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Stanford researchers find that small molecule may help treat enzyme deficiency

Stanford researchers have identified a small molecule that may help curb some of the symptoms of a genetic deficiency in glucose-6-phosphate dehydrogenase.

Scientists are one step closer to developing a treatment for a genetic enzyme deficiency that can cause red blood cells to break down in response to infections or certain drugs or foods, like fava beans. In extreme cases, reactions can be fatal.

The research, led by Stanford's Daria Mochly-Rosen, PhD, and Sunhee Hwang, PhD, identified a small molecule that can patch up the defective enzyme. The goal is to convert this molecule into a safe daily treatment for people with the enzyme deficiency.

The research appears in Nature Communications.

When it functions properly, the enzyme, called glucose-6-phosphate dehydrogenase or G6PD, protects red blood cells from oxidative stress, which occurs when unstable atoms called free radicals steal electrons from red blood cells' protective membrane, causing them to break down.

However more than 400 million individuals worldwide are born with mutated G6PDs, leaving their cells more susceptible to oxidative stress and deterioration. When exposed to specific foods, medications, infections or environmental factors, patients can experience hemolytic anemia, where their red blood cells are destroyed faster than the body can produce them. This results in symptoms such as abdominal pain, increased heart rate, shortness of breath, fever, jaundice and brain damage in severe cases or if left untreated.

Many of the people with the G6PD mutation live where malaria is common. Unfortunately, chloroquine, a commonly used antimalarial drug in low and middle income countries, is known to trigger hemolytic anemia in G6PD-deficient patients. Due to limited resources, malaria patients in these regions are rarely tested for G6PD deficiency before taking chloroquine. This puts individuals with the disorder in a dangerous predicament.

Mochly-Rosen and Hwang don't believe that patients should have to choose between malaria or a hemolytic episode.

They thought the molecule they had found, known as activator of G6PD-1 (abbreviated as AG1), might provide some protection from the condition. To see, the researchers and collaborator Karen Mruk, PhD, exposed zebrafish embryos to chloroquine, causing blood to pool in the veins and physical changes in the embryo's structure. Incredibly, when they treated the embryos with AG1, they noticed a decrease in both oxidative stress and the physical defects. Long term, the goal is to give a drug similar to AG1 together with chloroquine for people with G6PD deficiency who are exposed to malaria.

However, moving from fish to humans is a tricky business.

Along with correcting G6PD-deficiency, AG1 has an additional purpose. By testing AG1 on human blood samples, the team found that the molecule helps prolong red blood cells’ 42-day shelf-life by reducing the rate of hemolysis. This could be a huge help in lengthening the amount of available time between blood donation and transfusion.

But, "even though we have some promising data, this molecule is quite a mild activator," Hwang said. "We want to increase the mutant G6PD enzyme activity to 60 percent of the normal enzyme, which is known to be sufficient in humans. As of now, we have only activated it by 20 or 30 percent."

Currently, Andrew Raub, a graduate student who is working in the Mochly-Rosen lab, is trying to make a new form of AG1 that can be used in human trials. By examining the crystal structure of AG1, the team can understand where the molecule binds and create a more stable and effective drug.

And the new molecule could help with more than just red blood cells, Mochly-Rosen believes.

"It is assumed that the deficiency in this enzyme is only important for maintaining the integrity of red blood cells," Mochly-Rosen said. "But I'm quite confident that this is really an underestimation of the contribution of this mutation to human health."

For Mochly-Rosen, this study also holds personal significance. In addition to activator of G6PD, the acronym AG stands for the initials of the University of California, San Francisco professor and neuroscientist Adrienne Gordon, a close friend and mentor of Mochly-Rosen who died in 2015. "She was my mentor since graduate school, I was always bouncing ideas against her, and she love this G6PD project. And so, we named the molecule AG for her as well."

Photo of Sunhee Hwang, at left, and Daria Mochly-Rosen by Helen Santoro

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