2. Academic Validation
  3. Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency

Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency

  • Mol Ther. 2024 Jul 2:S1525-0016(24)00403-9. doi: 10.1016/j.ymthe.2024.06.021.
Philip M Zakas 1,  Sharon C Cunningham 2,  Ann Doherty 1,  Eva B van Dijk 2,  Raed Ibraheim 1,  Stephanie Yu 1,  Befikadu D Mekonnen 1,  Brendan Lang 1,  Elizabeth J English 1,  Gang Sun 1,  Miles C Duncan 1,  Matthew S Benczkowski 1,  Robert C Altshuler 1,  Malvenderjit Jagjit Singh 1,  Emily S Kibbler 1,  Gulen Y Tonga 1,  Zi Jun Wang 1,  Z Jane Wang 1,  Guangde Li 1,  Ding An 1,  James B Rottman 1,  Yashvi Bhavsar 1,  Cormac Purcell 1,  Rachit Jain 1,  Ryan Alberry 1,  Nathaniel Roquet 1,  Yanfang Fu 1,  Robert J Citorik 1,  Jacob R Rubens 1,  Michael C Holmes 1,  Cecilia Cotta-Ramusino 1,  William Querbes 1,  Ian E Alexander 3,  William E Salomon 4
Affiliations

Affiliations

  • 1 Tessera Therapeutics, Inc., Somerville, MA 02143, USA.
  • 2 Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia.
  • 3 Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, University of Sydney, Westmead, NSW 2145, Australia. Electronic address: ian.alexander@health.nsw.gov.au.
  • 4 Tessera Therapeutics, Inc., Somerville, MA 02143, USA. Electronic address: wsalomon@tesseratx.com.
PMID: 38981468 DOI: 10.1016/j.ymthe.2024.06.021
Abstract

Recombinant adeno-associated virus (rAAV) vector gene delivery systems have demonstrated great promise in clinical trials but continue to face durability and dose-related challenges. Unlike rAAV gene therapy, integrating gene addition approaches can provide curative expression in mitotically active cells and pediatric populations. We explored a novel in vivo delivery approach based on an engineered transposase, Sleeping Beauty (SB100X), delivered as an mRNA within a lipid nanoparticle (LNP), in combination with an rAAV-delivered transposable transgene. This combinatorial approach achieved correction of ornithine transcarbamylase deficiency in the neonatal Spfash mouse model following a single delivery to dividing hepatocytes in the newborn liver. Correction remained stable into adulthood, while a conventional rAAV approach resulted in a return to the disease state. In non-human primates, integration by transposition, mediated by this technology, improved gene expression 10-fold over conventional rAAV-mediated gene transfer while requiring 5-fold less vector. Additionally, integration site analysis confirmed a random profile while specifically targeting TA dinucleotides across the genome. Together, these findings demonstrate that transposable elements can improve rAAV-delivered therapies by lowering the vector dose requirement and associated toxicity while expanding target cell types.

Keywords

Sleeping Beauty transposase; adeno-associated virus vector; gene addition; lipid nanoparticle; mRNA liver delivery; macaque; ornithine transcarbamylase; partial hepatectomy; transposition.

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