Herpes vector-mediated gene transfer in the treatment of chronic pain

Abstract

Chronic pain is a major health concern with up to 50% of patients finding little if any relief following traditional pharmacotherapy. This review describes the treatment of chronic pain using herpes simplex virus type 1 (HSV)-based vectors. HSV can be effectively used to deliver pain-modulating transgenes to sensory neurons in vivo following intradermal inoculation. The vector genome persists in peripheral nerve bodies in an episomal state and serves as a platform for expression of natural pain-relieving molecules that access endogenous antinociceptive circuitry. The vectors are mutated to prevent reactivation from latency or spread to the central nervous system. Dermatome selection for administration of HSV vectors provides targeted delivery of pain gene therapy to primary afferent neurons. This novel approach alleviates pain without systemic side effects or the induction of tolerance and can be used in combination with standard pain treatments.

Figures

Figure 1

Herpes simplex virus (HSV) gene transfer to modify pain perception. The ascending pain transmission pathway is shown in black. Nonreplicating recombinant HSV vectors injected into the skin (a) are carried by retrograde axonal transport to the dorsal root ganglion (DRG) (b) where the vector establishes a pseudo-latent state. Transgene products produced in the DRG are released from afferent nerve terminals in the dorsal horn of spinal cord (c) to modulate nociceptive neurotransmission.

Figure 2

Propagation of nonreplicating herpes simplex virus (HSV) vectors. Replication of wild-type HSV requires the expression of essential immediate-early (IE) genes that are expressed on entry of the viral genome into the nucleus (a). Recombinants for gene transfer are rendered replication incompetent by disruption of expression of one or more essential IE genes (indicated by black circle, b). These replication-incompetent recombinants can be propagated to high titers in complementing cells engineered to express the required IE functions from the cellular genome (c).

Figure 3

Herpes simplex virus vectors have been reported to show analgesic effects in several different rodent models of chronic pain including: inflammatory pain,22 somatic neuropathic pain,11 facial neuropathic pain,12 visceral pain,15 and pain from cancer in bone.18