Read theCell paper, published September 10, 2024, titled Safe and Effective Delivery of DNA and RNA Using Proteolipid Vehicles.
DOI: 10.1016/j.cell.2024.07.023 Also available on ScienceDirect
Citation: Brown, D.W., Wee, P., Bhandari, P., Bukhari, A., Grin, L., Vega, H., Hejazi, M., Sosnowski, D., Ablack, J., Clancy, E.K., et al. Safe and effective delivery of DNA and RNA using proteolipid vehicles. Cell. 10.1016/j.cell.2024.07.023.
- This is the first study to demonstrate re-dosable systemic delivery of DNA and RNA to extrahepatic tissues and organs using a fusion-powered nanoparticle.
- FAST-PLVs showed broad biodistribution to tissues beyond the liver and lungs with effective mRNA and DNA delivery in mouse and non-human primate models.
- Administration of follistatin DNA gene therapy with FAST-PLVs raised circulating follistatin levels and significantly increased muscle mass and grip strength.
Summary
Genetic medicines show promise for treating various diseases, yet clinical success has been limited by tolerability, scalability, and immunogenicity issues of current delivery platforms. To overcome these, we developed a proteolipid vehicle (PLV) by combining features from viral and non-viral approaches. PLVs incorporate fusion-associated small transmembrane (FAST) proteins isolated from fusogenic orthoreoviruses into a well-tolerated lipid formulation, using scalable microfluidic mixing. Screening a FAST protein library, we identified a chimeric FAST protein with enhanced membrane fusion activity that improved gene expression from an optimized lipid formulation. Systemically administered FAST-PLVs showed broad biodistribution and effective mRNA and DNA delivery in mouse and non-human primate models. FAST-PLVs show low immunogenicity and maintain activity upon repeat dosing. Systemic administration of follistatin DNA gene therapy with FAST-PLVs raised circulating follistatin levels and significantly increased muscle mass and grip strength. These results demonstrate the promising potential of FAST-PLVs for redosable gene therapies and genetic medicines.