Studying the role of innate immunity in gene therapy and disease mechanisms

Innate immunity and nucleic acid sensors are involved in an increasing number of biological processes from antiviral defenses to tissue homeostasis and disease. As all current and emerging gene transfer and editing technologies expose cells to exogenous nucleic acids and/or viral vectors, we hypothesize that host antiviral factors and nucleic acid sensors play a pivotal role also in the efficacy and safety of genetic manipulation. On these premises our first aim is to dissect antiviral factors and innate sensing pathways in the context of genetic engineering. Building on our past work, we will address vector signaling and innate immune restriction across delivery platforms and in clinically relevant target cells. These basic studies of vector-host interactions will allow modulation of identified host factors or innate sensing pathways in the context of transduction or gene editing with the goal of rendering gene engineering as inert as possible, while maximizing its efficiency. Secondly, we aim to investigate innate immunity and nucleic acid sensing in the Aicardi-Goutières Syndrome (AGS), a rare monogenic encephalopathy in which aberrant activation of innate sensing is thought to drive disease but the precise molecular mechanisms and cell types involved remain elusive. Here, we will use human induced pluripotent stem cells harboring AGS loss of function alleles to dissect triggers of disease in cells of the central nervous system. These studies will provide insight into the pathological cascades in AGS informing the development of targeted therapies and of stealth gene engineering strategies that remain susceptible to similar mechanisms of innate sensing. Together, our efforts will provide insight into how nucleic acid sensing and innate immune signaling may affect efficacy and safety of gene therapy approaches in clinically relevant target cells as well as to shed light on how these same pathways may contribute to autoimmune and inflammatory pathologies.