(571d) Non-Viral Delivery of Gene Therapy and Gene Editing Using Polymer Nanoparticles

Despite the potential of gene therapy and gene editing, the lack of efficient targeted delivery systems limits the areas of therapeutic application. Even the most advanced delivery system, adeno-associated viruses (AAVs), faces issues like inefficient targeted delivery, pre-existing immunity, and genome integration. Non-viral delivery systems are an alternative with several advantages: low manufacturing cost, low chance of pre-existing immunity, and no genome integration. However, efficient targeted delivery beyond the liver has been a recurring challenge. Previously, our group demonstrated that CRISPR/Cas9 ribonucleoprotein (RNP) can be delivered to the brain in mice by polymer nanoparticles via direct intracranial (IC) injection. Compared to invasive IC injections, intrathecal lumbar (IT-L) injection is a minimally invasive alternative. Our study focused on the IT-L delivery of polymer nanoparticle encapsulated mRNA and RNPs. We synthesized a library of novel polymers and screened it in vitro to identify polymers that efficiently encapsulated mRNA and transfected primary human neural progenitor cells. We then evaluated candidate polymers to deliver CRE mRNA in vivo in a Loxp luciferase reporter gene mouse model. Iterative medicinal chemistry was conducted on the candidates to improve the efficiency of delivery in vivo. Our process identified a polymer that can efficiently encapsulate and deliver macromolecule cargos to the brain via IT-L administration.

Lastly, I will share my thoughts on the changes in the startup ecosystem and my story of founding a new startup company in the Bay Area.