted manner. Since protein sorting primarily takes place in MKs, the research team suspected that the expression of transgenic proteins equipped with suitable sorting signals in MKs could enable specific loading into the αGs. Storage in the αGs allows the proteins to remain hidden from the bloodstream until the platelets are activated. This causes the release to occur only in places where the substances are needed. This reduces unwanted reactions of the immune system (immunogenicity) and toxicity also decreases. This strategy aims to deliver high local doses of transgenic bioactive substances to the target site, which may not be well tolerated after systemic administration.
Using two complex molecular-biological strategies, the scientists developed lentiviral vectors for expression in MKs that encode transgenic proteins with specific αG-sorting signals. They were able to mediate the targeted transfer of certain proteins into the alpha granules of in vitro-differentiated human and mouse MKs and in vivo mouse platelets. In addition, an important cytokine, interferon-alpha (IFNα), was successfully stored as a potential antiviral cytokine in vivo in mouse platelets. After platelet activation, the cytokine was released as desired and viral replication was inhibited in vitro.
These newly developed vectors open up a number of new applications for cell therapy by using platelets as carriers for therapeutic proteins.
Woods VMA, Latorre-Rey LJ, Schenk F, Rommel MGE, Moritz T, Modlich U (2022): Targeting transgenic proteins to alpha granules for platelet-directed gene therapy.
Mol Ther Nucleic Acids 27: 774-786.
DOI: https://doi.org/10.1016/j.omtn.2021.12.038
https://www.sciencedirect.com/science/article/pii/S2162253122000038 Open Access Fulltext Version of the Publication
https://www.pei.de/EN/newsroom/press-releases/year/2022/04-platelets-thrombocyte... This Press Release on the Website of Paul-Ehrlich-Institut
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