Sanofi researchers are hunting for specific sequences on the surface of capsids that will help AAVs enter specific cells–and bypass others. The arrangement depends on a specific sequence of amino acids, and that sequence can be engineered in the lab. Their precise arrangement determines how easily the AAV will be detected, and whether it will target one type of cell or another. These spikes help the AAV interact with proteins on the surface of a cell. The overall shape of a capsid is like a soccer ball with little spikes sticking out. An AAV's capsid determines how visible it is to the immune system, and how easily it can deliver its DNA into different types of cells. Engineering AAVs that can deliver therapeutic DNA hinges on the capsid: a protein "shell" that protects a viral genome. To solve both problems, Sanofi researchers are using a proprietary technology platform that allows them to engineer a wide variety of AAVs. This must be done without wasting any of the precious dose on other cells – particularly those that get recycled before any benefit could be conferred. That is why gene therapies are thought to have only "one shot on goal".Ī second challenge is getting AAVs to deliver their DNA repair kit to specific cells involved in the disease, for example nerve or muscle. If an AAV were introduced to the body twice, neutralizing antibodies would be generated the second time, preventing it from reaching its target. One challenge for AAVs is the immune system, which is built to identify viruses, create antibodies to neutralize them, and commit them to memory.
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