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Researchers investigated immune-targeting therapies and hypoxia treatment in a mouse model of Leigh syndrome, a severe mitochondrial disease affecting children. They found that macrophages and monocytes drive disease pathology, and that immune-depleting drugs (pexidartinib and rapamycin) provide lasting benefits even after treatment stops, while hypoxia cessation leads to rapid disease onset. The findings suggest hypoxia acts upstream of immune activation and that immune-targeting therapies may offer more practical therapeutic approaches than continuous hypoxia treatment.
Why it matters
This study provides critical mechanistic insights for developing treatments for Leigh syndrome, for which no effective therapies currently exist. The discovery that immune-targeting drugs have persistent effects after cessation makes them more clinically feasible than continuous hypoxia treatment, potentially advancing therapeutic translation for this devastating pediatric disease.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Genetic mitochondrial diseases (GMDs) are major challenges to human health accounting for a significant fraction of heritable neurologic diseases, myopathies, and inborn errors of metabolism. Leigh syndrome (LS) is the most common clinical presentation of GMD in pediatric patients. LS is a severe and complex disease for which effective clinical therapies are currently lacking. Preclinical therapies identified in the Ndufs4(-/-) mouse model of LS include immune-targeting interventions and chronic mild hypoxia (11% oxygen). Immune-targeting interventions include rapamycin and high-dose pexidartinib, the latter appearing to fully suppress disease. The mechanisms underlying the benefits of hypoxia remain unclear, and the relationship between hypoxia and immune interventions have not been assessed. Here, we report the immune profile of brainstem of the Ndufs4(-/-) mouse model prior to and after disease onset and the impact of pexidartinib treatment. We provide evidence that macrophages/monocytes drive pathology, consistent with recent genetic studies. We additionally find that pre-disease onset animals lack signs of inflammation, and that the elimination of leukocytes fully suppresses the molecular signature of disease. Finally, using distinct post-developmental periods of treatment, we find pexidartinib and rapamycin provide benefits which persist long beyond treatment cessation, while cessation of hypoxia results in rapid disease onset and an acceleration of disease progression. These findings are consistent with hypoxia acting upstream of immune cell activation and have major implications for the therapeutic translation of both hypoxia and immune targeting interventions. Our findings establish hypoxia-cessation as a novel method for synchronizing inflammatory disease onset in the Ndufs4(-/-) model which will be useful in future mechanistic studies.