Safe and effective invivo delivery of DNA and RNA using proteolipid vehicles

Authors
Douglas W. Brown, Ping Wee, Prakash Bhandari, Amirali Bukhari, Liliya Grin, Hector 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 Morales, Natasha Govindasamy, Brendan Todd, Angela Delmage, Somnath Gupta, Nichole McMullen, Duncan MacKenzie, Perrin H. Beatty, Henry Garcia, Manoj Parmar, Jennifer Gyoba, Chandra McAllister, Matthew Scholz, Roy Duncan, Arun Raturi, John D. Lewis


Lab

Journal
Cell

Abstract

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.

Keywords/Topics
encapsulation FAST ;proteins FAST - PLV ;gene therapy ;nucleic acid delivery ;proteolipid vehicle PLV ;p14endo15; follistatin; extra - hepatic biodistribution

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.cell.com/cell/fulltext/S0092-8674(24)00783-9

Produits associés

Test d'agrippement

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