A pill that simulates the effects of high elevation and low oxygen on the brain seems to have eased neurological decline in mice with three neurodegenerative conditions, including Parkinson’s disease. Exactly how it has this effect is unclear, but lowering oxygen levels in the brain may lessen damage caused by an excess of the gas.
“Oxygen is essential for life, and if you go too low it is dangerous. But for some specific disorders, there may be a Goldilocks zone and dialling down a bit might be beneficial,” says at Massachusetts General Hospital. “With ‘hypoxia in a pill’, we can now manipulate the very air we breathe.”
People living long term at high elevation, where the air is thinner, seem to be healthier, on average, than those living near sea level, with lower rates of conditions like diabetes and . And while severe altitude sickness can be deadly, by causing the brain to swell, anecdotal evidence suggests that .
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For the past decade, Mootha and his colleagues have done studies in which mice with models of conditions like Parkinson’s are kept in air with 11 per cent oxygen, matching the environment . They have found that this can halt, prevent or even .
Although these mice didn’t experience any known side effects from the intervention, breathing thin air around the clock isn’t practical or safe for people in the long term. “We are still in the early research stages,” says Mootha. “Given that hypoxia can be dangerous, it should not be attempted at home.” But now, Mootha and his colleagues have combined two experimental drugs to create hypoxia in a pill.
One drug – called osivelotor, which is being developed for sickle cell anaemia – alters haemoglobin so it grips oxygen more tightly, preventing the gas from reaching tissues. But this can cause the body to produce a dangerous amount of red blood cells, which carry oxygen around the body. The second drug, PT2399, prevents this by blocking a protein called HIF-2α, which helps cells respond to low oxygen.
To put it to the test, the team gave the pill to mice modelling advanced Leigh syndrome, a severe neurological condition that causes progressive loss of mental and movement abilities. The life expectancy in people with the condition is usually two to three years, but the pill more than doubled the mice’s survival time from around 62 days to 158 days.
The researchers also tested the pill in mice modelling Friedreich’s ataxia, a rare condition that causes progressive damage to the nervous system, resulting in movement difficulties. The team observed that this stopped further declines in the mice’s strength and coordination. Finally, when tested in a Parkinson’s disease model, the treated mice improved their coordination and balance. The effects are comparable to when such animals breathe 11 per cent oxygen, says Mootha.
Research suggests that , which aid the formation of new connections between neurons. But Mootha proposes another idea: reducing excess oxygen may prevent cellular damage.
The three conditions he and his team focused on are partly characterised by damaged mitochondria, which provide cells with energy. These mitochondria may be failing to consume oxygen properly, leaving a local excess of the gas that damages other cell components, he says. “This high dissolved oxygen may be causing signalling anomalies or perhaps direct oxidation of precious cofactors [molecules that help enzymes do their job],” says Mootha.
at the University of Copenhagen, Denmark, says that taking a pill is much more convenient than other methods used to lower oxygen, such as via a mask or hypoxia chamber. “Taking a pill is much more feasible and much more something that could be implemented as a treatment. I’m quite excited about it.”
at the University of Florida says he is “pretty tickled” by the study, but cautions that it remains to be seen how well the effects translate to people. Mice cut their metabolism in low oxygen far more readily than we do, he says. “How much of the benefit was simply that everything slowed down?”
Safety in people also needs to be established. , but in 2024, Pfizer pulled a treatment from the same drug class, called Oxbryta, because . Mootha says his team is starting to plan human safety trials for osivelotor-PT2399.
bioRxiv
