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Herpes simplex virus vectors and gene transfer to brain
J C Glorioso1, W F Goins, D J Fink
1Department of Molecular Genetics & Biochemistry, University of Pittsburgh School of Medicine, PA.
Developments in Biological Standardization
|January 1, 1994
Summary
Researchers are engineering herpes simplex virus type 1 (HSV-1) as a gene therapy vector for the nervous system. Modifications aim to ensure long-term gene expression in neurons by overcoming challenges with viral latency and promoter activity.
Area of Science:
- Neuroscience
- Virology
- Gene Therapy
Background:
- Herpes simplex virus type 1 (HSV-1) is being explored as a gene transfer vector for the nervous system.
- HSV-1's natural ability to establish long-term latency in neurons makes it a promising candidate.
- However, HSV-1's inherent cytotoxicity and challenges with sustained gene expression during latency require significant engineering.
Purpose of the Study:
- To engineer HSV-1 into a safe and effective gene transfer vector for neuronal applications.
- To overcome limitations of viral cytotoxicity and achieve persistent gene expression from the latent viral genome.
- To develop novel promoter systems that ensure reliable foreign gene transcription during neuronal latency.
Main Methods:
- Deletion of viral genes essential for the lytic cycle (e.g., ICP0, ICP27, ICP4) to induce latency.
- Investigation and design of promoter regulatory elements for sustained gene expression.
- Evaluation of various viral and neuronal promoters for their activity during latency.
Main Results:
- Identifying essential viral genes (ICP0, ICP27, ICP4) for deletion to establish latency.
- Observing limitations with existing promoters, showing transient activity or weak expression in the brain.
- Current research focuses on developing auto-regulatable promoters for stable expression, even when the viral genome is chromatin-bound.
Conclusions:
- Engineering HSV-1 for neuronal gene therapy requires deleting lytic genes and developing robust latency promoters.
- Existing promoter strategies are insufficient for sustained gene expression in latent HSV-1 vectors.
- Development of auto-regulatable promoters is a key focus for achieving reliable gene transfer in the nervous system.