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High-Efficiency Transduction of Liver Cancer Cells by Recombinant Adeno-Associated Virus Serotype 3 Vectors

High-Efficiency Transduction of Liver Cancer Cells by Recombinant Adeno-Associated Virus Serotype 3 Vectors

Published on: March 22, 2011

AAV integration in human hepatocytes.

Dhwanil A Dalwadi¹, Andrea Calabria², Amita Tiyaboonchai¹

¹Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy

|August 30, 2021

Summary

This summary is machine-generated.

Recombinant adeno-associated viral (rAAV) vectors show high integration rates (1%-3%) in human liver cells. These integrated viral sequences are often rearranged and cause host DNA deletions, impacting gene therapy safety.

Keywords:

FRGN capture sequencing genotoxicity rAAV random integration

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Area of Science:

Gene Therapy
Molecular Biology
Hepatology

Background:

Recombinant adeno-associated viral (rAAV) vectors are promising for liver-directed gene therapy.
rAAV is typically considered an episomal vector, but its genome can undergo recombination and integrate into host DNA.

Purpose of the Study:

To determine the chromosomal integration frequency of rAAV in human hepatocytes.
To analyze the integrity of integrated rAAV sequences and associated host genomic changes.

Main Methods:

Human hepatocytes were transduced with rAAV ex vivo and in vivo.
Cells were expanded in a mouse model of xenogeneic liver regeneration.
Capture-PacBio sequencing, a long-read NGS method, was used to detect integration events and vector integrity.

Main Results:

Chromosomal rAAV integration occurred at a high frequency of 1%-3% in both in vitro and in vivo settings.
The majority of integrated rAAV sequences were significantly rearranged.
Host genomic sequences at integration sites frequently exhibited deletions.

Conclusions:

rAAV integration into the host genome is more frequent than previously assumed.
Rearrangements and host DNA deletions at integration sites raise concerns for rAAV gene therapy safety and efficacy.