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A herpesvirus vector can transduce axotomized brain neurons
John H Rogers1, Kate Rhodes, Suzanne Roberts
1Department of Physiology, University of Cambridge, Cambridge, UK. jhr11@cam.ac.uk
Experimental Neurology
|October 14, 2003
Summary
Replication-defective herpes simplex virus (HSV) vectors can deliver genes to injured neurons in the adult rat brain. These vectors show potential for promoting axon regeneration after spinal cord injury.
Area of Science:
- Neuroscience
- Gene Therapy
- Regenerative Medicine
Background:
- Gene therapy holds promise for promoting axon regeneration following spinal cord injury.
- Effective transgene delivery requires suitable viral vectors.
- Replication-defective herpes simplex virus (HSV) vectors are being investigated for this purpose.
Purpose of the Study:
- To evaluate the efficacy of replication-defective HSV vectors for expressing a LacZ transgene in injured neurons of the adult rat brain.
- To compare the expression patterns of two different promoter-driven HSV vectors (CMV immediate-early and HSV latency-associated promoters).
Main Methods:
- Adult rats underwent medial forebrain bundle transection to create a lesion.
- Replication-defective HSV/LacZ vectors, utilizing either the cytomegalovirus immediate-early promoter (CS5) or the HSV latency-associated promoter (CS1), were injected near the lesion site.
- Transgene expression was assessed at 2, 5, and 12-14 days post-lesion using LacZ staining.
- Axotomized neurons were confirmed using double immunofluorescence for c-Jun.
Main Results:
- Vector CS5 showed transient transfection near the lesion at 2 days but lacked persistent expression at 5 days.
- Vector CS1 demonstrated sustained LacZ expression in neurons within midbrain regions distant from the injection site, persisting from 5 to 12-14 days.
- Transduced neurons were identified in the substantia nigra pars compacta and parabrachial nuclei, both of which were axotomized by the lesion.
- While some substantia nigra neurons were lost by 12-14 days, transduced neurons persisted; no net loss of transduced neurons was observed in the parabrachial nuclei.
Conclusions:
- Replication-defective HSV vectors can successfully transduce axotomized neurons in the central nervous system.
- Sustained transgene expression (at least 2 weeks) is achievable in these neurons using specific HSV vectors (e.g., CS1 with the HSV latency-associated promoter).
- These findings support the potential of HSV vectors for gene therapy applications aimed at enhancing recovery from spinal cord injury.