Parsons Perez, Maria Christina; (2003) Use of disabled HSV-1 vectors to investigate the function of Reg-2. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Herpes Simplex Virus (HSV) has a number of properties which suggest it may be suitable as a vector for gene delivery to motor neurons. It is naturally neurotrophic and is capable of undergoing retrograde axonal transport in order to reach the neuronal cell body where it may establish latency for the lifetime of the host. Indeed, infection of the motor neuron through a peripheral route would offer an alternative to the more invasive direct approach through the ventral spinal cord. The work presented in this thesis aimed at testing different existing HSV-1 vectors for their capability to efficiently mediate transgene delivery to motor neurons following peripheral inoculation. Attenuated HSV-1 vectors with different combinations in essential and/or non-essential genes were thus identified and were found to vary greatly according to the species and age of animal used. The optimal vectors identified were then used to further elucidate the role of the Schwann cell mitogen, Reg-2. Given that Reg-2 has been strongly implicated in motor neuron regeneration, optimal HSV-1 vectors were used to overexpress Reg-2 in the neonate axotomy model of neuronal death. In this model, Reg-2 appeared to exert a survival effect on the injured motor neurons but not on the sensory neurons of the dorsal root ganglia (DRG). Interestingly, the latter was in accordance with results obtained in studies aimed at analysing the pattern of Reg-2 expression in the DRG. In this case, Reg-2 was found to be strongly upregulated following injury and to follow a dynamic pattern of expression similar to the one observed in the adult animal following peripheral insult. The work described in this thesis provides a basis for the development of vectors for gene delivery to motor neurons and illustrates the use of HSV-1 vectors as tools for the elucidation of gene function.

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