Lu Zhongyang, Liu Shufeng, Morales Maria G, Whitlock Andy, Ramkumar Ram, Ramkumar Hema L
Oculogenex Inc., 2250 W Whittier Blvd., Suite 300, La Habra, CA 90631, USA.
Int J Mol Sci. 2025 Jun 19;26(12):5907. doi: 10.3390/ijms26125907.
Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate (NaIO)-induced injury serves as a well-characterized model of oxidative damage to the retinal pigment epithelium (RPE) and photoreceptors. BMI1, a poly-comb group protein involved in DNA repair, mitochondrial function, and cellular renewal, has emerged as a promising therapeutic target for retinal neuroprotection. We evaluated the efficacy of AAV-mediated BMI1 gene delivery in murine models using two administration routes: subretinal (SR) and suprachoroidal (SC). AAV5.BMI1 (1 × 10 vg/eye) was delivered SR in Balb/c mice and evaluated at 4 and 15 weeks post-injection. AAV8.BMI1 (5 × 10 or 1 × 10 vg/eye) was administered SC in C57BL/6 mice and assessed at 4 weeks. Control groups received BSS or AAV8.stuffer. Following NaIO exposure, retinal structure and function were analyzed by optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays. SC delivery of AAV8.BMI1 achieved the highest levels of retinal BMI1 expression with no evidence of local or systemic toxicity. Treated eyes showed dose-dependent preservation of outer nuclear layer (ONL) thickness and significantly improved ERG responses indicating structural and functional protection. These findings support SC AAV.BMI1 gene therapy as a promising, minimally invasive, and translatable approach for early intervention in intermediate AMD.
干性年龄相关性黄斑变性（AMD）是50岁以上人群视力丧失的主要原因，但对于该疾病的早期或中期阶段，尚无获批的治疗方法。氧化应激是AMD视网膜变性的主要驱动因素，碘酸钠（NaIO）诱导的损伤是视网膜色素上皮（RPE）和光感受器氧化损伤的一个特征明确的模型。BMI1是一种参与DNA修复、线粒体功能和细胞更新的多梳蛋白组蛋白，已成为视网膜神经保护的一个有前景的治疗靶点。我们使用两种给药途径评估了腺相关病毒（AAV）介导的BMI1基因递送在小鼠模型中的疗效：视网膜下（SR）和脉络膜上（SC）。将AAV5.BMI1（1×10病毒基因组/眼）通过视网膜下注射到Balb/c小鼠体内，并在注射后4周和15周进行评估。将AAV8.BMI1（5×10或1×10病毒基因组/眼）通过脉络膜上注射到C57BL/6小鼠体内，并在4周时进行评估。对照组接受平衡盐溶液（BSS）或AAV8.填充序列。在暴露于NaIO后，通过光学相干断层扫描（OCT）、视网膜电图（ERG）、组织学和分子分析来分析视网膜的结构和功能。通过脉络膜上注射递送AAV8.BMI1可实现视网膜BMI1表达的最高水平，且无局部或全身毒性的证据。治疗后的眼睛显示出剂量依赖性的外核层（ONL）厚度保留，并且ERG反应显著改善，表明具有结构和功能保护作用。这些发现支持脉络膜上注射AAV.BMI1基因治疗作为一种有前景的、微创的且可转化的方法，用于中期AMD的早期干预。
