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

染色体治疗可以治疗唐氏综合症和其他核型失衡吗？

• 批准号: 7903514
• 负责人: JEANNE Bentley LAWRENCE
• 金额: $ 12.3万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903514
• 关键词: Affect; Age; Biological Process; Birth; Brain; Cells; Child; Childhood Leukemia; Chromosomes; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 21; Cognitive; Cognitive deficits; Congenital Heart Defects; Congenital chromosomal disease; Development; Dosage Compensation (Genetics); Down Syndrome; Educational Intervention; Event; Face; Family; Female; Functional RNA; Funding; Future; Genes; Genetic; Health; Human; Human Genetics; Incidence; Individual; Life; Link; Live Birth; Love; Mammals; Medical; Mild mental retardation; Modeling; Mus; Mutation; Nature; Neuronal Dysfunction; Outcome; Phenotype; Plant Roots; Presenile Alzheimer Dementia; Risk; Series; Single-Gene Defect; Societies; Somatic Cell; Structure; System; Testing; Transgenes; Translating; Trisomy; X Chromosome; abstracting; cost; forging; gene therapy; improved; mouse model; novel; novel strategies; social

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.

抽象的 三体性，即染色体的第三个拷贝的存在，是常见的人类遗传缺陷 巨大的医疗和社会费用。大约每 300 个活产儿中就有 1 个携带三体性， 涉及染色体 13、18、21、X (XXY、XXX) 或 Y (XYY)。 21 三体症，即唐氏综合症 (DS)，是最常见的 其中常见，并导致认知能力受损、面部结构改变和许多其他健康问题 问题，包括心脏缺陷、早发性阿尔茨海默病和儿童的发病率大大增加 白血病。虽然出生时的发育里程碑更接近正常，并且总体大脑结构也相对较正常。 正常情况下，DS 儿童通常表现出中度或轻度智力障碍。 DS 孩子通常很快乐并且 热爱，并且可以通过早期教育干预显示出更好的结果。但目前尚无系统医疗 可以治疗。认知缺陷可能会随着年龄的增长而恶化，因为有证据表明进行性神经元 功能障碍，因为 DS 个体在以后的生活中常常被评分为严重迟钝。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病治疗方法。需要的是一种手段 从根源上解决问题，即多余的染色体。该提案提出了一系列研究，旨在 利用每个雌性哺乳动物中发现的自然发生的染色体沉默机制 证明三体性“染色体疗法”方法的可行性。X-的剂量补偿 雌性哺乳动物的染色体是通过来自 X 连锁 XIST 基因的独特非编码 RNA 实现的， 它会引发一系列事件，使一条 X 染色体沉默。使用小鼠和人体实验 系统中，我们建议测试目标 XIST 转基因灭活体细胞染色体的能力 多种三体细胞，并试图证明治疗细胞和小鼠正常表型的恢复。 由于这一概念的新颖性、固有的风险以及巨大的医学和科学潜力，该项目 是 EUREKA 资助的优秀候选人。我们将测试这个独特的革命性想法的可行性。如果 我们可以证明在人类体细胞和/或 DS 小鼠模型中的可行性，这些发现 将开辟一条新的道路并促进未来将“染色体疗法”转化为可行的方法 人类。为了全世界数以百万计的 DS 个人、他们的家庭和社会， 支持他们，这个重要的、新颖的想法应该得到测试。