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Published on: October 11, 2024
Adeno-Associated Virus-Based Gene Therapy for Lifelong Correction of Genetic Disease
Christian M Brommel1, Ashley L Cooney2, Patrick L Sinn1,2
1Program in Molecular Medicine, University of Iowa, Iowa City, Iowa, USA.
Abstract:
The list of successful gene therapy trials using adeno-associated virus (AAV)-based vectors continues to grow and includes a wide range of monogenic diseases. Replication incompetent AAV genomes typically remain episomal and expression dilutes as cells divide and die. Consequently, long-term transgene expression from AAV is best suited for quiescent cell types, such as retinal cells, myocytes, or neurons. For genetic diseases that involve cells with steady turnover, AAV-conferred correction may require routine readministration, where every dose carries the risk of developing an adaptive immune response that renders treatment ineffective. Here, we discuss innovative approaches to permanently modify the host genome using AAV-based platforms, thus potentially requiring only a single dose. Such approaches include using AAV delivery of DNA transposons, homologous recombination templates into safe harbors, and nucleases for targeting integration. In tissues with continual cell turnover, genetic modification of progenitor cell populations will help ensure persistent therapeutic outcomes. Combining the safety profile of AAV-based gene therapy vectors with the ability to integrate a therapeutic transgene creates novel solutions to the challenge of lifelong curative treatments for human genetic diseases.
Insights
Gene therapy using adeno-associated virus (AAV) vectors shows promise for genetic diseases. Innovative AAV methods aim for permanent genome modification, potentially requiring only one dose for lasting treatments.
Area of Science:
- Biotechnology
- Genetics
- Molecular Biology
Background:
- Adeno-associated virus (AAV)-based gene therapy is increasingly successful for monogenic diseases.
- Current AAV vectors often lead to episomal genomes, causing expression dilution in dividing cells.
- Long-term expression from AAV is limited to quiescent cells, necessitating repeat dosing for others.
Purpose of the Study:
- To explore innovative AAV-based strategies for permanent host genome modification.
- To overcome limitations of transient AAV expression in rapidly dividing cells.
- To enable single-dose, lifelong curative treatments for genetic diseases.
Main Methods:
- Utilizing AAV to deliver DNA transposons for integration.
- Employing AAV to deliver homologous recombination templates into safe harbor loci.
- Using AAV to deliver nucleases for targeted genomic integration.
- Focusing on genetic modification of progenitor cells for sustained therapeutic effects.
Main Results:
- Discusses novel AAV platforms enabling permanent genome modification.
- Highlights strategies for achieving sustained therapeutic outcomes in tissues with cell turnover.
- Combines AAV safety with genome integration for potential lifelong cures.
Conclusions:
- Innovative AAV-based approaches offer potential for permanent genetic modification.
- Targeting progenitor cells ensures persistent therapeutic outcomes in dynamic tissues.
- Integrating therapeutic transgenes with AAV vectors presents a novel solution for lifelong genetic disease treatment.
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