Bartsch Udo, Storch Stephan
Department of Ophthalmology, Experimental Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Neurol. 2022 Apr 18;13:866983. doi: 10.3389/fneur.2022.866983. eCollection 2022.
The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of and to bipolar cells has been shown to attenuate the retinal dysfunction. Therapeutic benefits of ocular enzyme replacement therapies were evaluated in CLN2 and CLN10 animal models. Since brain-targeted gene or enzyme replacement therapies will most likely not attenuate retinal neurodegeneration, there is an unmet need for treatment options additionally targeting the retina in patients with NCL. The long-term benefits of these therapeutic interventions aimed at attenuating retinal degeneration and vision loss in patients with NCL remain to be investigated in future clinical studies.
神经元蜡样脂褐质沉积症（NCLs）是一组儿童期发病的神经退行性溶酶体贮积症，主要影响大脑和视网膜。在NCLs中，已鉴定出13种不同的蜡样脂褐质沉积症基因（CLN）中的致病突变。临床症状包括癫痫发作、进行性神经功能衰退、运动和语言技能退化以及导致过早死亡的痴呆症。此外，进行性视网膜变性导致的视力恶化和丧失是NCLs的另一个主要特征。迄今为止，尚无治疗NCL患者视网膜变性和视力丧失的治愈性疗法。在本综述中，讨论了NCL动物模型中旨在减轻进行性视网膜变性和视网膜功能下降的不同实验方法的关键发现。评估了包括实验性酶替代疗法、基因疗法、细胞疗法和免疫调节疗法在内的不同方法，并显示出令人鼓舞的治疗效果。最近在具有可溶性溶酶体酶缺陷和跨膜蛋白缺陷的NCL动物模型中进行的实验性眼部基因疗法显示了基于基因的方法治疗NCLs视网膜营养不良的强大潜力。在CLN3和CLN6小鼠模型中，已证明腺相关病毒（AAV）载体介导的向双极细胞递送[具体物质未给出]可减轻视网膜功能障碍。在CLN2和CLN10动物模型中评估了眼部酶替代疗法的治疗效果。由于脑靶向基因或酶替代疗法很可能无法减轻视网膜神经变性，因此NCL患者对额外靶向视网膜的治疗选择仍有未满足的需求。这些旨在减轻NCL患者视网膜变性和视力丧失的治疗干预措施的长期益处仍有待未来临床研究进行调查。
