New Drug Combination Reduces Tissue Oxygen to Improve Parkinson’s Symptoms in Mice
- Researchers at the Broad Institute reported in the Proceedings of the National Academy of Sciences that an optimized two-drug combination designed to reduce oxygen delivery to tissues successfully...
- Scientists previously discovered that excess oxygen in the brain associates with neuronal death in Parkinson's disease and that lowering the oxygen mice breathe helps reverse symptoms.
- In 2024, researchers established a proof-of-concept hypoxia pill combining GBT440, which increases hemoglobin's affinity for oxygen to prevent tissue delivery, and PT2399, which blocks red blood cell production...
Researchers at the Broad Institute reported in the Proceedings of the National Academy of Sciences that an optimized two-drug combination designed to reduce oxygen delivery to tissues successfully improved symptoms in a mouse model of Parkinson’s disease, medicalxpress.com reported.
Targeting Tissue Oxygenation to Treat Neurodegeneration
Scientists previously discovered that excess oxygen in the brain associates with neuronal death in Parkinson’s disease and that lowering the oxygen mice breathe helps reverse symptoms. Vamsi Mootha, an institute member at the Broad Institute who led the new study, has spent the last decade investigating how low-oxygen conditions improve symptoms in rare mitochondrial disorders. Mitochondrial dysfunction generates unused oxygen that can damage tissues in conditions such as Leigh syndrome and Friedreich’s ataxia. Mootha’s team evaluated whether a pharmacological approach could replicate the benefits of hypoxia therapy without requiring patients to enter controlled low-oxygen environments.
Optimized Drug Regimen Extends Lifespan in Disease Models
In 2024, researchers established a proof-of-concept hypoxia pill combining GBT440, which increases hemoglobin’s affinity for oxygen to prevent tissue delivery, and PT2399, which blocks red blood cell production by inhibiting the HIF-2α pathway. The newly published study details an optimized version that replaces GBT440 with GBT601, a second-generation molecule that is stronger and lasts longer in the body. When administered to 50-day-old mice with advanced Leigh syndrome, the new drug combination extended the expected lifespan from approximately 62 days to 158 days. In the Parkinson’s disease mouse model, the regimen reversed movement-related symptoms in advanced disease comparably to breathing 11 percent oxygen. In a mouse model of Friedreich’s ataxia, the combination halted further disease progression without reversing existing symptoms.
Safety Profiles and Preclinical Hurdles Ahead
Long-term exposure to hypoxia typically risks pulmonary hypertension and right-sided heart failure. However, the research team found that the two-drug regimen was well tolerated in mice for over three weeks of daily treatment without inducing the cardiac side effects commonly associated with chronic hypoxia. Both GBT601 and PT2399 belong to drug classes that are FDA-approved for other uses and have demonstrated safety tolerance in healthy human volunteers. Mootha emphasized that the findings remain strictly preclinical and that more work is required before translating the regimen into human treatments, noting that chronic hypoxia remains dangerous outside controlled clinical settings.
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