image: 'Reverse engineering' the BH4 pathway reveals sepiapterin reductase as a new target for analgesic treatments. This take on Michelangelo's famous Sistine Chapel image symbolizes the link between human pain patients and the mouse model: The lab-designed SPR inhibitor (in green), shown within the active pocket of SPR itself (in gray with its atomic structure in colored lines), is the 'bridge' between the two species. view more
Credit: Image: Alban Latremoliere
Non-narcotic treatments for chronic pain that work well in people, not just mice, are sorely needed. Drawing from human pain genetics, an international team led by Boston Children's Hospital demonstrates a way to break the cycle of pain hypersensitivity without the development of addiction, tolerance or side effects.
Their findings, reported June 17 in the journal Neuron, could lead to treatments for chronic pain conditions caused by nerve damage, such as diabetic peripheral neuropathy (DPN) and post-herpetic neuralgia (PHN), as well as chronic inflammation, 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 with Michael Costigan, PhD. "Here, we used human genetic findings to guide our search from the beginning."
In 2006, Costigan, Woolf and colleagues showed in Nature Medicine 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 produce less BH4 after nerve injury. This suggested that BH4 regulates pain sensitivity.
"We wanted to use pharmacologic means to get the same effect as the gene variant," says Alban Latremoliere, PhD, also of Boston Children's Kirby Center, who led the current study along with Woolf and Costigan.
In a "reverse engineering" approach, the researchers modeled the human biology in mice. They first showed that mice with severed sensory nerves produce excessive BH4, churned out both by the injured nerve cells themselves and by macrophages--immune cells that infiltrate damaged nerves and inflamed tissue. Mice engineered to make excess BH4 had heightened pain sensitivity even when they were uninjured, suggesting that BH4 is sufficient to produce pain. On the flip side, mice that were genetically unable to produce BH4 in their sensory nerves had decreased pain hypersensitivity after peripheral nerve injury.
"We then asked, if we could reduce production of BH4 using a drug, could we bring about reduction of pain?" says Latremoliere.
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 the nerve injury (or accompanying inflammation) but did not affect nociceptive pain--the protective pain sensation that helps us avoid injury.
Fine-tuning pain relief
Because BH4 is active all over the body, with important roles 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 and colleagues 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."
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Woolf is academic cofounder of Quartet Medicine, a company launched in 2013 that plans to test small-molecule inhibitors of BH4 synthesis. Highlighted by Nature Biotechnology as a top startup in 2014, Quartet has received $17 million in venture funding from Atlas Ventures, Pfizer, Novartis and the Partners Innovation Fund.
Supporters of the study include the National Institutes of Health (R01NS58870, R37NS039518, RO1NS074430, RO1DE022912); the Foundation for Peripheral Neuropathy; the Anesthesia Trailblazer Award 2014; the Massachusetts Life Science Consortium; and the Technology Development Fund, Neurodevelopmental Behavior Core and Pharmacokinetics Core, Boston Children's Hospital.
Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including 7 members of the National Academy of Sciences, 11 members of the Institute of Medicine and 9 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital, Boston Children's today is a 397-bed comprehensive center for pediatric and adolescent health care and the primary pediatric teaching affiliate of Harvard Medical School. For more, visit vector.childrenshospital.org and follow us on Twitter (@BostonChildrens @BCH_Innovation), Facebook and YouTube.
Journal
Neuron