*Please note all spring 2020 seminars will be online and hosted on ZOOM.

Zoom Link: https://ucla.zoom.us/j/3578398609

Selective Organ Targeting (SORT): A strategy for effective tissue specific mRNA delivery and CRISPR/Cas gene editing

CRISPR/Cas gene editing and messenger RNA (mRNA)-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently impossible to rationally design nanoparticles that selectively target specific tissues. In this presentation, I will describe a universal strategy termed Selective ORgan Targeting (SORT) wherein nanoparticles (including DLNPs, SNALPs, and LLNPs) are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen-, and liver-targeted SORT LNPs selectively edited therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells, and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9 ribonucleoprotein (RNP) complexes. It is envisioned that SORT will dramatically accelerate development of protein replacement and gene correction therapeutics in targeted tissues.

Biography:

Dr. Daniel J. Siegwart is an Associate Professor in the Department of Biochemistry and Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. He received a B.S. in Biochemistry from Lehigh University (2003), and a Ph.D. in Chemistry from Carnegie Mellon University (2008) with University Professor Krzysztof Matyjaszewski. He also studied as a Research Fellow at the University of Tokyo with Professor Kazunori Kataoka (2006). He then completed a Postdoctoral Fellowship at MIT with Institute Professor Robert Langer and Professor Daniel G. Anderson (2008-2012). The central goal of the Siegwart Lab is to use materials chemistry to solve challenges in disease therapy and diagnosis. An array of coding and non-coding RNAs can now be used as therapeutics (siRNA, miRNA, tRNA, mRNA, CRISPR RNAs) because they are able to manipulate and edit expression of the essential genes that drive disease development and progression. Although great advances have been made in the delivery of short RNAs, the ideal chemical and formulation composition is poorly understood for longer RNA cargo. The Siegwart Lab aims to discover and define the critical physical and chemical properties of synthetic carriers required for therapeutic delivery of small (e.g. ~22 base pair miRNA) to large (e.g. ~5,000 nucleotide mRNA) RNAs. They have designed synthetic carriers for CRISPR/Cas and applied these technologies for correction of genetic diseases. Their research is grounded in chemical design and takes advantage of the unique opportunities for collaborative research at UT Southwestern.