Discovery, People

Serial startup scientist Ronald Evans tests a new Mighty Mouse drug, making marathon runners with a pill

Ronald Evans

Salk Institute’s legendary scientist Ronald Evans has co-founded a string of new biotech companies over the years, including Ligand Pharmaceuticals, Syndax and more recently San Diego-based Metacrine. And now he’s completed new preclinical research on a drug that he says has attracted attention from some other companies in the biopharma world interested in trying it on humans.

And this one is a doozie.

It starts with a pair of questions: “How does endurance work?” he asked. “And if we really understand the science, can we replace training with a drug?”

Evans and his lab crew have already done work on mice that demonstrate how permanently activating the PPARδ gene could turn your average rodent into the animal world’s marathon runners. Then they came up with a drug — GW1516 — that activated the target gene, but found that the mice still had to exercise in order to build endurance.

So they tried it again, upping the dose and doubling the treatment time from 4 weeks to 8.

This time the drug worked on building endurance, with mice on the control arm able to run for 160 minutes compared to the marathon-like 270 minutes in the drug arm.

So what’s going on here?

The scientists say that exhaustion for these running mice set in when blood sugar dropped to a certain level. The mechanism of action improved expression in genes that are involved in breaking down fat for energy but blocked a similar effect on sugar, preserving glucose for brain activity.

“This study suggests that burning fat is less a driver of endurance than a compensatory mechanism to conserve glucose,” says Michael Downes, a Salk senior scientist and co-senior author of the paper. “PPARδ is suppressing all the points that are involved in sugar metabolism in the muscle so glucose can be redirected to the brain, thereby preserving brain function.”

Partial view of a mouse calf muscle stained for different types of muscle fibers: oxidative slow-twitch (blue), oxidative fast-twitch (green), glycolytic fast-twitch (red). Salk Institute/Waitt Center

“Exercise activates PPARδ, but we’re showing that you can do the same thing without mechanical training. It means you can improve endurance to the equivalent level as someone in training, without all of the physical effort,” says Weiwei Fan, a Salk research associate and the paper’s first author.

In a none too subtle pitch to drug developers, the team says that their work has attracted some active interest on the part of biopharma companies intrigued by the notion that a drug like this could be a major help to the obese, diabetics and people weakened by surgery.

It’s also worth noting that the more wonderful a drug’s effect is in mice, whether it’s curing cancer or creating Mighty Mouse with drugs, the higher the bar on getting a drug like that into humans. And that goes double for anything related to burning fat.

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