Advancing Gene Transfer Capabilities

forthcoming

Innovation: We recently developed a targeted lipid nanopar We recently developed a targeted lipid nanoparticle (tLNP) that can insert a gene directly into the genome of T cells in vivo, with efficiency comparable to viral methods. This innovation creates a unique opportunity to track gene delivery using barcoded synthetic vectors. These barcodes help us understand the key factors needed for effective DNA delivery and the biological consequences of gene transfer. Background: Gene therapy holds great promise for treating various diseases. Viral vectors are currently the most common method for gene transfer, but they come with limitations like size restrictions on nucleic acids, triggering immune responses, and complicated production processes. Synthetic vectors like LNP have made significant strides, as shown by the success of mRNA COVID-19 vaccines, which demonstrate the efficacy, scalability and cost-effectiveness of LNP. However, LNP have struggled with efficient gene transfer. Improving this is challenging due to the vast nanomedicine design space and poor correlation between in vitro and in vivo results. Barcoding technology has revolutionized LNP design by allowing higher throughput screening, enabling comprehensive sampling of the design space in living organisms. To apply this to gene transfer, a working prototype is necessary. Our recent success with LNP-mediated gene transfer serves as this foundation for rational optimization of synthetic vectors using DNA-encoded peptide barcodes. Objectives: The AGTC project will explore three main research lines: 1. Nanomedicine Design: Efficiently explore the design space to optimize LNP. 2. Targeting: Investigate precision and flexibility of targeting, particularly in T cells. 3. T Cell Biology: Link gene transfer to biological activity, focusing on CAR T cells. Outcomes: AGTC will enhance our understanding of what drives effective DNA delivery, paving the way for a new generation of synthetic gene transfer therapies.