Gene therapy for neurological, and in particular neurodegenerative, disease is now a reality. A number of early phase clinical trials have been completed and several are currently in progress. In view of this, it is critically important to evaluate the immunological risk associated with neurological gene therapy, which has clear implications for trial safety and efficacy. Moreover, it is imperative in particular to identify factors indicating potential high risk. In the light of recent advances in understanding immune regulation in the central nervous system (CNS) and with the continued development of new gene delivery vectors, this review critically assesses the current knowledge of immunobiology within the CNS in terms of likely immunological risk pertaining to viral vectors and gene therapy applications for neurodegenerative disease.
An approach currently being explored as treatment for Parkinson's disease is gene therapy. An important question concerns the duration of transgene expression in dopamine neurons and the issues of vector persistence, neuronal damage and the feasibility of readministering vector to the same neuronal population. We show, using an adenoviral vector expressing the LacZ reporter gene, that transgene expression declined over time but with minimal loss of dopamine neurons or vector DNA. Readministration of vector resulted in low levels of transgene delivery to the neurons. Moreover, the neurons to which vector had already been delivered were unable to transport the retrograde tracer fluorogold. Our findings indicate that transgene expression declined in dopamine neurons despite the persistence of virus, and the capacity to readminister vector to these neurons was limited.
The central nervous system (CNS) is a site of relative immunological privilege; despite this it can be a target of the immune system under certain conditions. For example, adenoviral vectors elicit an immune response strong enough to result in antigen elimination, in immunologically primed animals. Fas ligand (FasL) contributes to the immune privilege of certain tissues by inducing apoptosis in activated T cells. We therefore investigated whether local overexpression of FasL could downregulate the immune response to adenovirus in the brain. Adenoviral vectors expressing FasL (AdFasL) and the reporter gene b-galactosidase (Adbgal) were co-injected into the striatum of naïve or immunologically primed mice. A co-injection of an adenovirus lacking a transgene (Ad0) and Adbgal acted as a control. At 2 weeks after inoculation, reporter protein expression was significantly reduced with the AdFasL:Adbgal combination compared with the Ad0:Adbgal controls. This was accompanied by a strong inflammatory cell infiltrate, local demyelination and upregulation of pro-inflammatory cytokine gene expression. These experiments demonstrate that FasL overexpression elicits a pro-inflammatory response in the CNS rather than immunosuppression. This was characterized by chronic inflammation and accelerated loss of transgene expression. Induction of such an unexpected pro-inflammatory response caused by introducing FasL may be a peculiarity of the relative immunoprivilege of the unique environment of the brain.
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