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Engineering and Evolution of Synthetic Adeno-Associated Virus AAV Gene Therapy Vectors via DNA Family Shuffling
Published on: April 2, 2012
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Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration
Jenny A Greig1, Kelly M Martins1, Camilo Breton1
1Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nature Biotechnology
|November 6, 2023
Summary
Adeno-associated virus (AAV) gene therapy shows initial high transgene expression in primates, followed by a stable, lower expression. Vector DNA persists, with integration occurring in a small fraction of cells.
Area of Science:
- Gene Therapy
- Hepatology
- Virology
Background:
- Liver-based adeno-associated virus (AAV) gene therapies face challenges with expression efficiency and durability.
- Understanding transduction mechanisms is crucial for improving AAV vector performance in hepatocytes.
Purpose of the Study:
- To investigate the long-term mechanisms of adeno-associated virus (AAV) vector transduction and transgene expression in nonhuman primate hepatocytes.
- To define factors influencing the efficiency and durability of AAV gene therapy in the liver.
Main Methods:
- Intravenous administration of AAV8 and AAVrh10 vectors to nonhuman primates.
- Long-term monitoring (over 2 years) of transgene expression and vector DNA persistence.
- Analysis of vector DNA integration and genomic localization.
Main Results:
- High initial transduction of non-immunogenic transgenes, followed by a decline within 90 days to a stable lower level.
- Persistent vector DNA observed in over 10% of hepatocytes, even after expression loss.
- Immunogenic transgenes showed greater reduction in vector DNA and RNA.
- Genomic integration detected in ~1% of cells at diverse loci, not near cancer-associated genes.
Conclusions:
- AAV-mediated transgene expression in primate hepatocytes is a biphasic process: transient high expression from episomes and sustained low expression, likely from integrated vectors.
- Vector DNA persistence and integration are key features of long-term AAV gene therapy in the liver.
- The findings provide insights into AAV vector behavior, informing the development of more effective liver-based gene therapies.
