Ling Qinglan, Rioux Matthew, Higgs Harrison, Hu Yuhui, Dwyer Scarlett E, Gray Steven J
Department of Genetic & Cellular Medicine, Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA 01605, USA.
Department of Microbiology, UMass Chan Medical School, Worcester, MA 01605, USA.
Mol Ther Methods Clin Dev. 2025 Aug 11;33(3):101554. doi: 10.1016/j.omtm.2025.101554. eCollection 2025 Sep 11.
Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for -related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for -related Leigh syndrome, warranting further translational studies.
与过表达位点蛋白1（SURF1）相关的 Leigh 综合征是一种早发性神经退行性疾病，其特征是复合体IV活性降低，从而破坏线粒体功能。目前，尚无改善病情的治疗方法。此前，我们报道已开发出一种针对相关 Leigh 综合征的基因替代疗法，该疗法在野生型（WT）小鼠中显示出复合体IV活性提高、运动诱发的乳酸性酸中毒得到恢复，且安全性良好。然而，对这种原始SURF1载体设计的进一步研究发现，尽管免疫反应极小，但在WT大鼠的多个组织中仍存在细胞毒性。我们推测这种细胞毒性是由强泛在启动子CBh驱动的SURF1蛋白过表达引起的。在此，我们报告通过使用不同的启动子和聚腺苷酸化序列，开发出一种针对SURF1 Leigh综合征的改进基因疗法。我们的数据表明，在SURF1蛋白表达较低的情况下，新设计具有相似的疗效水平，但在小鼠或大鼠中细胞毒性极小。我们提出这种新的载体设计作为相关Leigh综合征有前景的治疗候选方案，值得进一步开展转化研究。
