The herpes simplex virus might start getting some good press for a change. Anesthesiology researchers at the University of Miami Miller School of Medicine, in Florida, are using the virus to deliver genetic instructions in the hope of rewriting chronic pain signals at the source.
Spurred by success in animal models and encouraged by results from initial trials in cancer patients, Shaunglin Hao, MD, PhD, Roy C. Levitt, MD, and their colleagues use the virus’s predilection for neurons to their advantage in delivering anti-nociceptive neuromodulating molecules directly to the dorsal root ganglia to treat chronic pain.
Herpes simplex virus (HSV) bears a genome big enough to carry a relatively large “payload” of genetic instructions compared with other vectors, according to the researchers. In addition, HSV remains latent after it enters the neurons of sensory ganglia, a feature that allows gene transfer to continue while evading an immune system reaction, another positive aspect of this approach. Importantly, HSV rendered to prevent replication (“replication-defective”) can still deliver genes during the latency phase exclusively within the sensory nerves targeted.
“We are one of the few centers worldwide working with this innovative technology in preclinical studies,” said Dr. Levitt, director of translational research and clinical professor of anesthesiology, perioperative medicine and pain management at the institution. “We certainly hope to continue this close collaboration with the inventors and develop new applications and innovative uses of this technology to anesthesiology.”
The inventors are David Fink, MD, of the University of Michigan, Ann Arbor, Joseph C. Glorioso, PhD, of the University of Pittsburgh, and their colleagues at Periphagen Holdings, a team that pioneered this HSV-mediated gene-transfer strategy. The group has brought HSV vectors into the clinic in Phase I (Ann Neurol 2011;70:207-212) and Phase II clinical trials for the treatment of intractable cancer pain.
Blocking Pain Signals
The trials have assessed the effectiveness of a modified HSV that delivers a gene that encodes for preproenkephalin. Preproenkephalin is a precursor protein that cleaves to produce the endogenous opioid peptides met-enkephalin and leu-enkephalin. These enkephalin peptides inhibit pain signals in the spinal cord.
Dr. Fink, a neurologist, said his group plans another trial with the enkephalin vector. With funding from the National Institutes of Health and from the Department of Veterans Affairs, they are progressing toward clinical trials of an HSV vector expressing glutamic acid decarboxylase for neuropathic pain and an HSV vector expressing a neurotrophin for the prevention of neuropathy, Dr. Fink said.
Dr. Levitt said the applications of the approach for clinical medicine “seem almost limitless.” For instance, in anesthesiology, “I can envision an approach where we might treat a patient preoperatively with a nerve block and ‘activate’ the dormant pain treatment just before the surgery to treat acute pain, and possibly post-op to treat and/or avoid chronic pain development in susceptible individuals.
“Only time will tell us the true risk–benefit ratio of this approach as these clinical trials and large-scale patient-use progress and new applications are developed,” Dr. Levitt added. He predicted if the current trajectory of research continues and HSV-mediated gene transfer continues to prove safe and effective, a product launch could come within three to five years.
“This is the frontier of modern medicine and where our specialty will benefit enormously in the future,” Dr. Levitt said. “HSV-mediated gene therapy with localized delivery to sensory nerves important to the care of patients who experience pain will transform our specialty, and as a consequence, change the paradigm of current practice.”
Dr. Levitt reported no relevant financial disclosures. Dr. Fink is a co-inventor on patents related to this research.