Abstract: Transcutaneous, ultrasound-mediated methods for administering compound(s) to subject tissue(s) are provided. Examples involve positioning an occluding device in a vessel such that the blockage is adjacent to target tissue; engaging the device to occlude outflow from a region adjacent to the tissue; administering compound(s) to the vessel such that it is substantially retained adjacent to the target tissue; determining the location of the compound and/or a detectable adjunct compound optionally administered with the compound, using diagnostic ultrasound, radiography, or fluorography; administering therapeutic ultrasound energy transcutaneously to mediate delivery of the compound across the vessel wall and into adjacent target tissue.

Abstract: Methods, compositions, and systems for treating subject(s) in need of plasma Factor VIII, particularly a subject having preexisting anti-FVIII inhibitory antibodies, are provided. The methods involve administering to the subject a therapeutically effective amount of an inflammation suppressor, a therapeutically effective amount of a CD8+ T cell depleting agent, and a therapeutically effective amount of a composition comprising a lentiviral vector (LV) comprising an optimized FVIII expression cassette expressibly linked to a megakaryocyte-specific promoter. Such methods, compositions, and systems are useful to treat subjects with blood clotting disorder(s), such as hemophilia A.