Project Summary Advances in genetic technologies have made it possible to develop therapies individualized for specific patients with rare genetic diseases. Consistent with the focus of our CEER on identifying and exploring emerging issues in the ELSI of neuropsychiatric genetics, this project will explore some of the critical ELSI issues raised by individualized treatments for rare genetic disorders. These include substantial societal, ethical, regulatory, and conceptual questions. From a societal perspective, when does the potential benefit to a single patient warrant the resources involved, including a sustained time investment by an entire research team, the costs of developing an individualized intervention, and the ongoing expense of administration? In terms of traditional medical ethics concerns, how can we determine when the possible benefits to the patient exceed the risks of a treatment never before used in humans? This is likely to be a difficult task when, as will often be the case, benefit is seen in some degree of symptom improvement, but not cure, and risks are difficult to anticipate. Even when the physicians involved believe use is warranted, since it will often be parents of a severely affected child making a decision about whether to proceed, what concerns should we have about their abilities to make fully informed decisions? In the regulatory context, who should be overseeing individualized genetic therapies and what standards should they use for review and approval? Can current regulatory and oversight procedures accommodate such cases, or will new procedures need to be developed? From a conceptual perspective, is this best understood as clinical research, medical innovation, or treatment? Or some hybrid of the three? To begin to address these questions, we propose a combined empirical study and ELSI analysis (with a focus on societal, ethical, regulatory, and conceptual questions). We will use a hypothetical case example of a genetic disorder with childhood onset and severe neurological symptoms. We will undertake interviews with patients and parents of children with similar rare genetic disorders, clinical geneticists who diagnose and treat such conditions, and IRB members who will have come face-to-face with new ethical challenges as a result of these approaches (7-10 in each group). After being presented with the hypothetical case, they will be asked to identify the conceptual, ethical, societal, and regulatory issues they perceive, the solutions they envision, and what additional data would be useful in shaping policy. Interviews will be coded and analyzed, with their results forming the basis for our mapping of the issues, conceptual analysis, and proposed research agenda.