2026-07-10 | An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.
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2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
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2026-06-28 | DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.
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