Daily medication can imitate the health benefits of a high altitude life and low oxygen content for mitochondrial disease

For the average person, living at high altitude – where oxygen is clearer than in sea level – can have health benefits ranging from lower heart disease to increased endurance. But for those who were born with hereditary mitochondrial diseases, which rarely survive beyond childhood and the air with low oxygen like that found at Mountain Peaks could be saved life, potentially prolong their lifespan And eliminate their symptoms.

Now scientists from Gladstone Institutes have developed A medication that imitates the effects of low oxygen breathing. In mice with Leigh syndrome – the most common mitochondrial disease of childhood – the hypooxystatic drug has extended the lifespan more than brain and reversed trauma of brain damage and muscle weakness, even when they are data during the late stages of the disease.

“It is not practical for each patient with this disease to move to the mountains,” said Gladstone Isha Jain’s investigator, PH.D., the main author of the study, published in Cell. “But this medication could be a controlled and sure way to apply the same advantages to patients.”

The chemical compound used in the hypooxystat has been identified in collaboration with Maze Therapeutics based in South San Francisco. Gladstone’s research team now explores the second generation versions of hypoxystat to allow clinical translation.

Prevent oxygen overload

Leigh syndrome is a rare genetic disease in which mitochondria – parts of cells that produce energy using oxygen – do not work effectively, causing an accumulation of unused oxygen in the tissues. Although the body needs oxygen to survive, these high oxygen levels quickly damage and kill cells.

In 2016, Jain was part of a research team that showed that air breathing with low oxygen content, equivalent to what is 4,500 meters (or 14,764 feet) could treat Leigh syndrome in mice.

Therapy works because, with less oxygen insufficient in the lungs and returned to the organs, the defective mitochondria does not become submerged and excess oxygen does not accumulate.

“With Leigh syndrome and related disorders, it is not only the exhaustion of energy that is the problem, but the accumulation of oxygen,” explains Jain, who is also a basic researcher ‘ARC Institute, as well as professor of biochemistry at UC San Francisco.

“It is a removal of the supply. So, if you can lower the oxygen supply, you repair this shift.”

Jain’s laboratory has decided to discover a way to have this same hypo oxygen effect on the body without requiring low oxygen content. They focused on hemoglobin, the molecule which carries oxygen through the blood circulation and the book to the tissues.

“If you handle the efficiency of hemoglobin that binds oxygen, you can change the way it is delivered to the tissues,” said Skyler Blume, research associate in Gladstone and the first author of the new study.

“Although it could be counter-intuitive, we wanted a medication that makes hemoglobin binds more closely to oxygen.

With Maze Therapeutics, Jain and Blume have sought through scientific literature To identify the compounds that correspond to this description, landing on what they now call hypooxystat.

A pill with promising results

The hypooxystat is a reused compound which was initially designed for an indication of unrelated anemia. Researchers have shown that the drug manufactured by hemoglobin links oxygen more closely and lowered the amount of oxygen delivered to the tissues.

The team has treated mice with Leigh syndrome with daily daily hypooxystat in life, when symptoms of the disease usually start in animals. As a result, mice have no longer developed brain damage, no longer showed muscular weakness or loss of coordination, and has experienced more than three times longer.

Remarkably, the drug had similar effects even when the mice started taking it until they were older and the major symptoms had already appeared, especially brain damageAltered behavior and chronically low body temperature. The compound reversed the symptoms of the brain, muscles and behavior.

“The drug not only stopped the progression of the disease, but reversed it,” said Blume. “This is something we knew that it was true with a low inhaled oxygen and we were able to summarize it widely.”

Researchers say that hypoxystat could possibly be useful under conditions beyond Leigh syndrome, including other mitochondrial diseases as well as common brain and cardiovascular conditions for which low oxygen turned out to be beneficial. They also point out that other drugs could be developed that handle hemoglobin in the opposite direction – to deliver more oxygen to the tissues.

“Gas therapies for the disease are really unique, and being able to bottle them in medication is a new unusual concept,” said Jain. “We are delighted to see where this promising strategy takes us.”