Transmissible spongiform encephalopathies (TSEs), such as Creutzfeld-Jakob disease and BSE, are thought to be caused by an abnormal, infectious form (PrPSc) of the normal cellular prion protein (PrPC). PrPSc accumulates in the brains of infected individuals and seems to convert the endogenous PrPC into more PrPSc. There is currently no cure for these diseases, but one idea is to take advantage of naturally occurring forms of PrPC that cannot be converted to PrPSc. These can have dominant negative effects and could thus be used for gene therapy. On p. 5591, Véronique Perrier and co-workers show this approach holds promise. They demonstrate that lentiviral gene transfer can be used to deliver the PrP mutants Q167R and Q218K into chronically PrPSc-infected cultured cells. Using vectors derived from feline-immunodeficiency virus (FIV), they obtain an ∼80% transduction efficiency and show that the PrP mutants abolish replication of PrPSc in the cells. The authors go on to show that the FIV-derived vectors can efficiently deliver a β-galactosidase marker to neurons and lymphoreticular cells in vivo. Since both are affected in TSEs, their results represent an important advance towards gene therapy for these diseases.