HSV gene transfer in the treatment of chronic pain

Abstract

It has proven difficult to use systemic administration of small molecules to selectively modulate nociception. Over the past decade, we and others have developed non-replicating herpes simplex virus (HSV)-based vectors to treat chronic pain. Subcutaneous inoculation of an HSV vector effectively transduces sensory neurons in the dorsal root ganglion; release of transgene-coded inhibitory neurotransmitters or anti-inflammatory peptides reduces pain-related behaviors in rodent models of chronic inflammatory and neuropathic pain. A phase 1 trial of this therapy in patients is set to begin soon.

Fig. 1

HSV-mediated gene transfer approach (schematic). The vector inoculated under the skin is taken up by sensory nerve terminals and carried to the neuronal cell body in the DRG by retrograde axonal transport. Latent vector genomes in the nucleus produce the transgene product that is then transported to the afferent terminals in the dorsal horn of spinal cord.

Fig. 2

Subcutaneous inoculation of the endomorphin-2 expressing vector (QHEND) one week prior to complete Freund’s adjuvant (CFA) delays the onset of mechanical allodynia. The loss of effect by 4 weeks after vector inoculation (3 weeks after CFA) corresponds to the known timecourse of HSV mediated transgene expression driven by the HCMV IEp. QDZHG: the control vector.

Fig. 3

Subcutaneous inoculation of the GAD-expressing vector (QHGAD67) one week after selective L5 spinal nerve ligation (vertical arrow) provides a substantial antiallodynic and anti-hyperalgesia effect that can be reestablished by reinoculation.

Fig. 4

The effect of vector inoculation on spontaneous and dilatory pain in mice with osteogenic sarcoma in the head of the femur (inset).