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Adenoviruses as gene-delivery vectors took a hit 20 years ago, with the tragic death of a young man who was being treated for ornithine transcarbamylase deficiency using an adenovirus-delivered gene therapy. Since then, adeno-associated viruses (AAVs) and lentiviruses have been the mainstay gene deliverers. With their 2022 start-up Vector Biopharma, Andreas Plückthun of the University of Zurich and serial pharmaceutical executive Lorenz Mayr aim to bring adenoviruses back. In this, his fourth start-up, Plückthun has turned his protein engineering acumen to the task of solving several challenges that plague delivery vehicle designers: inactivation by the immune system, nonspecific uptake by the liver and restrictions on payload size. Their platform, described in a 2013 Proceedings of the National Academy of Sciences paper and called SHREAD (for SHielded REtargeted Adenovirus), takes on all three issues. It's essentially an empty adenovirus shell, which, being devoid of any genetic material, can harbor as much as 37 kilobases of nucleic acid. It is cloaked with a human protein that makes it invisible to the immune system, and it is adorned at each vertex, with triplets of high-affinity targeting moieties. “If someone can shield [a therapy] from the immune system, if they could make it highly targeted, you can open up the door, which was pretty much blocked from the last decades,” says Mayr, who, before stepping up to lead Vector as CEO, was a principal in or served on the board of several major pharma companies.