Chronic pain is a serious problem that is often refractory to the best available conventional therapies. Advances over the past decades have provided substantial insight into the anatomy, physiology, and molecular biology of acute pain perception (nociception) and many of the alterations responsible for the transition to chronic pain states. But because a limited repertoire of ion channels, neurotransmitters, and neurotransmitter receptors are employed in common in both pain and non-pain pathways in the nervous system, it has been difficult to identify small molecules that selectively target pain-related pathways.

The use of gene transfer to achieve targeted release of short-lived bioactive peptides in or near the spinal dorsal horn underlies our strategy for gene therapy of pain. Neurons of the dorsal root ganglia (DRG) are transduced by injection of herpes simplex virus (HSV) based vectors into the skin. These naturally neurotropic vectors are carried by retrograde axonal transport from the skin to the neuronal perikaryon of the DRG to effect the focal production of transgene-derived peptides.

We have demonstrated that a nonreplicating HSV vector coding for preproenkephalin reduces pain-related behaviors in rodent models of inflammatory pain, neuropathic pain, and pain caused by cancer in bone. Basic research in our pain program is focused on elucidating the mechanisms underlying the transition from acute to chronic pain, using HSV-based vectors as an important tool.

An HSV vector expressing preproenkephalin is in phase 2 clinical trial for intracxtable pain from cancer (Annals Neurology, 2011). More detail can be found on the Clinical Trials page. A VA translational grant is funding production of a human-grade HSV vector expressing glutamic acid decarboxylase that will be tested in the treatment of neuropathic pain.



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