Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?

摘要 三体，即染色体的第三个拷贝，是常见的人类遗传缺陷，具有 巨大的医疗和社会成本。大约每300个活产婴儿中就有一个携带三体，这种三体可以 涉及13、18、21、X(XXY、XXX)或Y(XYY)。21三体或唐氏综合症(DS)是最常见的 这些都很常见，会导致认知能力受损、面部结构改变和许多其他健康问题 问题，包括心脏缺陷的发生率大大增加，早发性阿尔茨海默病和儿童 白血病。虽然出生时的发育里程碑更接近正常，但大脑皮层结构相对 正常的DS儿童最典型的表现为中度或轻度智力低下。DS儿童通常很快乐，而且 爱，并可以通过早期教育干预显示出更好的结果。然而，没有系统性的医疗 治疗是可用的。认知障碍可能会随着年龄的增长而恶化，因为有证据表明存在进行性神经元 功能障碍，因为DS患者通常在以后的生活中被评为严重智力低下。对任何染色体的治疗 混乱是一项艰巨的任务。DS涉及额外存在的数百个基因的不平衡表达 21号染色体，影响许多生物过程。因此，与单基因缺陷不同，它具有挑战性。 想象如何设计一种有效的遗传方法来治疗DS。现在需要的是一种手段来 从根本上解决问题，额外的染色体。这项提案提出了一系列旨在 利用一种自然发生的染色体沉默机制，在每一只雌性哺乳动物中都能找到 证明染色体疗法治疗三体的可行性。X-染色体的剂量补偿 雌性哺乳动物的染色体是通过X连锁的XIST基因中独特的非编码RNA实现的， 这引发了一连串的事件，使一条X染色体沉默。用小白鼠和人类做实验 系统中，我们建议测试靶向XIST转基因灭活体细胞染色体的能力。 三体细胞的多样性，并试图证明在处理的细胞和小鼠中拯救正常的表型。 由于这一概念的新颖性，其固有的风险，以及巨大的医学和科学潜力，该项目 是尤里卡基金的极佳候选者。我们将测试这一独特的、革命性的想法的可行性。如果 我们可以在人类体细胞和/或DS的小鼠模型中证明其可行性，这些发现 将开辟一条新的道路，并推动未来的努力，将“染色体疗法”转化为一种可行的 人类。为了世界各地数以百万计的DS个人、他们的家人和社会 支持他们，这个重要的、新颖的想法应该得到检验。

ABSTRACT Trisomies, the presence of a third copy of a chromosome, are common human genetic defects that have enormous medical and social costs. Approximately 1 in every 300 live births carries a trisomy which can involve chromosome 13, 18, 21, X (XXY, XXX), or Y (XYY). Trisomy 21, or Down syndrome (DS), is the most common of these, and results in impaired cognitive abilities, altered facial structure and numerous other health issues, including greatly increased incidence of cardiac defects, early onset Alzheimer Disease, and childhood leukemia. While developmental milestones are closer to normal at birth, and gross brain structure is relatively normal, DS children most typically show moderate or mild mental retardation. DS children are often happy and loving, and can show improved outcomes with early educational intervention. However, no systemic medical treatment is available. Cognitive deficits may worsen with age, as there is evidence for progressive neuronal dysfunction since DS individuals often score as severely retarded later in life. Treatment of any chromosomal disorder is a daunting task. DS involves imbalanced expression of hundreds of genes present on the extra chromosome 21, affecting numerous biological processes. Thus, unlike single gene defects, it is challenging to imagine how an effective genetic approach to therapy in DS can be devised. What is needed is a means to deal with the problem at its root, the extra chromosome. This proposal presents a series of studies intended to utilize a naturally occurring mechanism for chromosome silencing, found in every mammalian female, to demonstrate feasibility of a "chromosome therapy' approach for trisomy. Dosage compensation of the X- chromosome in female mammals is realized through a unique non-coding RNA from the X-linked XIST genes, which initiates a cascade of events that silences one X chromosome. Using mouse and human experimental systems, we propose to test the ability of a targeted XIST transgene to inactivate somatic chromosomes in a variety of trisomic cells and attempt to demonstrate a rescue of normal phenotype in treated cells and mice. Due to the novelty of this concept, its inherent risks, and enormous medical and scientific potential, this project is an excellent candidate for EUREKA funding. We will test the feasibility of this singular, revolutionary idea. If we can demonstrate feasibility in human somatic cells and/or in the murine mouse model of DS, these findings would forge a new path and promote future efforts to translate "chromosome therapy" to a viable approach for humans. For the sake of the millions of DS individuals across the world, their families and the societies that support them, this important, novel idea should be tested.