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  11. Stable Transduction Of The Neonatal Mouse Liver Using A Hybrid Raav/sleeping Beauty Transposon Gene Delivery System

Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system

Sharon C Cunningham1, Philip M Zakas2, Natsuki Sasaki1

  • 1Gene 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, Australia.

The Journal of Gene Medicine
|August 20, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

A novel hybrid adeno-associated viral (AAV)/Sleeping Beauty (SB) transposon system achieves stable gene transfer in newborn mouse livers. This approach offers a promising new avenue for treating neonatal metabolic liver diseases.

Area of Science:

  • Gene Therapy
  • Molecular Biology
  • Hepatology

Background:

  • Conventional adeno-associated viral (AAV) vectors show limited durability in proliferating cells, hindering treatment for neonatal liver disorders.
  • A previously developed recombinant AAV (rAAV)/piggyBac system demonstrated improved stable gene transfer in hepatocytes.
  • The Sleeping Beauty (SB) transposon system is established for ex vivo gene delivery, but its in vivo liver application via a hybrid rAAV approach is underexplored.

Purpose of the Study:

  • To investigate the efficacy of a Sleeping Beauty (SB)-based dual rAAV virion system for stable gene transfer in the newborn murine liver.
  • To assess the therapeutic potential of this hybrid system for genetic metabolic liver diseases.

Main Methods:

  • Utilized a hybrid rAAV/SB100X dual virion system for in vivo delivery to newborn mouse livers.
Keywords:
murine liverrecombinant AAVsleeping beautystable gene transfer

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  • Employed transposable therapeutic cassettes encoding coagulation factor IX or ornithine transcarbamylase (OTC).
  • Evaluated hepatocyte transduction efficiency, transgene expression stability, and therapeutic outcomes in relevant mouse models.

    • Main Results:

    • The rAAV/SB100X system efficiently transduced hepatocytes, achieving stable transgene expression into adulthood.
    • Compared to conventional AAV, a 4- to 8-fold increase in stably transduced hepatocytes was observed.
    • Significant improvements in factor IX and OTC activity levels were noted, leading to enhanced survival and metabolic correction in treated mice.

    Conclusions:

    • This study presents the first in vivo demonstration of a hybrid rAAV/SB100X transposon system for stable gene expression in the neonatal liver.
    • The findings highlight the potential of this approach for treating genetic metabolic liver diseases with neonatal onset.
    • The rAAV/SB100X system offers a promising strategy for durable gene therapy in rapidly dividing liver cells.