Stagni Fiorenza, Bartesaghi Renata
Department for Life Quality Studies, University of Bologna, Rimini, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Front Cell Neurosci. 2022 May 11;16:903729. doi: 10.3389/fncel.2022.903729. eCollection 2022.
Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer's disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.
唐氏综合征（DS），又称21三体综合征，是一种由21号染色体三体化引起的遗传疾病。基因三体化可能会损害身体的不同功能，但从婴儿期开始就会不可避免地损害智力。此外，40岁以后，唐氏综合征患者很可能会患上阿尔茨海默病。胎儿期神经发生受损以及婴儿早期出现的树突病理被认为是唐氏综合征脑功能改变的关键决定因素。尽管医疗护理的不断进步使唐氏综合征患者的预期寿命显著增加，但目前尚无治疗智力残疾的方法。越来越多在唐氏综合征小鼠模型中的证据表明，胚胎期和新生儿期的药物干预可能对大脑发育和认知表现大有裨益。在胚胎期进行药物治疗取得了最显著的成果，这表明有可能通过药物治疗挽救与三体状况相关的严重神经发育缺陷。这些发现为唐氏综合征患者可能获得类似益处带来了希望。本综述总结了关于以下方面的现有知识：（i）唐氏综合征神经发生（和树突）改变的范围和时间线，以便确定合适的治疗窗口期；（ii）最有可能是这些改变关键决定因素的三体化基因的作用，以便突出可能的治疗靶点；（iii）已在小鼠模型中证明有效的产前和新生儿治疗方法，以便合理选择用于人类的治疗方法。基于这些证据，我们将讨论对唐氏综合征个体进行胎儿治疗作为一种可能有效对抗基因三体化有害影响的潜在手段的前景和挑战。
