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Intracranial Injection of Adeno-associated Viral Vectors
Published on: November 18, 2010
Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity
M J Driesse1, M C Esandi, J M Kros
1Department of Neurosurgery, University Hospital Rotterdam, The Netherlands.
Gene Therapy
|September 12, 2000
Summary
High doses of adenovirus vectors injected into cerebrospinal fluid caused meningitis in nonhuman primates and toxicity in rats. Immune responses, including T and B cell infiltration and antibody synthesis, were observed, suggesting careful dose-finding is crucial for clinical applications.
Area of Science:
- Neuroscience
- Immunology
- Gene Therapy
Background:
- Adenovirus vectors are explored for treating central nervous system (CNS) disorders.
- Intrathecal delivery bypasses the blood-brain barrier but may elicit immune responses.
Purpose of the Study:
- To evaluate the safety and immunogenicity of high-dose intrathecal adenovirus vector administration in preclinical models.
- To understand the immune response to adenoviral vectors delivered directly into the cerebrospinal fluid (CSF).
Main Methods:
- Adenovirus vectors (AdenoTk, AdenoLacZ) were administered intrathecally to rats and nonhuman primates (Macaca mulatta).
- Animals were monitored for clinical signs, and CSF and CNS tissues were analyzed for inflammation and vector presence.
- Immunohistochemistry and cytokine analysis (IL-8, IL-6) were performed to characterize immune responses.
Main Results:
- Nonhuman primates developed viral meningitis with T and B lymphocyte infiltrates and intrathecal antibody synthesis, despite no initial clinical symptoms.
- Rats exhibited transient, dose-dependent toxicity including lethargy and weight loss, with evolving meningeal inflammatory infiltrates.
- Elevated IL-8 and IL-6 levels were detected in CSF, suggesting a role in the innate immune response.
Conclusions:
- High-dose intrathecal adenovirus vector administration can induce significant neuroinflammation and toxicity.
- Preclinical data highlight the importance of immune responses to adenoviral vectors in the CNS.
- Careful dose-finding studies are essential before clinical application in treating leptomeningeal metastases.
