Authors had shown that tetrahydrobioptrin -- a protein also known as BH4 -- is a primary natural modulator of neuropathic and inflammatory pain sensitivity. A company called Quartet was founded on the premise that inhibiting BH4 production could prevent the progression of acute pain to chronic pain in millions of patients, without threat of addiction or tolerance.
With solid human genetic data and chemical biology, plus $17 million in series A funding, Quartet looked primed for success. But in the summer of 2017, toxicology studies of the company's lead candidate revealed neurologic side effects. Hope for the promising pain drug cratered, taking Quartet with it.
Now, however, a surprising discovery about BH4 will likely rekindle interest in the once-promising pathway and could have profound implications for treating autoimmunity and cancer. In Nature, the team report that BH4 also functions as a kind of immunological thermostat in the body, raising and lowering the activity levels of T cells.
In animal models of autoimmune disease and human cell lines, the researchers were able to inhibit T cell proliferation by blockading the BH4 pathway pharmacologically. In models of cancer, they were able to enhance T cell responses by elevating BH4 levels.
"By targeting BH4, we are able to suppress T cell activity in inflammatory conditions and increase their activity in the case of cancer," says the co-lead the study. "The ability to target the same pathway in opposite directions is significant and represents a whole new therapeutic approach."
Specifically, the researchers found that BH4 regulates the balance of available iron for mitochondria. To transition to an activated state, T cells need higher levels of mitochondrial energy; to produce it, mitochondria need higher levels of iron. When T cells are under pressure, the body produces more BH4, increasing the supply of available iron, allowing the cells to divide and activate. When BH4 levels are low, mitochondria can't get the iron they need and T cell activity is suppressed. In the case of cancer, the study revealed that a metabolite produced by tumors works to block BH4, inhibiting T cell activation and cancer surveillance. It also showed that this response could be countered by augmenting BH4.
"The beauty of it is that the effect is upstream of specific types of T cell function," says co-lead. "Most drugs being developed now to treat autoimmune conditions are targeting specific kinds of T cells. This covers them all."
The team found that the BH4 pathway is only active in cases of infection or when proliferation needs to occur -- and is not required for the normal formation of T cells.
Finally, the paper reports the development of a highly potent small molecule, QM385, that inhibits the BH4 pathway, blocking T cell proliferation and autoimmunity.
Failed pain drug to treat autoimmunity and cancer
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