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Adenovirus-mediated transgene expression in nonhuman primate brain.

M C Bohn1, D L Choi-Lundberg, B L Davidson

  • 1Department of Pediatrics, Children's Memorial Institute for Education and Research, Northwestern University Medical School, Chicago, IL 60614, USA. m-bohn@nwu.edu

Human Gene Therapy
|May 26, 1999
PubMed
Summary
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Finding the right adeno-associated virus (AAV) titer is key for sustained transgene expression in primate brains. Too high a viral vector dose triggers immune responses, limiting expression, while lower doses show better persistence.

Area of Science:

  • Neuroscience
  • Gene Therapy
  • Virology

Background:

  • Adenoviral vectors are used for gene delivery to the brain.
  • Understanding optimal vector titers is crucial for effective gene therapy in primates.

Purpose of the Study:

  • To investigate transgene expression duration and host response in primate brains using an E1E3-deleted adenovirus vector.
  • To determine the optimal vector titer for persistent gene expression in the St. Kitts green monkey (Cercopithecus aethiops sabeus).

Main Methods:

  • Injection of E1E3-deleted adenovirus vector carrying the beta-galactosidase (beta-Gal) transgene into the caudate nuclei of 18 monkeys.
  • Administration of dexamethasone and sacrifice at various time points (1 week to 3 months).
  • Quantification of beta-Gal expressing cells and assessment of host immune response via MHC II DR staining.

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Main Results:

  • Transgene expression was observed in neurons and astrocytes at 1 week post-injection.
  • Persistent transgene expression was detected up to 3 months in some cases, with optimal expression at specific titers.
  • Higher vector titers led to intense MHC II DR staining, correlating with reduced transgene persistence, suggesting an immune response.

Conclusions:

  • An optimal range of vector titers exists for achieving persistent transgene expression in primate brains using E1E3-deleted adenoviruses.
  • Elevated vector titers can elicit host immune responses that limit transgene stability.
  • These findings have implications for optimizing gene therapy strategies in non-human primates.