Varea Olga, Guinovart Joan J, Duran Jordi
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
Brain Commun. 2022 Jun 23;4(4):fcac168. doi: 10.1093/braincomms/fcac168. eCollection 2022.
Lafora disease is a fatal neurodegenerative childhood dementia caused by loss-of-function mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of abnormal glycogen aggregates known as Lafora bodies (LBs) in the brain and other tissues. These aggregates are responsible for the pathological features of the disease. As a monogenic disorder, Lafora disease is a good candidate for gene therapy-based approaches. However, most patients are diagnosed after the appearance of the first symptoms and thus when LBs are already present in the brain. In this context, it was not clear whether the restoration of a normal copy of the defective gene (either laforin or malin) would prove effective. Here we evaluated the effect of restoring malin in a malin-deficient mouse model of Lafora disease as a proof of concept for gene replacement therapy. To this end, we generated a malin-deficient mouse in which malin expression can be induced at a certain time. Our results reveal that malin restoration at an advanced stage of the disease arrests the accumulation of LBs in brain and muscle, induces the degradation of laforin and glycogen synthase bound to the aggregates, and ameliorates neuroinflammation. These results identify malin restoration as the first therapeutic strategy to show effectiveness when applied at advanced stages of Lafora disease.
拉福拉病是一种致命的儿童神经退行性痴呆，由拉福林或malin基因的功能丧失突变引起。该疾病的标志是大脑和其他组织中出现异常糖原聚集体，即所谓的拉福拉小体（LBs）。这些聚集体是该疾病病理特征的成因。作为一种单基因疾病，拉福拉病是基于基因治疗方法的良好候选对象。然而，大多数患者在首次出现症状后才被诊断出来，此时大脑中已经存在拉福拉小体。在这种情况下，尚不清楚恢复缺陷基因（拉福林或malin）的正常拷贝是否会被证明有效。在此，我们评估了在拉福拉病的malin缺陷小鼠模型中恢复malin的效果，以此作为基因替代疗法概念验证。为此，我们培育了一种malin缺陷小鼠，其中malin的表达可在特定时间被诱导。我们的结果显示，在疾病晚期恢复malin可阻止大脑和肌肉中拉福拉小体的积累，诱导与聚集体结合的拉福林和糖原合酶的降解，并改善神经炎症。这些结果表明，在拉福拉病晚期应用时，恢复malin是首个显示出有效性的治疗策略。
