New drug mimics low-oxygen treatment for Leigh Syndrome

For the average person, living at high altitude-where oxygen is sparser than at sea level-can have health benefits ranging from lower rates of heart disease to increased endurance. But for those born with inherited mitochondrial diseases, who rarely survive past childhood, low-oxygen air like that found at mountain peaks could be life-saving, potentially extending their lifespan and eliminating their symptoms.

Now, scientists at Gladstone Institutes have developed a drug that mimics the effects of breathing low oxygen. In mice with Leigh Syndrome-the most common childhood mitochondrial disease-the HypoxyStat drug extended lifespan by more than 3-fold and reversed brain damage and muscle weakness, even when given during late stages of disease.

"It's not practical for every patient with this disease to move to the mountains," says Gladstone Investigator Isha Jain, PhD, senior author of the new study, published in Cell. "But this drug could be a controlled and safe way to apply the same benefits to patients."

The chemical compound used in HypoxyStat was identified in collaboration with South San Francisco-based Maze Therapeutics. Gladstone's research team is now exploring second-generation versions of HypoxyStat to enable clinical translation.

Preventing oxygen overload

Leigh Syndrome is a rare genetic disease in which mitochondria-the parts of cells that produce energy using oxygen-don't work efficiently, causing unused oxygen to build up within tissues. Although the body needs oxygen to survive, these high levels of oxygen quickly damage and kill cells.

In 2016, Jain was part of a research team that showed that breathing low-oxygen air, equivalent to what is found at 4,500 meters (or 14,764 feet) of elevation could treat Leigh syndrome in mice. The therapy works because, with less oxygen being breathed into the lungs and shuttled to organs, the faulty mitochondria don't become overwhelmed and excess oxygen doesn't accumulate.

"With Leigh syndrome and related disorders, it isn't just the depletion of energy that is the issue, but the accumulation of oxygen," explains Jain, who is also a core investigator at Arc Institute, as well as a professor of biochemistry at UC San Francisco. "It's a supply-demand mismatch. So, if you can lower the supply of oxygen, you fix that mismatch."

Jain's lab set out to discover a way to have this same oxygen-lowering effect on the body without requiring low-oxygen air. They focused on hemoglobin, the molecule that carries oxygen through the bloodstream and delivers it to tissues.

If you manipulate how effectively hemoglobin is binding oxygen, you can change how it's delivered to tissues. Though it may be counterintuitive, we wanted a drug that makes hemoglobin bind oxygen more tightly. That means it doesn't get delivered to tissues and they experience lower oxygen levels than usual."

Skyler Blume, research associate at Gladstone and first author of the new study

With Maze Therapeutics, Jain and Blume searched through published scientific literature to identify compounds that fit this description, landing on what they now call HypoxyStat.

One pill with promising results

HypoxyState is a repurposed compound that was initially designed for an unrelated indication of sickle cell anemia. The researcher showed that the drug made hemoglobin bind oxygen more tightly and lowered the amount of oxygen delivered to tissues.

The team treated mice with Leigh Syndrome with daily HypoxyStat early in life, when disease symptoms usually begin in the animals. As a result, the mice no longer developed brain lesions, no longer showed muscle weakness or loss of coordination, and lived more than three times as long.

Remarkably, the drug had similar effects even when mice did not begin taking it until they were older and major symptoms had already appeared-including extensive brain damage, impaired behavior, and chronically low body temperature. The compound reversed brain, muscle, and behavioral symptoms.

"The drug not only stopped the progression of the disease, but actually reversed it," says Blume. "That is something we knew was true with inhaled low oxygen and we were able to largely recapitulate it."

The researchers say that HypoxyStat could eventually be useful in conditions beyond Leigh Syndrome, including other mitochondrial diseases as well as common brain and cardiovascular conditions for which low oxygen has been shown to be beneficial. They also point out that other drugs could be developed that manipulate hemoglobin in the opposite direction-to deliver more oxygen to tissues.

"Gas-based therapies for disease are really unique, and being able to bottle them up into drugs is a new, unusual concept," says Jain. "We're excited to see where this promising strategy takes us."