Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles
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.
Authors
- Duncan S. MacKenzie
- Henry David Mogollón García
- Arun Raturi (ORCID: https://orcid.org/0000-0001-6972-6078)
- Desmond Pink (ORCID: https://orcid.org/0000-0002-7543-3199)
- Maryam Hejazi
- Brendan Todd (ORCID: https://orcid.org/0000-0002-3536-6382)
- Luis Carlos Morales (ORCID: https://orcid.org/0000-0003-4194-2961)
- Liliya Grin
- Prakash Bhandari
- Amirali B. Bukhari (ORCID: https://orcid.org/0000-0003-0543-1339)
- Jennifer Gyoba
- Roy Duncan (ORCID: https://orcid.org/0000-0002-5162-5081)
- Jailal Ablack (ORCID: https://orcid.org/0000-0001-6156-4967)
- Héctor Vega
- Fahed Elian
- Deborah Sosnowski
- Somnath Gupta
- Suellen Lamb
- Eileen K. Clancy (ORCID: https://orcid.org/0000-0001-9565-7985)
- Perrin H. Beatty (ORCID: https://orcid.org/0000-0002-9240-447X)
- Nichole McMullen (ORCID: https://orcid.org/0000-0002-0710-5900)
- Matthew Scholz (ORCID: https://orcid.org/0000-0003-3686-1227)
- Bijal Rawal
- Chandra H. McAllister
- Ping Wee (ORCID: https://orcid.org/0000-0002-9566-8622)
- John D. Lewis (ORCID: https://orcid.org/0000-0002-7734-1204)
- Douglas W. Brown (ORCID: https://orcid.org/0000-0003-0790-3408)
- Jitendra Kumar (ORCID: https://orcid.org/0000-0003-4222-446X)
- Manoj Parmar
- Rodrigo Quevedo
- Angela Delmage
- Maria Paola Solis Ares
- Natasha Govindasamy
- Natasha Rana
Institutions
- Dalhousie University (CA)
- University of Alberta (CA)
- Adaptive Biotechnologies (United States) (US)
Publication Details
- Journal
- Cell
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.cell.2024.07.023
- Citations
- 57
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 13.33