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10.02.2015: Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors

We describe receptor-targeted adeno-associated viral (AAV) vectors that allow genetic modification of rare cell types ex vivo and in vivo while showing no detectable off-targeting. Displaying designed ankyrin repeat proteins (DARPins) on the viral capsid and carefully depleting DARPin-deficient particles, AAV vectors were made specific for Her2/neu, EpCAM or CD4. A single intravenous administration of vector targeted to the tumour antigen Her2/neu was sufficient to track 75% of all tumour sites and to extend survival longer than the cytostatic antibody Herceptin. CD4-targeted AAVs hit human CD4-positive cells present in spleen of a humanized mouse model, while CD8-positive cells as well as liver or other off-target organs remained unmodified. Mimicking conditions of circulating tumour cells, EpCAM-AAV detected single tumour cells in human blood opening the avenue for tumour stem cell tracking. Thus, the approach developed here delivers genes to target cell types of choice with antibody-like specificity.

Publication

Münch RC, Muth A, Muik A, Friedel T, Schmatz J, Dreier B, Trkola A, Plückthun A, Büning H, Buchholz CJ (2015): Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors. Nature Communications 2015 Feb 10; doi: 10.1038/ncomms7246

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March 2015: Gene regulates healing process after myocardial infarction

Reg3beta controls wound-healing process in the myocardium by attracting immune cells to the infarct tissue

In the wake of a myocardial infarction, parts of the myocardium die and are replaced by scar tissue. The formation and stability of scar tissue is key to the survival of patients following an acute myocardial infarction. Scientists at the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now discovered a gene, known as Reg3beta, which plays an important role in healing damaged tissue in the heart.

In their study, the researchers investigated hundreds of proteins that are expressed by surviving myocardial cells. In the process, they discovered Reg3beta. In subsequent experiments it became clear that Reg3beta acts as an attractant of macrophages, specifically promoting their migration into the damaged myocardium. “In mice lacking the Reg3beta gene, far fewer immune cells migrate into the infarction area,” says Lörchner. The result is a disturbed wound-healing process, which has fatal consequences for the animal’s survival. “In comparison to controls with normal Reg3beta activity, we observed cardiac rupture much more frequently in animals without Reg3beta. The heart literally rips.”

The Bad Nauheim-based researchers conclude from their study that Reg3beta plays a key role in the regulation of wound healing. “Because of the reduced migration of macrophages, we observed a disturbed wound-healing process. Thus, the connective tissue produced in mice without Reg3beta was significantly poorer than in control animals. In addition, far fewer new blood vessels formed in the infarction region. Ultimately, this leads to an unstable scar,” says Pöling.

Reg3beta attracts white blood cells to the infarct area: After injection of Reg3beta, many more macrophages (stained green) migrate into the infarct tissue (right) than without injection (left). The nuclei of various cells are stained blue. The white contour shows the outline of a blood vessel. Photo: Max Planck Institute for Heart and Lung Research.

Publication

Holger Lörchner, Jochen Pöling, Praveen Gajawada, Yunlong Hou, Viktoria Polyakova, Sawa Kostin, Juan M Adrian-Segarra, Thomas Böttger, Astrid Wietelmann, Henning Warnecke, Manfred Richter, Thomas Kubin, Thomas Braun: Myocardial healing requires Reg3β-dependent accumulation of macrophages in the ischemic heart. Nature Medicine (2015) doi:10.1038/nm.3816

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