By Pat Anson, Editor
After more than a decade of study, researchers at Boston Children’s Hospital are close to developing a new class of non-narcotic drugs that relieve chronic nerve pain by targeting a protein that enhances pain and inflammation.
Their findings, reported in the journal Neuron, could lead to new treatments for diabetic peripheral neuropathy, post-herpetic neuralgia, and inflammatory diseases like rheumatoid arthritis. Current treatments provide meaningful pain relief in only about 15 percent of patients.
"Most pain medications that have been tested in the past decade have failed in Phase II human trials despite performing well in animal models," notes Clifford Woolf, MD, PhD, director of Boston Children's F.M. Kirby Neurobiology Center and a co-senior investigator on the study. "Here, we used human genetic findings to guide our search from the beginning."
Previous research by Woolf and his colleagues found that people with variants of the gene for GTP cyclohydrolase (GCH1) -- about 2 percent of the population -- are at markedly lower risk for chronic pain. GCH1 is needed to synthesize the protein tetrahydrobiopterin (BH4), and people with GCH1 variants produced less BH4 after a nerve injury. This suggested that BH4 regulates pain sensitivity.
To test their theory, researchers took a "reverse engineering" approach in genetic experiments on mice. First they showed that mice with severed sensory nerves produce excess BH4, created by the injured nerve cells and by macrophages-- immune cells that infiltrate damaged nerves and inflamed tissue.
Mice that were genetically engineered to make excess BH4 had heightened pain sensitivity even when they were uninjured. Conversely, mice that were genetically unable to produce BH4 had lower pain hypersensitivity after a peripheral nerve injury.
"We then asked, if we could reduce production of BH4 using a drug, could we bring about reduction of pain?" said Alban Latremoliere, PhD, also of Boston Children's Kirby Center, who led the current study.
The answer was yes. The researchers blocked BH4 production using a specifically designed drug that targets sepiapterin reductase (SPR), a key enzyme that makes BH4. The drug reduced the pain hypersensitivity induced by nerve injury and without any detectable side effects.
Because BH4 plays an important role in the brain and blood vessels, the goal of any treatment would be to dial down excessive BH4 production, but not eliminate it entirely. Latremoliere showed that blocking SPR still allowed minimal BH4 production through a separate pathway and reduced pain without causing neural or cardiovascular side effects.
"Our findings suggest that SPR inhibition is a viable approach to reducing clinical pain hypersensitivity," says Woolf. "They also show that human genetics can lead us to novel disease pathways that we can probe mechanistically in animal models, leading us to the most suitable targets for human drug development."