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Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles

2024; Cell Press; Volume: 187; Issue: 19 Linguagem: Inglês

10.1016/j.cell.2024.07.023

1097-4172

Douglas W. Brown, Ping Wee, Prakash Bhandari, Amirali B. Bukhari, Liliya Grin, Héctor Vega, Maryam Hejazi, Deborah Sosnowski, Jailal Ablack, Eileen K. Clancy, Desmond Pink, Jitendra Kumar, Maria Paola Solis Ares, Suellen Lamb, Rodrigo Quevedo, Bijal Rawal, Fahed Elian, Natasha Rana, Luis Carlos Morales, Natasha Govindasamy, Brendan Todd, Angela Delmage, Somnath Gupta, Nichole McMullen, Duncan S. MacKenzie, Perrin H. Beatty, Henry David Mogollón García, Manoj Parmar, Jennifer Gyoba, Chandra H. McAllister, Matthew Scholz, Roy Duncan, Arun Raturi, John D. Lewis,

RNA Research and Splicing

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.