It’s been an elusive goal. Researchers have for years searched for biotherapies that could provide substantial and prolonged pain relief to people with chronic syndromes like osteoarthritis, rheumatoid arthritis, sciatica and persistent post-surgical pain.
Now researchers are a step closer to that reality. In a new study published in NeuroReport, senior author Roy C. Levitt, M.D., lead author Eugene S. Fu, M.D., and their colleagues of the University of Miami Miller School of Medicine Department of Anesthesiology, Perioperative Medicine and Pain Management, showed delivering a key regulatory gene using an adeno-associated viral (AAV) vector could provide prolonged and profound analgesia in mice.
These findings build on their previous research, which demonstrated the carbonic anhydrase-8 gene (mouse symbol, Car8; human symbol, CA8) in the dorsal root ganglia (neurons in the spine) correlated with pain behavior in mice. Specifically, mice missing Car8 were more susceptible to inflammatory pain.
“However, it was unclear how significant this effect was compared to well-known analgesics like morphine,” said Levitt, vice chairman of translational research and academic affairs. “Therefore, the next step in our research strategy was to measure the analgesic effect of the human CA8 expressing gene therapy AAV vector after peripheral nerve injection in comparison to morphine given parenterally.”
“We show that the AAV analgesic effects were profound and equivalent to a very high dose of morphine,” said Fu, associate professor of clinical anesthesiology.
Mice treated with the gene therapy withdrew their hind paws from a thermal heat source a peak mean of four seconds longer. This observation was equal to how mice act when given 10-mg/kg morphine. Allometric conversion of this morphine dose in mice is equal to a 146 mg oral morphine dose in a 60-kg adult human.
Aiming to Fill an Unmet Need
“We believe this approach answers a major unmet need in medicine today,” said Levitt, “Specifically, local anesthetics are amazingly effective against many forms of pain, even severe pain. However, local anesthetics today are very limited by their short duration of action — hours — and the complete inactivation of desirable protective nervous functions, such as motor function and sensory functions that do not mediate pain. What we have created and characterized in our work represents a potential solution to this problem with a very long acting local analgesic biotherapeutic agent.”
Importantly, the research could someday help mitigate a major public health crisis. “We believe that this type of treatment strategy would significantly reduce the need for opioids and possibly stem the tide associated with the opioid epidemic,” Levitt said.
Potential Future Applications
The UM investigators are developing biotherapeutic molecules based on this research.
“These biotherapeutic agents are designed to quiet selected sensory nerves involved in different types of pain, different locations in the body, and with on-off switches to control the action of these analgesics,” Levitt said. The University of Miami has submitted patent protection for this novel biotherapy.
An unanswered question and possible focus of future therapeutic research is the specific role of intracellular calcium in prolonged pain relief.
“We know that CA8 regulates intracellular calcium to produce analgesia, yet CA8 has opposing actions to morphine on calcium release,” Fu said. “We hypothesize that these mechanistic differences may be important in devising strategies for pain therapy.”
Miller School of Medicine