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Biological Chemistry

Researchers Mine Genetic Variations In People To Find New Pain Target

Drug Development: Inhibiting an enzyme relieves nerve and inflammatory pain in mice

by Michael Torrice
June 24, 2015 | A version of this story appeared in Volume 93, Issue 26

Structures of BH4 and SPRi3.
Researchers designed a small molecule (SPRi3) that relieves pain in mice by slowing production of tetrahydrobiopterin (BH4) in cells.

Some people have won the genetic lottery when it comes to pain: They have small genetic variations that have been associated with a lower chance of developing serious nerve pain.

Now a team of researchers reports a possible way to mimic the effects of those genetic differences by slowing the production of a certain biomolecule in cells.

“It’s a terrific advance for the field,” which could lead to new pain drug targets, says Theodore Price, a neurobiologist at the University of Texas, Dallas, who was not involved in the study.

Doctors want new pain drugs because current ones often fail to relieve types of chronic pain caused by nerve damage. These medications can also cause serious side effects, including addiction in the case of opioids. “Patients sometimes decide to drop the treatment because the side effects are worse than the pain,” says Alban Latremoliere of Harvard Medical School, a coauthor of the new study.

Researchers have identified some new pain targets through animal studies, but these haven’t yet translated into effective targets in people, Latremoliere says.

Latremoliere and coworkers, including Michael Costigan and Clifford J. Woolf at Harvard, wanted to go after a target they knew was associated with pain in people. So they turned to genetic-lottery winners for help.

These more pain-tolerant people have genetic differences in the gene that codes for the enzyme GTP cyclohydrolase 1 (GCH1). The enzyme plays a critical role in the production of tetrahydrobiopterin (BH4), a molecule that other enzymes use to catalyze reactions. Some members of the team had previously shown that rats suffering from painful nerve injuries had high levels of BH4. So the researchers wanted to see whether lowering those levels led to less pain.

In the new study, the researchers genetically engineered mice to produce a defective version of GCH1 in their sensory neurons. These mice produced less BH4 in those cells and showed less sensitivity to pressure applied to their paws, an indicator of pain, after an injury to their nerves.

The team then designed and tested an inhibitor for the BH4-production pathway. The molecule didn’t block GCH1 because inhibiting that enzyme would completely shut down BH4 synthesis, possibly leading to side effects. BH4 is critical for making a handful of neurotransmitters and nitric oxide, which regulates cardiovascular function. By going after another enzyme, sepiapterin reductase, the team could reduce BH4 but not abolish it.

Mice receiving the inhibitor not only had less nerve-related pain but also had less inflammatory pain of the type experienced by people with arthritis (Neuron 2015, DOI: 10.1016/j.neuron.2015.05.033). Also, the animals showed no signs of side effects related to disrupting the BH4 pathway, such as reductions in neurotransmitter levels or disrupted heart function.

The findings, Latremoliere says, suggest that targeting BH4 synthesis could be a reliable and safe way to treat pain. Quartet Medicine, a biotechnology company cofounded by some members of the team, is now developing new inhibitors of sepiapterin reductase.

Price says the method of identifying new targets by examining genetic variations in people is a promising one that could lower the failure rate in pain drug development. “It would be exciting to see success in the approach for the benefit of patients that are in need of better therapeutics,” he says.


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