PROJECT SUMMARY Approximately 50 million people suffer from one or more autoimmune diseases in the US alone. Over the last decades, the discovery of biologics has considerably improved the care for patients with autoimmune diseases. However, current treatments require weekly or more frequent injections and can lead to missed doses and to poor patient compliance, especially in the younger population. Slow-release formulations of therapeutics have been developed, but these still require multiple administrations. Since many of the novel therapeutics on the market or being developed to treat multiple sclerosis, rheumatoid arthritis, and other T lymphocyte-mediated chronic autoimmune diseases are biologics, our long-term goal is to have the body itself produce the therapeutic for sustained release, using the liver as a “bio-factory”. As a first step, through this high risk / high reward R21 project, as a proof of concept, we propose to develop an adeno-associated virus (AAV) based methodology to induce the production of an immunomodulatory peptide by rat liver and test its efficacy in rat models of multiple sclerosis and rheumatoid arthritis. Specifically, we will define the relationships between vector dose and liver transduction, as well as immunomodulator activity in the plasma (Specific Aim 1). We will then determine the efficacy of this novel gene therapy for correcting two autoimmune diseases, multiple sclerosis and rheumatoid arthritis, in rats (Specific Aim 2).