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 demonstrates a way to break the cycle of pain hypersensitivity without the development of addiction, tolerance or side effects. Their findings were published online today in the journal Neuron.
Chronic pain is a daily fact of life in people with conditions such as diabetic peripheral neuropathy, post-herpetic neuralgia and chronic inflammation. 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,” says Clifford Woolf, MD, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and co-senior investigator on the study with Michael Costigan, PhD. “Here, we used human genetic findings to guide our search from the beginning.”
What were those genetic findings? In 2006, Costigan, Woolf and colleagues showed in Nature Medicine that people having two copies of a variant of the gene for GTP cyclohydrolase (GCH1)—about 2 percent of the population—are at lower risk for developing 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.
From human pain genes to mice
Could a drug replicate the effects of the gene variant? The study in Neuron took a “reverse engineering” approach, modeling the human biology in mice. Led by Alban Latremoliere, PhD, of the Woolf Lab, the researchers first showed that mice with severed sensory nerves produce excessive BH4. The protein was churned out both by the injured neurons and by macrophages (immune cells that infiltrate damaged nerves and inflamed tissue).
Next, the team showed that mice that were genetically unable to produce BH4 in their sensory nerves had visibly less pain hypersensitivity after peripheral nerve injury. On the flip side, mice engineered to make excess BH4 had heightened pain sensitivity even when they were uninjured, suggesting that BH4 by itself is sufficient to produce pain.
“We then asked, if we could reduce production of BH4 using a drug, could we bring about reduction of pain?” says Latremoliere, first author of the Neuron paper.
The answer was yes. As detailed in Nature Biotechnology, French researcher Kai Johnsson, PhD, of École Polytechnique Fédérale de Lausanne, a co-author on the paper, had independently found a sulfa drug that targets sepiapterin reductase (SPR), a key enzyme involved in making BH4. Since sulfa drugs have side effects and variable absorption, the team conducted further screens and structure-based drug design, guided by X-ray crystallography data. This yielded a potent small-molecule SPR inhibitor dubbed SPRi3.
Fine-tuning pain relief
The lab-designed compound effectively blocked BH4 production and reduced the pain hypersensitivity induced by the nerve injury (or accompanying inflammation). And it did this without affecting nociceptive pain—the protective pain sensation that helps us avoid injury.
“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.”
Targeting SPR has an additional benefit: Since 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. In further experiments, the researchers showed that blocking SPR still allowed minimal BH4 production through a separate pathway, reducing pain without causing neural or cardiovascular side effects.
Woolf and Johnsson are academic co-founders of Cambridge, Mass.-based Quartet Medicine, a biotech company launched in 2013. Quartet plans to test additional small-molecule inhibitors of BH4 synthesis and develop BH4 as an objective blood biomarker to measure drug efficacy, given the highly subjective nature in pain. Potentially, BH4 testing could even help identify patients likely to benefit from treatment. Highlighted by Nature Biotechnology as a top startup in 2014, Quartet has received $17 million in venture funding from Atlas Venture, Novartis Venture Fund, Pfizer Venture Investments and Partners Innovation Fund.
The study published today “underscores sepiapterin reductase as an attractive drug target for the development of a potentially safe and efficacious treatment for chronic pain and inflammation,” said Kevin Pojasek, PhD, Quartet’s President and acting Chief Executive Officer, in a press release. Pojasek elaborates on the company’s mission to develop novel painkillers and its enthusiasm for the BH4 pathway in this 2014 blog post.