Gupta Khusali, Czerminski Jan T, Lawrence Jeanne B
Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA.
Medical Scientist Training Program, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA.
Hum Genet. 2024 Jul;143(7):843-855. doi: 10.1007/s00439-024-02651-8. Epub 2024 Mar 9.
XIST RNA is heavily studied for its role in fundamental epigenetics and X-chromosome inactivation; however, the translational potential of this singular RNA has been much less explored. This article combines elements of a review on XIST biology with our perspective on the translational prospects and challenges of XIST transgenics. We first briefly review aspects of XIST RNA basic biology that are key to its translational relevance, and then discuss recent efforts to develop translational utility of XIST for chromosome dosage disorders, particularly Down syndrome (DS). Remarkably, it was shown in vitro that expression of an XIST transgene inserted into one chromosome 21 can comprehensively silence that chromosome and "dosage compensate" Trisomy 21, the cause of DS. Here we summarize recent findings and discuss potential paths whereby ability to induce "trisomy silencing" can advance translational research for new therapeutic strategies. Despite its common nature, the underlying biology for various aspects of DS, including cell types and pathways impacted (and when), is poorly understood. Recent studies show that an inducible iPSC system to dosage-correct chromosome 21 can provide a powerful approach to unravel the cells and pathways directly impacted, and the developmental timing, information key to design pharmacotherapeutics. In addition, we discuss prospects of a more far-reaching and challenging possibility that XIST itself could be developed into a therapeutic agent, for targeted cellular "chromosome therapy". A few rare case studies of imbalanced X;autosome translocations indicate that natural XIST can rescue an otherwise lethal trisomy. The potential efficacy of XIST transgenes later in development faces substantial biological and technical challenges, although recent findings are encouraging, and technology is rapidly evolving. Hence, it is compelling to consider the transformative possibility that XIST-mediated chromosome therapy may ultimately be developed, for specific pathologies seen in DS, or other duplication disorders.
XIST RNA因其在基础表观遗传学和X染色体失活中的作用而受到广泛研究；然而，这种独特RNA的翻译潜力却鲜有人探索。本文结合了对XIST生物学的综述内容以及我们对XIST转基因翻译前景与挑战的看法。我们首先简要回顾XIST RNA基础生物学中与其翻译相关性的关键方面，然后讨论近期为开发XIST用于染色体剂量紊乱（特别是唐氏综合征，DS）的翻译效用所做的努力。值得注意的是，体外实验表明，插入一条21号染色体的XIST转基因表达可全面沉默该染色体并“剂量补偿”21三体，即DS的病因。在此，我们总结近期研究结果，并讨论诱导“三体沉默”的能力推动新治疗策略翻译研究的潜在途径。尽管DS具有普遍性，但其各个方面的潜在生物学机制，包括受影响的细胞类型和途径（以及何时受影响），仍知之甚少。近期研究表明，一种可诱导的iPSC系统用于校正21号染色体剂量，可为直接揭示受影响的细胞和途径以及发育时间提供有力方法，而这些信息对于设计药物治疗至关重要。此外，我们还讨论了一种更具深远意义且具有挑战性的可能性，即XIST本身可被开发成一种治疗剂，用于靶向细胞的“染色体治疗”。一些罕见的X;常染色体不平衡易位病例研究表明，天然XIST可挽救原本致命的三体。尽管近期研究结果令人鼓舞且技术发展迅速，但XIST转基因在发育后期的潜在疗效仍面临重大生物学和技术挑战。因此，考虑XIST介导的染色体治疗最终可能针对DS或其他重复紊乱中出现的特定病理情况而开发的变革性可能性是很有必要的。
