恢复神经元亚群的氧化磷酸化缺陷可预防线粒体脑病。

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI:10.1038/s44321-024-00111-4
Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes
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引用次数: 0

摘要

氧化磷酸化(OXPHOS)缺陷可导致严重的脑病,目前还没有治疗这些疾病的有效方法。为了评估基因替代预防疾病进展的能力,我们对两种不同的中枢神经系统缺陷小鼠模型(Ndufs3/复合体I或Cox10/复合体IV条件性基因敲除)进行了基因治疗。我们使用经腹腔注射的 AAV-PHP.eB 将缺失基因送入这些小鼠的中枢神经系统。在这两种情况下,我们观察到小鼠的存活期从 5-6 个月延长到 15 个月以上,而且没有发现疾病表型。同样,接受治疗的小鼠的分子和细胞表型也基本恢复。令人惊讶的是,在所用条件下,只有约30%的神经元表达了AAV-PHP.eB载体的转基因,却实现了这些显著的表型改善。这些研究结果表明,缺乏 OXPHOS 的神经元会受到周围神经元环境的保护,而部分补偿神经元 OXPHOS 的缺失会产生不成比例的积极影响。
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Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.

Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.

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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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